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Find video protocols related to scientific articles indexed in Pubmed.
Shroom3 contributes to the maintenance of the glomerular filtration barrier integrity.
Genome Res.
PUBLISHED: 10-03-2014
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Genome-wide association studies (GWAS) identify regions of the genome correlated with disease risk, but are restricted in their ability to identify the underlying causative mechanism(s). Thus, GWAS are useful 'roadmaps' that require functional analysis to establish the genetic and mechanistic structure of a particular locus. Unfortunately, direct functional testing in humans is limited, demonstrating the need for complimentary approaches. Here we used an integrated approach combining zebrafish, rat, and human data to interrogate the function of an established GWAS locus (SHROOM3) lacking prior functional support for chronic kidney disease (CKD). Congenic mapping and sequence analysis in rats suggested Shroom3 was a strong positional candidate gene. Transferring of a 6.1 Mb region containing the wild-type Shroom3 gene significantly improved the kidney glomerular function in FHH (Fawn-Hooded Hypertensive) rat. The wild-type Shroom3 allele, but not the FHH Shroom3 allele, rescued glomerular defects induced by knockdown of endogenous shroom3 in zebrafish, suggesting that the FHH Shroom3 allele is defective and likely contributes to renal injury in the FHH rat. We also show for the first time that variants disrupting the actin-binding domain of SHROOM3 may cause podocyte effacement and impairment of the glomerular filtration barrier.
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Lack of Association of the APOL1 G3 Haplotype in African Americans with ESRD.
J. Am. Soc. Nephrol.
PUBLISHED: 09-25-2014
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Apolipoprotein L1 gene (APOL1) G1 and G2 variants are strongly associated with progressive nondiabetic nephropathy in populations with recent African ancestry. Selection for these variants occurred as a result of protection from human African trypanosomiasis (HAT). Resequencing of this region in 10 genetically and geographically distinct African populations residing in HAT endemic regions identified eight single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium and comprising a novel G3 haplotype. To determine whether the APOL1 G3 haplotype was associated with nephropathy, G1, G2, and G3 SNPs and 70 ancestry informative markers spanning the genome were genotyped in 937 African Americans with nondiabetic ESRD, 965 African Americans with type 2 diabetes-associated ESRD, and 1029 non-nephropathy controls. In analyses adjusting for age, sex, APOL1 G1/G2 risk (recessive), and global African ancestry, the G3 haplotype was not significantly associated with ESRD (P=0.05 for nondiabetic ESRD, P=0.57 for diabetes-associated ESRD, and P=0.27 for all-cause ESRD). We conclude that variation in APOL1 G3 makes a nominal, if any, contribution to ESRD in African Americans; G1 and G2 variants explain the vast majority of nondiabetic nephropathy susceptibility.
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Cerebral Structural Changes in Diabetic Kidney Disease: African American-Diabetes Heart Study MIND.
Diabetes Care
PUBLISHED: 09-11-2014
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Albuminuria and reduced kidney function are associated with cognitive impairment. Relationships between nephropathy and cerebral structural changes remain poorly defined, particularly in African Americans (AAs), a population at higher risk for both cognitive impairment and diabetes than European Americans. We examined the relationship between urine albumin:creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and cerebral MRI volumes in 263 AAs with type 2 diabetes.
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Cross-sectional analysis of calcium intake for associations with vascular calcification and mortality in individuals with type 2 diabetes from the Diabetes Heart Study.
Am. J. Clin. Nutr.
PUBLISHED: 08-06-2014
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The use of calcium supplements to prevent declines in bone mineral density and fractures is widespread in the United States, and thus reports of elevated cardiovascular disease (CVD) risk in users of calcium supplements are a major public health concern. Any elevation in CVD risk with calcium supplement use would be of particular concern in individuals with type 2 diabetes (T2D) because of increased risks of CVD and fractures observed in this population.
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Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.
PLoS Genet.
PUBLISHED: 08-01-2014
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Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)
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The ras responsive transcription factor RREB1 is a novel candidate gene for type 2 diabetes associated end-stage kidney disease.
Hum. Mol. Genet.
PUBLISHED: 07-15-2014
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Familial clustering and presumed genetic risk for type 2 diabetic (T2D) and non-diabetic end-stage kidney disease (ESKD) appear strong in African Americans. Examination of exome sequencing data in African American T2D-ESKD cases and non-diabetic non-nephropathy controls identified two low-frequency variants in the RREB1 gene, a repressor of the angiotensinogen (AGT) gene previously associated with kidney function, as being associated with T2D-ESKD: rs9379084 (P = 0.00087, OR = 0.26; D1171N) and rs41302867 (P = 0.00078, OR = 0.21; splice site variant). Rs41302867 replicated association in an independent sample of African Americans with T2D-ESKD [rs41302867 P = 0.033 (OR = 0.50)], and a trend towards rs9379084 association was observed (P = 0.070). In European Americans with T2D-ESKD compared with European American population based controls, both RREB1 variants replicated association [rs9379084 P = 1.67 × 10(-4) (OR = 0.54) and rs41302867 P = 0.013 (OR = 0.69)]. Rs9379084 was not associated with non-T2D-ESKD or T2D in African Americans (P = 0.55 and P = 0.37, respectively), but was associated with T2D in European Americans (P = 0.014, OR = 0.65). In African Americans, rs41302867 was associated with non-T2D-ESKD [P = 0.036 (OR = 0.54)] and hypertension attributed ESKD [H-ESKD, P = 0.029 (OR = 0.50)]. A meta-analysis combining African American and European American T2D-ESKD data revealed P = 3.52 × 10(-7) and 3.70 × 10(-5) for rs9379084 and rs41302867 association, respectfully. A locus-wide analysis evaluating putatively functional SNPs revealed several nominal associations with T2D-ESKD, non-T2D-ESKD and T2D in African and European Americans. RREB1 is a large, complex gene which codes a multidomain zinc finger binding protein and transcription factor. We posit that variants in RREB1 modulate seemingly disparate phenotypes (i.e. T2D, T2D-ESKD and non-T2D-ESKD) through altered activity resulting from splice site and missense variants.
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Contributors to mortality in high-risk diabetic patients in the Diabetes Heart Study.
Diabetes Care
PUBLISHED: 07-02-2014
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Not all individuals with type 2 diabetes and high coronary artery calcified plaque (CAC) experience the same risk for adverse outcomes. This study examined a subset of high-risk individuals based on CAC >1,000 mg (using a total mass score) and evaluated whether differences in a range of modifiable cardiovascular disease (CVD) risk factors provided further insights into risk for mortality.
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Coding variants in nephrin (NPHS1) and susceptibility to nephropathy in African Americans.
Clin J Am Soc Nephrol
PUBLISHED: 06-19-2014
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Presumed genetic risk for diabetic and nondiabetic end stage renal disease is strong in African Americans.
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Kidney Disease and Cognitive Function: African American-Diabetes Heart Study MIND.
Am. J. Nephrol.
PUBLISHED: 05-29-2014
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Albuminuria and reduced estimated glomerular filtration rate (eGFR) are linked with poorer cognitive performance in European-ancestry populations with advanced nephropathy; relationships in African Americans (AAs) with type 2 diabetes (T2D) are less clear. Tests of cognitive performance, urine albumin:creatinine ratio (UACR), and CKD-EPI eGFR were performed in unrelated AAs with T2D to determine relationships.
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?-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment.
Diabetes Care
PUBLISHED: 05-08-2014
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This article examines the foundation of ?-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment.
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A comparison of type 2 diabetes risk allele load between African Americans and European Americans.
Hum. Genet.
PUBLISHED: 04-10-2014
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The prevalence of type 2 diabetes (T2D) is greater in populations of African descent compared to European-descent populations. Genetic risk factors may underlie the disparity in disease prevalence. Genome-wide association studies (GWAS) have identified >60 common genetic variants that contribute to T2D risk in populations of European, Asian, African and Hispanic descent. These studies have not comprehensively examined population differences in cumulative risk allele load. To investigate the relationship between risk allele load and T2D risk, 46 T2D single nucleotide polymorphisms (SNPs) in 43 loci from GWAS in European, Asian, and African-derived populations were genotyped in 1,990 African Americans (n = 963 T2D cases, n = 1,027 controls) and 1,644 European Americans (n = 719 T2D cases, n = 925 controls) ascertained and recruited using a common protocol in the southeast United States. A genetic risk score (GRS) was constructed from the cumulative risk alleles for each individual. In African American subjects, risk allele frequencies ranged from 0.024 to 0.964. Risk alleles from 26 SNPs demonstrated directional consistency with previous studies, and 3 SNPs from ADAMTS9, TCF7L2, and ZFAND6 showed nominal evidence of association (p < 0.05). African American individuals carried 38-67 (53.7 ± 4.0, mean ± SD) risk alleles. In European American subjects, risk allele frequencies ranged from 0.084 to 0.996. Risk alleles from 36 SNPs demonstrated directional consistency, and 10 SNPs from BCL11A, PSMD6, ADAMTS9, ZFAND3, ANK1, CDKN2A/B, TCF7L2, PRC1, FTO, and BCAR1 showed evidence of association (p < 0.05). European American individuals carried 38-65 (50.9 ± 4.4) risk alleles. African Americans have a significantly greater burden of 2.8 risk alleles (p = 3.97 × 10(-89)) compared to European Americans. However, GRS modeling showed that cumulative risk allele load was associated with risk of T2D in European Americans, but only marginally in African Americans. This result suggests that there are ethnic-specific differences in genetic architecture underlying T2D, and that these differences complicate our understanding of how risk allele load impacts disease susceptibility.
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?-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment.
J. Clin. Endocrinol. Metab.
PUBLISHED: 04-08-2014
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This article examines the foundation of ?-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment.
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APOL1 associations with nephropathy, atherosclerosis, and all-cause mortality in African Americans with type 2 diabetes.
Kidney Int.
PUBLISHED: 03-17-2014
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Albuminuria and reduced estimated glomerular filtration rate (eGFR) associate with two apolipoprotein L1 gene (APOL1) variants in nondiabetic African Americans (AAs). Whether APOL1 associates with subclinical atherosclerosis and survival remains unclear. To determine this, 717 African American-Diabetes Heart Study participants underwent computed tomography to determine coronary artery-, carotid artery-, and aorta-calcified atherosclerotic plaque mass scores in addition to the urine albumin:creatinine ratio (UACR), eGFR, and C-reactive protein (CRP). Associations between mass scores and APOL1 were assessed adjusting for age, gender, African ancestry, body mass index (BMI), hemoglobin A1c, smoking, hypertension, use of statins and angiotensin-converting enzyme inhibitors, albuminuria, and eGFR. Participants were 58.9% female with mean age 56.5 years, eGFR 89.5?ml/min per 1.73?m(2), UACR 169.6?mg/g, and coronary artery-, carotid artery-, and aorta-calcified plaque mass scores of 610, 171, and 5378, respectively. In fully adjusted models, APOL1 risk variants were significantly associated with lower levels of carotid artery-calcified plaque (?=-0.42, s.e. 0.18; dominant model) and marginally lower coronary artery plaque (?=-0.36, s.e. 0.21; dominant model), but not with aorta-calcified plaque, CRP, UACR, or eGFR. By the end of a mean follow-up of 5.0 years, 89 participants had died. APOL1 nephropathy risk variants were significantly associated with improved survival (hazard ratio 0.67 for one copy; 0.44 for two copies). Thus, APOL1 nephropathy variants associate with lower levels of subclinical atherosclerosis and reduced risk of death in AAs with type 2 diabetes mellitus.Kidney International advance online publication, 23 July 2014; doi:10.1038/ki.2014.255.
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Complement factor H gene associations with end-stage kidney disease in African Americans.
Nephrol. Dial. Transplant.
PUBLISHED: 02-28-2014
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Mutations in the complement factor H gene (CFH) region associate with renal-limited mesangial proliferative forms of glomerulonephritis including IgA nephropathy (IgAN), dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Lack of kidney biopsies could lead to under diagnosis of CFH-associated end-stage kidney disease (ESKD) in African Americans (AAs), with incorrect attribution to other causes. A prior genome-wide association study in AAs with non-diabetic ESKD implicated an intronic CFH single nucleotide polymorphism (SNP).
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Genetic risk score associations with cardiovascular disease and mortality in the Diabetes Heart Study.
Diabetes Care
PUBLISHED: 02-26-2014
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OBJECTIVE Given the high rates of cardiovascular disease (CVD) and associated mortality in individuals with type 2 diabetes, identifying and understanding predictors of CVD events and mortality could help inform clinical management in this high-risk group. Recent large-scale genetic studies may provide additional tools in this regard. RESEARCH DESIGN AND METHODS Genetic risk scores (GRSs) were constructed in 1,175 self-identified European American (EA) individuals comprising the family-based Diabetes Heart Study based on 1) 13 single nucleotide polymorphisms (SNPs) and 2) 30 SNPs with previously documented associations with CVD in genome-wide association studies. Associations between each GRS and a self-reported history of CVD, coronary artery calcified plaque (CAC) determined by noncontrast computed tomography scan, all-cause mortality, and CVD mortality were examined using marginal models with generalized estimating equations and Cox proportional hazards models. RESULTS The weighted 13-SNP GRS was associated with prior CVD (odds ratio [OR] 1.51 [95% CI 1.22-1.86]; P = 0.0002), CAC (?-coefficient [?] 0.22 [0.02-0.43]; P = 0.04) and CVD mortality (hazard ratio [HR] 1.35 [1.10-1.81]; P = 0.04) when adjusting for the other known CVD risk factors: age, sex, type 2 diabetes affection status, BMI, current smoking status, hypertension, and dyslipidemia. The weighted 30-SNP GRS was also associated with prior CVD (OR 1.33 [1.08-1.65]; P = 0.008), CAC (? 0.29 [0.08-0.50]; P = 0.006), all-cause mortality (HR 1.28 [1.05-1.56]; P = 0.01), and CVD mortality (HR 1.46 [1.08-1.96]; P = 0.01). CONCLUSIONS These findings support the utility of two simple GRSs in examining genetic associations for adverse outcomes in EAs with type 2 diabetes.
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Heart rate-corrected QT interval is an independent predictor of all-cause and cardiovascular mortality in individuals with type 2 diabetes: the Diabetes Heart Study.
Diabetes Care
PUBLISHED: 02-26-2014
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Heart rate-corrected QT (QTc) interval is associated with mortality in the general population, but this association is less clear in individuals with type 2 diabetes. We assessed the association of QTc interval with all-cause and cardiovascular disease (CVD) mortality in the Diabetes Heart Study.
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Thalassemia bone disease: a 19-year longitudinal analysis.
J. Bone Miner. Res.
PUBLISHED: 02-16-2014
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Thalassemia is an inherited disorder of alpha or beta globin chain synthesis leading to ineffective erythropoiesis requiring chronic transfusion therapy in its most severe form. This leads to iron overload, marrow expansion, and hormonal complications, which are implicated in bone deformity and loss of bone mineral density (BMD). In this 19-year retrospective longitudinal study, the relationships between BMD (determined by dual-energy X-ray absorptiometry) and risk factors for osteoporosis in 277 subjects with transfusion-dependent thalassemia were examined. The mean age at first review was 23.2?±?11.9 years and 43.7% were male. Hypogonadism was present in 28.9%. Fractures were confirmed in 11.6% of subjects and were more frequent in males (16.5%) compared with females (7.7%). Lumbar spine (LS), femoral neck (FN), and total body (TB) Z-scores were derived. Patients with transfusion-dependent thalassemia had a significant longitudinal decline in BMD at the FN and TB. In the linear mixed-model analysis of BMD and risk factors for bone loss, FN Z-score was more significantly associated with risk factors compared with the LS and TB. The rate of decline at the FN was 0.02 Z-score per year and was 3.85-fold greater in males. The decline in FN Z-score over the last 5 years (years 15 to 19) was 2.5-fold that of the previous 7 years (years 8 to 14) and coincided with a change in iron chelator therapy from desferrioxamine to deferasirox. Hemoglobin (Hb) levels positively correlated with higher TB and LS Z-scores. In conclusion, the FN is the preferred site for follow-up of BMD. Male patients with ?-thalassemia experienced a greater loss of BMD and had a higher prevalence of fractures compared with females. Transfusing patients (particularly males) to a higher Hb target may reduce the decline in BMD. Whether deferasirox is implicated in bone loss warrants further study. © 2014 American Society for Bone and Mineral Research.
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Heritability and genetic association analysis of cognition in the Diabetes Heart Study.
Neurobiol. Aging
PUBLISHED: 02-15-2014
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Cognitive performance is an important component of healthy aging. Type 2 diabetes (T2D) is associated with negative outcomes for the brain and cognition, although causal mechanisms have not been definitely determined. Genetic risk factors warrant further consideration in this context. This study examined the heritability of cognitive function as assessed by (1) the Digit Symbol Substitution Task; (2) the Modified Mini-Mental State Examination; (3) the Stroop Task; (4) the Rey Auditory-Verbal Learning Task; and (5) the Controlled Oral Word Association Task for Phonemic and Semantic Fluency, in the family-based, T2D-enriched, Diabetes Heart Study sample (n = 550 participants from 257 families). The genetic basis of these cognitive measures was further evaluated by association analysis with candidate single-nucleotide polymorphisms (SNPs) and genome-wide SNP data. Measures of cognitive function were significantly heritable (hˆ(2) = 0.28-0.62) following adjustment for age, gender, and education. A total of 31 SNPs (from 26 genes/regions) selected to form an a priori set of candidate SNPs showed limited evidence of association with cognitive function when applying conservative metrics of significance. Genome-wide assessment of both noncoding and coding variants revealed suggestive evidence of association for several coding variants including rs139509083 in CNST (p = 4.9 × 10(-9)), rs199968569 in PLAA (p = 4.9 × 10(-9)) and rs138487371 in PCDH8 (p = 3.7 × 10(-8)). The identification of a heritable component to cognitive performance in T2D suggests a role for genetic contributors to cognitive performance even in the presence of metabolic disease and other associated comorbidities and is supported by the identification of genetic association signals in functionally plausible candidates.
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Genome-wide family-based linkage analysis of exome chip variants and cardiometabolic risk.
Genet. Epidemiol.
PUBLISHED: 02-14-2014
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Linkage analysis of complex traits has had limited success in identifying trait-influencing loci. Recently, coding variants have been implicated as the basis for some biomedical associations. We tested whether coding variants are the basis for linkage peaks of complex traits in 42 African-American (n = 596) and 90 Hispanic (n = 1,414) families in the Insulin Resistance Atherosclerosis Family Study (IRASFS) using Illumina HumanExome Beadchips. A total of 92,157 variants in African Americans (34%) and 81,559 (31%) in Hispanics were polymorphic and tested using two-point linkage and association analyses with 37 cardiometabolic phenotypes. In African Americans 77 LOD scores greater than 3 were observed. The highest LOD score was 4.91 with the APOE SNP rs7412 (MAF = 0.13) with plasma apolipoprotein B (ApoB). This SNP was associated with ApoB (P-value = 4 × 10(-19)) and accounted for 16.2% of the variance in African Americans. In Hispanic families, 104 LOD scores were greater than 3. The strongest evidence of linkage (LOD = 4.29) was with rs5882 (MAF = 0.46) in CETP with HDL. CETP variants were strongly associated with HDL (0.00049 < P-value <4.6 × 10(-12)), accounting for up to 4.5% of the variance. These loci have previously been shown to have effects on the biomedical traits evaluated here. Thus, evidence of strong linkage in this genome wide survey of primarily coding variants was uncommon. Loci with strong evidence of linkage was characterized by large contributions to the variance, and, in these cases, are common variants. Less compelling evidence of linkage and association was observed with additional loci that may require larger family sets to confirm.
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Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.
, Anubha Mahajan, Min Jin Go, Weihua Zhang, Jennifer E Below, Kyle J Gaulton, Teresa Ferreira, Momoko Horikoshi, Andrew D Johnson, Maggie C Y Ng, Inga Prokopenko, Danish Saleheen, Xu Wang, Eleftheria Zeggini, Gonçalo R Abecasis, Linda S Adair, Peter Almgren, Mustafa Atalay, Tin Aung, Damiano Baldassarre, Beverley Balkau, Yuqian Bao, Anthony H Barnett, Inês Barroso, Abdul Basit, Latonya F Been, John Beilby, Graeme I Bell, Rafn Benediktsson, Richard N Bergman, Bernhard O Boehm, Eric Boerwinkle, Lori L Bonnycastle, Noel Burtt, Qiuyin Cai, Harry Campbell, Jason Carey, Stéphane Cauchi, Mark Caulfield, Juliana C N Chan, Li-Ching Chang, Tien-Jyun Chang, Yi-Cheng Chang, Guillaume Charpentier, Chien-Hsiun Chen, Han Chen, Yuan-Tsong Chen, Kee-Seng Chia, Manickam Chidambaram, Peter S Chines, Nam H Cho, Young Min Cho, Lee-Ming Chuang, Francis S Collins, Marylin C Cornelis, David J Couper, Andrew T Crenshaw, Rob M Van Dam, John Danesh, Debashish Das, Ulf de Faire, George Dedoussis, Panos Deloukas, Antigone S Dimas, Christian Dina, Alex S Doney, Peter J Donnelly, Mozhgan Dorkhan, Cornelia van Duijn, Josée Dupuis, Sarah Edkins, Paul Elliott, Valur Emilsson, Raimund Erbel, Johan G Eriksson, Jorge Escobedo, Tonu Esko, Elodie Eury, Jose C Florez, Pierre Fontanillas, Nita G Forouhi, Tom Forsén, Caroline Fox, Ross M Fraser, Timothy M Frayling, Philippe Froguel, Philippe Frossard, Yutang Gao, Karl Gertow, Christian Gieger, Bruna Gigante, Harald Grallert, George B Grant, Leif C Grrop, Chrisropher J Groves, Elin Grundberg, Candace Guiducci, Anders Hamsten, Bok-Ghee Han, Kazuo Hara, Neelam Hassanali, Andrew T Hattersley, Caroline Hayward, Asa K Hedman, Christian Herder, Albert Hofman, Oddgeir L Holmen, Kees Hovingh, Astradur B Hreidarsson, Cheng Hu, Frank B Hu, Jennie Hui, Steve E Humphries, Sarah E Hunt, David J Hunter, Kristian Hveem, Zafar I Hydrie, Hiroshi Ikegami, Thomas Illig, Erik Ingelsson, Muhammed Islam, Bo Isomaa, Anne U Jackson, Tazeen Jafar, Alan James, Weiping Jia, Karl-Heinz Jöckel, Anna Jonsson, Jeremy B M Jowett, Takashi Kadowaki, Hyun Min Kang, Stavroula Kanoni, Wen Hong L Kao, Sekar Kathiresan, Norihiro Kato, Prasad Katulanda, Kirkka M Keinanen-Kiukaanniemi, Ann M Kelly, Hassan Khan, Kay-Tee Khaw, Chiea-Chuen Khor, Hyung-Lae Kim, Sangsoo Kim, Young Jin Kim, Leena Kinnunen, Norman Klopp, Augustine Kong, Eeva Korpi-Hyövälti, Sudhir Kowlessur, Peter Kraft, Jasmina Kravic, Malene M Kristensen, S Krithika, Ashish Kumar, Jesus Kumate, Johanna Kuusisto, Soo Heon Kwak, Markku Laakso, Vasiliki Lagou, Timo A Lakka, Claudia Langenberg, Cordelia Langford, Robert Lawrence, Karin Leander, Jen-Mai Lee, Nanette R Lee, Man Li, Xinzhong Li, Yun Li, Junbin Liang, Samuel Liju, Wei-Yen Lim, Lars Lind, Cecilia M Lindgren, Eero Lindholm, Ching-Ti Liu, Jian Jun Liu, Stéphane Lobbens, Jirong Long, Ruth J F Loos, Wei Lu, Jian'an Luan, Valeriya Lyssenko, Ronald C W Ma, Shiro Maeda, Reedik Mägi, Satu Mannisto, David R Matthews, James B Meigs, Olle Melander, Andres Metspalu, Julia Meyer, Ghazala Mirza, Evelin Mihailov, Susanne Moebus, Viswanathan Mohan, Karen L Mohlke, Andrew D Morris, Thomas W Mühleisen, Martina Müller-Nurasyid, Bill Musk, Jiro Nakamura, Eitaro Nakashima, Pau Navarro, Peng-Keat Ng, Alexandra C Nica, Peter M Nilsson, Inger Njølstad, Markus M Nöthen, Keizo Ohnaka, Twee Hee Ong, Katharine R Owen, Colin N A Palmer, James S Pankow, Kyong Soo Park, Melissa Parkin, Sonali Pechlivanis, Nancy L Pedersen, Leena Peltonen, John R B Perry, Annette Peters, Janini M Pinidiyapathirage, Carl G Platou, Simon Potter, Jackie F Price, Lu Qi, Venkatesan Radha, Loukianos Rallidis, Asif Rasheed, Wolfgang Rathman, Rainer Rauramaa, Soumya Raychaudhuri, N William Rayner, Simon D Rees, Emil Rehnberg, Samuli Ripatti, Neil Robertson, Michael Roden, Elizabeth J Rossin, Igor Rudan, Denis Rybin, Timo E Saaristo, Veikko Salomaa, Juha Saltevo, Maria Samuel, Dharambir K Sanghera, Jouko Saramies, James Scott, Laura J Scott, Robert A Scott, Ayellet V Segrè, Joban Sehmi, Bengt Sennblad, Nabi Shah, Sonia Shah, A Samad Shera, Xiao Ou Shu, Alan R Shuldiner, Gunnar Sigurđsson, Eric Sijbrands, Angela Silveira, Xueling Sim, Suthesh Sivapalaratnam, Kerrin S Small, Wing Yee So, Alena Stančáková, Kari Stefansson, Gerald Steinbach, Valgerdur Steinthorsdottir, Kathleen Stirrups, Rona J Strawbridge, Heather M Stringham, Qi Sun, Chen Suo, Ann-Christine Syvänen, Ryoichi Takayanagi, Fumihiko Takeuchi, Wan Ting Tay, Tanya M Teslovich, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Emmi Tikkanen, Joseph Trakalo, Elena Tremoli, Mieke D Trip, Fuu Jen Tsai, Tiinamaija Tuomi, Jaakko Tuomilehto, André G Uitterlinden, Adán Valladares-Salgado, Sailaja Vedantam, Fabrizio Veglia, Benjamin F Voight, Congrong Wang, Nicholas J Wareham, Roman Wennauer, Ananda R Wickremasinghe, Tom Wilsgaard, James F Wilson, Steven Wiltshire, Wendy Winckler, Tien Yin Wong, Andrew R Wood, Jer-Yuarn Wu, Ying Wu, Ken Yamamoto, Toshimasa Yamauchi, Mingyu Yang, Loïc Yengo, Mitsuhiro Yokota, Robin Young, Delilah Zabaneh, Fan Zhang, Rong Zhang, Wei Zheng, Paul Z Zimmet, David Altshuler, Donald W Bowden, Yoon Shin Cho, Nancy J Cox, Miguel Cruz, Craig L Hanis, Jaspal Kooner, Jong-Young Lee, Mark Seielstad, Yik Ying Teo, Michael Boehnke, Esteban J Parra, Jonh C Chambers, E Shyong Tai, Mark I McCarthy, Andrew P Morris.
Nat. Genet.
PUBLISHED: 01-17-2014
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To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.
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Analysis of common and coding variants with cardiovascular disease in the Diabetes Heart Study.
Cardiovasc Diabetol
PUBLISHED: 01-14-2014
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Type 2 diabetes mellitus (T2DM) is a major cardiovascular disease (CVD) risk factor. Identification of genetic risk factors for CVD is important to understand disease risk. Two recent genome-wide association study (GWAS) meta-analyses in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium detected CVD-associated loci.
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Analysis of coding variants identified from exome sequencing resources for association with diabetic and non-diabetic nephropathy in African Americans.
Hum. Genet.
PUBLISHED: 01-03-2014
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Prior studies have identified common genetic variants influencing diabetic and non-diabetic nephropathy, diseases which disproportionately affect African Americans. Recently, exome sequencing techniques have facilitated identification of coding variants on a genome-wide basis in large samples. Exonic variants in known or suspected end-stage kidney disease (ESKD) or nephropathy genes can be tested for their ability to identify association either singly or in combination with known associated common variants. Coding variants in genes with prior evidence for association with ESKD or nephropathy were identified in the NHLBI-ESP GO database and genotyped in 5,045 African Americans (3,324 cases with type 2 diabetes associated nephropathy [T2D-ESKD] or non-T2D ESKD, and 1,721 controls) and 1,465 European Americans (568 T2D-ESKD cases and 897 controls). Logistic regression analyses were performed to assess association, with admixture and APOL1 risk status incorporated as covariates. Ten of 31 SNPs were associated in African Americans; four replicated in European Americans. In African Americans, SNPs in OR2L8, OR2AK2, C6orf167 (MMS22L), LIMK2, APOL3, APOL2, and APOL1 were nominally associated (P = 1.8 × 10(-4)-0.044). Haplotype analysis of common and coding variants increased evidence of association at the OR2L13 and APOL1 loci (P = 6.2 × 10(-5) and 4.6 × 10(-5), respectively). SNPs replicating in European Americans were in OR2AK2, LIMK2, and APOL2 (P = 0.0010-0.037). Meta-analyses highlighted four SNPs associated in T2D-ESKD and all-cause ESKD. Results from this study suggest a role for coding variants in the development of diabetic, non-diabetic, and/or all-cause ESKD in African Americans and/or European Americans.
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Evaluation of candidate nephropathy susceptibility genes in a genome-wide association study of African American diabetic kidney disease.
PLoS ONE
PUBLISHED: 01-01-2014
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Type 2 diabetes (T2D)-associated end-stage kidney disease (ESKD) is a complex disorder resulting from the combined influence of genetic and environmental factors. This study contains a comprehensive genetic analysis of putative nephropathy loci in 965 African American (AA) cases with T2D-ESKD and 1029 AA population-based controls extending prior findings. Analysis was based on 4,341 directly genotyped and imputed single nucleotide polymorphisms (SNPs) in 22 nephropathy candidate genes. After admixture adjustment and correction for multiple comparisons, 37 SNPs across eight loci were significantly associated (1.6E-05
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Sclerostin is positively associated with bone mineral density in men and women and negatively associated with carotid calcified atherosclerotic plaque in men from the african american-diabetes heart study.
J. Clin. Endocrinol. Metab.
PUBLISHED: 12-20-2013
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Context: Bone mineral density (BMD) and calcified atherosclerotic plaque (CP) demonstrate inverse relationships. Sclerostin, an endogenous regulator of the Wnt pathway and bone formation, has been associated with impaired osteoblast activation and may play a role in vascular calcification. Objective: Our objective was to assess the relationships between sclerostin, BMD, and CP. Design: Generalized linear models were fitted to test for associations between sclerostin, volumetric BMD (vBMD), and CP. Participants: A targeted population of 450 unrelated African Americans (AAs) with type 2 diabetes (T2D) was 56% female with mean/SD/median age of 55.4/9.5/55.0 years and a diabetes duration of 10.3/8.2/8.0 years. Main Outcome Measures: Plasma sclerostin, computed tomography-derived thoracic and lumbar vertebrae trabecular vBMD, coronary artery, carotid artery, and aortoiliac CP were measured. Results: Plasma sclerostin was 1119/401/1040 pg/mL, thoracic vBMD was 206.3/52.4/204.8 mg/cm(3), lumbar vBMD was 180.7/47.0/179.0 mg/cm(3), coronary artery CP score was 284/648/13, carotid artery CP score was 46/132/0, and aortoiliac CP score was 1613/2910/282. Sclerostin levels were higher in men than women (P < .0001). Before and after adjusting for age, sex, body mass index, blood pressure, smoking, hemoglobin A1c, and low-density lipoprotein-cholesterol, plasma sclerostin levels were positively associated with thoracic and lumbar vertebrae vBMD (P < .0001). Sex-stratified analyses verified significant relationships in both men and women (both P < .001). Sclerostin was not associated with CP except for an inverse relationship with carotid CP in men (fully adjusted model, P = .03). Conclusions: In this cross-sectional study of AA men and women with T2D, circulating sclerostin was positively associated with vBMD in the spine in both sexes and inversely associated with carotid artery CP in men. Sclerostin may play a role in skeletal mineral metabolism in AA but fails to explain inverse relationships between BMD and CP.
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Is genetic testing of value in predicting and treating obesity?
N C Med J
PUBLISHED: 12-10-2013
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Obesity is a multifactorial disease resulting from the interaction between genetic factors and lifestyle. Identification of rare genetic variations with strong effects on obesity has been useful in diagnosing and designing personalized therapy for early-onset or syndromic obesity. However, common variants identified in recent genome-wide association studies have limited clinical value.
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Gene-gene interactions in APOL1-associated nephropathy.
Nephrol. Dial. Transplant.
PUBLISHED: 10-24-2013
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Two APOL1 nephropathy variants confer substantial risk for non-diabetic end-stage kidney disease (ESKD) in African Americans (AAs). Since not all genetically high-risk individuals develop ESKD, modifying factors likely contribute. Forty-two potentially interactive single nucleotide polymorphisms (SNPs) from a genome-wide association study in non-diabetic ESKD were tested for interaction with APOL1 to identify genes modifying risk for non-diabetic nephropathy.
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Genetic variants in selenoprotein P plasma 1 gene (SEPP1) are associated with fasting insulin and first phase insulin response in Hispanics.
Gene
PUBLISHED: 08-07-2013
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Insulin resistance is not fully explained on a molecular level, though several genes and proteins have been tied to this defect. Knockdowns of the SEPP1 gene, which encodes the selenoprotein P (SeP) protein, have been shown to increase insulin sensitivity in mice. SeP is a liver-derived plasma protein and a major supplier of selenium, which is a proposed insulin mimetic and antidiabetic agent.
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Relationships between electrochemical skin conductance and kidney disease in Type 2 diabetes.
J. Diabetes Complicat.
PUBLISHED: 07-22-2013
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SUDOSCAN® non-invasively measures peripheral small fiber and autonomic nerve activity using electrochemical skin conductance. Since neuropathy and nephropathy are microvascular Type 2 diabetes (T2D) complications, relationships between skin conductance, estimated glomerular filtration rate (eGFR), and urine albumin:creatinine ratio (UACR) were assessed.
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Variants in adiponectin signaling pathway genes show little association with subclinical CVD in the diabetes heart study.
Obesity (Silver Spring)
PUBLISHED: 05-13-2013
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Understanding the interplay between adiposity, inflammation, and cardiovascular complications in type 2 diabetes mellitus (T2DM) remains a challenge. Signaling from adipocytes is considered important in this context. Adiponectin is the most abundant adipocytokine and has been associated with various measures of cardiovascular disease (CVD). This study examines the relationships between genetic variants in the adiponectin (ADIPOQ) and adiponectin-related signaling pathway genes and measures of subclinical CVD (vascular calcified plaque and carotid intima-media thickness), plasma lipids, and inflammation in T2DM.
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Transfusion suppresses erythropoiesis and increases hepcidin in adult patients with ?-thalassemia major: a longitudinal study.
Blood
PUBLISHED: 05-08-2013
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?-Thalassemia major causes ineffective erythropoiesis and chronic anemia and is associated with iron overload due to both transfused iron and increased iron absorption, the latter mediated by suppression of the iron-regulatory hormone hepcidin. We sought to determine whether, in ?-thalassemia major, transfusion-mediated inhibition of erythropoiesis dynamically affects hepcidin. We recruited 31 chronically transfused patients with ?-thalassemia major and collected samples immediately before and 4 to 8 days after transfusion. Pretransfusion hepcidin was positively correlated with hemoglobin and ferritin and inversely with erythropoiesis. The hepcidin-ferritin ratio indicated hepcidin was relatively suppressed given the degree of iron loading. Posttransfusion, hemoglobin and hepcidin increased, and erythropoietin and growth differentiation factor-15 decreased. By multiple regression, pre- and posttransfusion hepcidin concentrations were both associated positively with hemoglobin, inversely with erythropoiesis, and positively with ferritin. Although men and women had similar pretransfusion hemoglobin, men had significantly increased erythropoiesis and lower hepcidin, received a lower transfusion volume per liter blood volume, and experienced a smaller posttransfusion reduction in erythropoiesis and hepcidin rise. Age of blood was not associated with posttransfusion hemoglobin or ferritin change. Hepcidin levels in patients with ?-thalassemia major dynamically reflect competing influences from erythropoiesis, anemia, and iron overload. Measurement of these indices could assist clinical monitoring.
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Impact of HDL genetic risk scores on coronary artery calcified plaque and mortality in individuals with type 2 diabetes from the Diabetes Heart Study.
Cardiovasc Diabetol
PUBLISHED: 05-03-2013
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Patients with type 2 diabetes (T2D) are at elevated risk for cardiovascular disease (CVD) events and mortality. Recent studies have assessed the impact of genetic variants affecting high-density lipoprotein cholesterol (HDL) concentrations on CVD risk in the general population. This study examined the utility of HDL-associated single nucleotide polymorphisms (SNPs) for CVD risk prediction in European Americans with T2D enrolled in the Diabetes Heart Study (DHS).
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The influence of subclinical cardiovascular disease and related risk factors on cognition in type 2 diabetes mellitus: The DHS-Mind study.
J. Diabetes Complicat.
PUBLISHED: 04-04-2013
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We hypothesized that measures of coronary artery calcified plaque (CAC) collected at baseline from the Diabetes Heart Study (DHS) would explain associations between cognition and diabetes collected at follow-up approximately 7 years later. The DHS is a sibling study of cardiovascular disease (CVD) in a cohort with a high prevalence of type 2 diabetes (~80%). Associations between baseline CAC and cognitive performance were tested using generalized estimating equations and mixed effects models to adjust for familial relationships. Diabetes status was associated (p<0.05) with poorer performance on tests of verbal memory, processing speed, and semantic fluency adjusting for age, sex, education, and hypertension status. As hypothesized, including CAC in the statistical model attenuated this association. Additionally, CAC and fasting glucose predicted performance in tasks not associated with diabetes status in this study (Stroop Task, Phonemic Fluency). These results confirm work attributing the heterogeneity of cognitive outcomes in type 2 diabetes to subclinical risk factors that combine to affect different aspects of brain function. Importantly, these results imply that risk factor intervention should begin before comorbidities, particularly CVD, become clinically apparent.
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Relationships between serum adiponectin and bone density, adiposity and calcified atherosclerotic plaque in the African American-Diabetes Heart Study.
J. Clin. Endocrinol. Metab.
PUBLISHED: 03-29-2013
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Adiposity, bone mineral density (BMD), and calcified atherosclerotic plaque (CP) exhibit complex interrelationships that are not well understood. Adipokines vary in relation to changes in body composition and may play roles in regulation of BMD and risk of cardiovascular disease.
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Association of SNPs in the UGT1A gene cluster with total bilirubin and mortality in the Diabetes Heart Study.
Atherosclerosis
PUBLISHED: 03-19-2013
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A negative relationship between total bilirubin concentration (TBili) and CVD risk has been documented in a series of epidemiological studies. In addition, TBili is thought to be under strong genetic regulation via the UGT1A gene family, suggesting it may be a heritable CVD risk factor. However, few studies directly relate TBili-associated UGT1A variants to CVD severity or outcome. This study replicated the genetic association for TBili in the Diabetes Heart Study (DHS), and examined the relationships of TBili-associated SNPs with measures of subclinical CVD and mortality.
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A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.
Keri L Monda, Gary K Chen, Kira C Taylor, Cameron Palmer, Todd L Edwards, Leslie A Lange, Maggie C Y Ng, Adebowale A Adeyemo, Matthew A Allison, Lawrence F Bielak, Guanjie Chen, Mariaelisa Graff, Marguerite R Irvin, Suhn K Rhie, Guo Li, Yongmei Liu, Youfang Liu, Yingchang Lu, Michael A Nalls, Yan V Sun, Mary K Wojczynski, Lisa R Yanek, Melinda C Aldrich, Adeyinka Ademola, Christopher I Amos, Elisa V Bandera, Cathryn H Bock, Angela Britton, Ulrich Broeckel, Quiyin Cai, Neil E Caporaso, Chris S Carlson, John Carpten, Graham Casey, Wei-Min Chen, Fang Chen, Yii-Der I Chen, Charleston W K Chiang, Gerhard A Coetzee, Ellen Demerath, Sandra L Deming-Halverson, Ryan W Driver, Patricia Dubbert, Mary F Feitosa, Ye Feng, Barry I Freedman, Elizabeth M Gillanders, Omri Gottesman, Xiuqing Guo, Talin Haritunians, Tamara Harris, Curtis C Harris, Anselm J M Hennis, Dena G Hernandez, Lorna H McNeill, Timothy D Howard, Barbara V Howard, Virginia J Howard, Karen C Johnson, Sun J Kang, Brendan J Keating, Suzanne Kolb, Lewis H Kuller, Abdullah Kutlar, Carl D Langefeld, Guillaume Lettre, Kurt Lohman, Vaneet Lotay, Helen Lyon, JoAnn E Manson, William Maixner, Yan A Meng, Kristine R Monroe, Imran Morhason-Bello, Adam B Murphy, Josyf C Mychaleckyj, Rajiv Nadukuru, Katherine L Nathanson, Uma Nayak, Amidou N'Diaye, Barbara Nemesure, Suh-Yuh Wu, M Cristina Leske, Christine Neslund-Dudas, Marian Neuhouser, Sarah Nyante, Heather Ochs-Balcom, Adesola Ogunniyi, Temidayo O Ogundiran, Oladosu Ojengbede, Olufunmilayo I Olopade, Julie R Palmer, Edward A Ruiz-Narváez, Nicholette D Palmer, Michael F Press, Evandine Rampersaud, Laura J Rasmussen-Torvik, Jorge L Rodriguez-Gil, Babatunde Salako, Eric E Schadt, Ann G Schwartz, Daniel A Shriner, David Siscovick, Shad B Smith, Sylvia Wassertheil-Smoller, Elizabeth K Speliotes, Margaret R Spitz, Lara Sucheston, Herman Taylor, Bamidele O Tayo, Margaret A Tucker, David J Van Den Berg, Digna R Velez Edwards, Zhaoming Wang, John K Wiencke, Thomas W Winkler, John S Witte, Margaret Wrensch, Xifeng Wu, James J Yang, Albert M Levin, Taylor R Young, Neil A Zakai, Mary Cushman, Krista A Zanetti, Jing Hua Zhao, Wei Zhao, Yonglan Zheng, Jie Zhou, Regina G Ziegler, Joseph M Zmuda, Jyotika K Fernandes, Gary S Gilkeson, Diane L Kamen, Kelly J Hunt, Ida J Spruill, Christine B Ambrosone, Stefan Ambs, Donna K Arnett, Larry Atwood, Diane M Becker, Sonja I Berndt, Leslie Bernstein, William J Blot, Ingrid B Borecki, Erwin P Bottinger, Donald W Bowden, Gregory Burke, Stephen J Chanock, Richard S Cooper, Jingzhong Ding, David Duggan, Michele K Evans, Caroline Fox, W Timothy Garvey, Jonathan P Bradfield, Hakon Hakonarson, Struan F A Grant, Ann Hsing, Lisa Chu, Jennifer J Hu, Dezheng Huo, Sue A Ingles, Esther M John, Joanne M Jordan, Edmond K Kabagambe, Sharon L R Kardia, Rick A Kittles, Phyllis J Goodman, Eric A Klein, Laurence N Kolonel, Loic Le Marchand, Simin Liu, Barbara McKnight, Robert C Millikan, Thomas H Mosley, Badri Padhukasahasram, L Keoki Williams, Sanjay R Patel, Ulrike Peters, Curtis A Pettaway, Patricia A Peyser, Bruce M Psaty, Susan Redline, Charles N Rotimi, Benjamin A Rybicki, Michèle M Sale, Pamela J Schreiner, Lisa B Signorello, Andrew B Singleton, Janet L Stanford, Sara S Strom, Michael J Thun, Mara Vitolins, Wei Zheng, Jason H Moore, Scott M Williams, Shamika Ketkar, Xiaofeng Zhu, Alan B Zonderman, , Charles Kooperberg, George J Papanicolaou, Brian E Henderson, Alex P Reiner, Joel N Hirschhorn, Ruth J F Loos, Kari E North, Christopher A Haiman.
Nat. Genet.
PUBLISHED: 03-18-2013
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Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.
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Glomerular filtration rate and albuminuria predict mortality independently from coronary artery calcified plaque in the Diabetes Heart Study.
Cardiovasc Diabetol
PUBLISHED: 03-07-2013
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Risk stratification in individuals with type 2 diabetes (T2D) remains an important priority in the management of associated morbidity and mortality, including from cardiovascular disease (CVD). The current investigation examined whether estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (UACR) were independent predictors of CVD-mortality in European Americans (EAs) with T2D after accounting for subclinical CVD.
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JC polyoma virus interacts with APOL1 in African Americans with nondiabetic nephropathy.
Kidney Int.
PUBLISHED: 02-20-2013
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Individuals with HIV infection and two apolipoprotein L1 gene (APOL1) risk variants frequently develop nephropathy. Here we tested whether non-HIV viral infections influence nephropathy risk via interactions with APOL1 by assessing APOL1 genotypes and presence of urine JC and BK polyoma virus and plasma HHV6 and CMV by quantitative polymerase chain reaction. We analyzed 300 samples from unrelated and related first-degree relatives of African Americans with nondiabetic nephropathy using linear and nonlinear mixed models to account for familial relationships. The four groups evaluated were APOL1 zero/one versus two risk alleles, with or without nephropathy. Urine JCV and BKV were detected in 90 and 29 patients, respectively, whereas HHV6 and CMV were rare. Adjusting for family age at nephropathy, gender, and ancestry, presence of JCV genomic DNA in urine and APOL1 risk alleles were significantly negatively associated with elevated serum cystatin C, albuminuria (albumin-to-creatinine ratio over 30?mg/g), and kidney disease defined as an eGFR under 60?ml/min per 1.73?m(2) and/or albuminuria in an additive (APOL1 plus JCV) model. BK viruria was not associated with kidney disease. Thus, African Americans at increased risk for APOL1-associated nephropathy (two APOL1 risk variants) with JC viruria had a lower prevalence of kidney disease, suggesting that JCV interaction with APOL1 genotype may influence kidney disease risk.
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Genetic analysis of adiponectin variation and its association with type 2 diabetes in African Americans.
Obesity (Silver Spring)
PUBLISHED: 02-04-2013
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Adiponectin is an adipocytokine that has been implicated in a variety of metabolic disorders, including T2D and cardiovascular disease. Studies evaluating genetic variants in ADIPOQ have been contradictory when testing association with T2D in different ethnic groups.
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Genetic analysis of haptoglobin polymorphisms with cardiovascular disease and type 2 diabetes in the Diabetes Heart Study.
Cardiovasc Diabetol
PUBLISHED: 02-01-2013
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Haptoglobin (HP) is an acute phase protein that binds to freely circulating hemoglobin. HP exists as two distinct forms, HP1 and HP2. The longer HP2 form has been associated with cardiovascular (CVD) events and mortality in individuals with type 2 diabetes (T2DM).
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Associations between NOS1AP single nucleotide polymorphisms (SNPs) and QT interval duration in four racial/ethnic groups in the Multi-Ethnic Study of Atherosclerosis (MESA).
Ann Noninvasive Electrocardiol
PUBLISHED: 01-26-2013
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QT is a risk factor for sudden cardiac death (SCD). A genome-wide association study identified NOS1AP variants associated with QT, which have been replicated in predominantly Caucasian (CAU) populations. We used the Multi-Ethnic Study of Atherosclerosis to examine association of QT with NOS1AP variants in an ethnically diverse cohort.
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Usefulness of biventricular volume as a predictor of mortality in patients with diabetes mellitus (from the Diabetes Heart Study).
Am. J. Cardiol.
PUBLISHED: 01-23-2013
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Patients with type 2 diabetes mellitus are at increased risk for cardiovascular disease (CVD) and mortality. Beyond traditional CVD risk factors, novel measures reflecting additional aspects of disease pathophysiology, such as biventricular volume (BiVV), may be useful for risk stratification. The aim of this study was to examine the relationship between BiVV and risk for mortality in European Americans with type 2 diabetes mellitus from the Diabetes Heart Study (DHS). BiVV was calculated from 771 noncontrast computed tomographic scans performed to image coronary artery calcified plaque. Relationships between BiVV and traditional CVD risk factors were examined. Cox proportional-hazards regression was performed to determine risk for mortality (all-cause and CVD mortality) associated with increasing BiVV. Area under the curve analysis was used to assess BiVV utility in risk prediction models. During 8.4 ± 2.4 years of follow-up, 23% of the patients died. In unadjusted analyses, BiVV was significantly associated with increasing body mass index, height, coronary artery calcified plaque, history of hypertension, and previous myocardial infarction (p <0.0001 to 0.012). BiVV was significantly associated with all-cause (hazard ratio 2.45, 95% confidence interval 1.06 to 5.67, p = 0.036) and CVD (hazard ratio 4.36, 95% confidence interval 1.36 to 14.03, p = 0.014) mortality in models adjusted for other known CVD risk factors. Area under the curve increased from 0.76 to 0.78 (p = 0.04) and from 0.74 to 0.77 (p = 0.02) for all-cause and CVD mortality with the inclusion of BiVV. In conclusion, in the absence of echocardiography or other noninvasive imaging modalities to assess ventricular volumes, or when such methods are contraindicated, BiVV from computed tomography may be considered a tool for the stratification of high-risk patients, such as those with type 2 diabetes mellitus.
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An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects.
PLoS ONE
PUBLISHED: 01-07-2013
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Acetyl coenzyme A carboxylase B gene (ACACB) single nucleotide polymorphism (SNP) rs2268388 is reproducibly associated with type 2 diabetes (T2DM)-associated nephropathy (DN). ACACB knock-out mice are also protected from obesity. This study assessed relationships between rs2268388, body mass index (BMI) and gene expression in multiple populations, with and without T2DM. Among subjects without T2DM, rs2268388 DN risk allele (T) associated with higher BMI in Pima Indian children (n?=?2021; p-additive?=?0.029) and African Americans (AAs) (n?=?177; p-additive?=?0.05), with a trend in European Americans (EAs) (n?=?512; p-additive?=?0.09), but not Germans (n?=?858; p-additive?=?0.765). Association with BMI was seen in a meta-analysis including all non-T2DM subjects (n?=?3568; p-additive?=?0.02). Among subjects with T2DM, rs2268388 was not associated with BMI in Japanese (n?=?2912) or EAs (n?=?1149); however, the T allele associated with higher BMI in the subset with BMI?30 kg/m(2) (n?=?568 EAs; p-additive?=?0.049, n?=?196 Japanese; p-additive?=?0.049). Association with BMI was strengthened in a T2DM meta-analysis that included an additional 756 AAs (p-additive?=?0.080) and 48 Hong Kong Chinese (p-additive?=?0.81) with BMI?30 kg/m(2) (n?=?1575; p-additive?=?0.0033). The effect of rs2268388 on gene expression revealed that the T risk allele associated with higher ACACB messenger levels in adipose tissue (41 EAs and 20 AAs with BMI>30 kg/m(2); p-additive?=?0.018) and ACACB protein levels in the liver tissue (mixed model p-additive?=?0.03, in 25 EA bariatric surgery patients with BMI>30 kg/m(2) for 75 exams). The T allele also associated with higher hepatic triglyceride levels. These data support a role for ACACB in obesity and potential roles for altered lipid metabolism in susceptibility to DN.
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Examination of Rare Variants in HNF4 ? in European Americans with Type 2 Diabetes.
J Diabetes Metab
PUBLISHED: 10-20-2011
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The hepatocyte nuclear factor 4-? (HNF4?) gene codes for a transcription factor which is responsible for regulating gene transcription in pancreatic beta cells, in addition to its primary role in hepatic gene regulation. Mutations in this gene can lead to maturity-onset diabetes of the young (MODY), an uncommon, autosomal dominant, non-insulin dependent form of diabetes. Mutations in HNF4? have been found in few individuals, and infrequently have they segregated completely with MODY in families. In addition, due to similarity of phenotypes, it is unclear what proportion of type 2 diabetes (T2DM) in the general population is due to MODY or HNF4? mutations specifically. In this study, 27 documented rare and common variants were genotyped in a European American population of 1270 T2DM cases and 1017 controls from review of databases and literature implicating HNF4? variants in MODY and T2DM. Seventeen variants were found to be monomorphic. Two cases and one control subject had one copy of a 6-bp P2 promoter deletion. The intron 1 variant (rs6103716; MAF = 0.31) was not significantly associated with disease status (p>0.8) and the missense variant Thr130Ile (rs1800961; MAF = 0.027) was also not significantly different between cases and controls (p>0.2), but showed a trend consistent with association with T2DM. Four variants were found to be rare as heterozygotes in small numbers of subjects. Since many variants were infrequent, a pooled chi-squared analysis of rare variants was used to assess the overall burden of variants between cases and controls. This analysis revealed no significant difference (P=0.22). We conclude there is little evidence to suggest that HNF4? variants contribute significantly to risk of T2DM in the general population, but a modest contribution cannot be excluded. In addition, the observation of some mutations in controls suggests they are not highly penetrant MODY-causing variants.
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Polymorphisms in MYH9 are associated with diabetic nephropathy in European Americans.
Nephrol. Dial. Transplant.
PUBLISHED: 10-03-2011
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Polymorphisms in the non-muscle myosin IIA gene (MYH9) are associated with focal segmental glomerulosclerosis (FSGS) and non-diabetic end-stage renal disease (ESRD) in African Americans and FSGS in European Americans. We tested for association of single nucleotide polymorphisms (SNPs) in MYH9 with T2DM-ESRD in European Americans; additionally, three APOL1 gene variants were evaluated.
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Apolipoprotein L1 nephropathy risk variants associate with HDL subfraction concentration in African Americans.
Nephrol. Dial. Transplant.
PUBLISHED: 09-19-2011
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Coding variants in the apolipoprotein L1 gene (APOL1) are strongly associated with non-diabetic nephropathy in African Americans. ApoL1 proteins associate with high-density lipoprotein (HDL) particles in the circulation. Plasma HDL particle subclass concentrations were compared in 73 African Americans based on APOL1 genotypes to detect differences potentially contributing to renal disease.
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Sickle cell trait is not independently associated with susceptibility to end-stage renal disease in African Americans.
Kidney Int.
PUBLISHED: 08-17-2011
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Conflicting reports exist as to whether sickle cell trait is a risk factor for the progression of nephropathy. In order to determine whether African Americans with sickle cell trait are at increased risk for kidney disease, we assessed the genetic association between sickle cell trait and end-stage renal disease (ESRD). Hemoglobin S, non-muscle myosin heavy chain 9 (MYH9), and apolipoprotein L1 (APOL1) risk variants were genotyped in 3258 unrelated African Americans: 1085 with non-diabetic ESRD, 996 with type 2 diabetes-associated ESRD, and 1177 controls. Since APOL1 is strongly associated with ESRD in African Americans, interactions between APOL1 and MYH9 risk variants and hemoglobin S were assessed using case-only and case-control centered two-way logistic regression interaction analyses. The sickle cell trait genotype frequencies were 8.7% in non-diabetic ESRD, 7.1% in type 2 diabetes-ESRD, and 7.2% in controls. There was no age-, gender-, and admixture-adjusted significance for sickle cell trait association with non-diabetic ESRD (odds ratio 1.16); type 2 diabetes-ESRD (odds ratio 1.01); or all-cause ESRD (combined non-diabetic and type 2 diabetic-ESRD patients compared to the controls; odds ratio 1.05) in dominant models. In addition, no evidence of APOL1 or MYH9 interactions with sickle cell trait was detected. Hence, sickle cell trait is not associated with diabetic or non-diabetic ESRD in a large sample of African Americans.
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Differences in arachidonic acid levels and fatty acid desaturase (FADS) gene variants in African Americans and European Americans with diabetes or the metabolic syndrome.
Br. J. Nutr.
PUBLISHED: 07-04-2011
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Over the past 50 years, increases in dietary n-6 PUFA, such as linoleic acid, have been hypothesised to cause or exacerbate chronic inflammatory diseases. The present study examines an individuals innate capacity to synthesise n-6 long-chain PUFA (LC-PUFA) with respect to the fatty acid desaturase (FADS) locus in Americans of African and European descent with diabetes or the metabolic syndrome. Compared with European Americans (EAm), African Americans (AfAm) exhibited markedly higher serum levels of arachidonic acid (AA) (EAm 7·9 (sd 2·1), AfAm 9·8 (sd 1·9) % of total fatty acids; P < 2·29 × 10??) and the AA:n-6-precursor fatty acid ratio, which estimates FADS1 activity (EAm 5·4 (sd 2·2), AfAm 6·9 (sd 2·2); P = 1·44 × 10??). In all, seven SNP mapping to the FADS locus revealed strong association with AA, EPA and dihomo-?-linolenic acid (DGLA) in the EAm. Importantly, EAm homozygous for the minor allele (T) had significantly lower AA levels (TT 6·3 (sd 1·0); GG 8·5 (sd 2·1); P = 3·0 × 10??) and AA:DGLA ratios (TT 3·4 (sd 0·8), GG 6·5 (sd 2·3); P = 2·2 × 10??) but higher DGLA levels (TT 1·9 (sd 0·4), GG 1·4 (sd 0·4); P = 3·3 × 10??) compared with those homozygous for the major allele (GG). Allele frequency patterns suggest that the GG genotype at rs174537 (associated with higher circulating levels of AA) is much higher in AfAm (0·81) compared with EAm (0·46). Similarly, marked differences in rs174537 genotypic frequencies were observed in HapMap populations. These data suggest that there are probably important differences in the capacity of different populations to synthesise LC-PUFA. These differences may provide a genetic mechanism contributing to health disparities between populations of African and European descent.
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Genome-wide association of BMI in African Americans.
Obesity (Silver Spring)
PUBLISHED: 06-23-2011
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Recent genome-wide association studies (GWAS) have identified multiple novel loci associated with obesity in Europeans but results in other ethnicities are less convincing. Here, we report a two-stage GWAS of BMI in African Americans. The GWAS was performed using the Affymetrix 6.0 platform in 816 nondiabetic and 899 diabetic nephropathy subjects. 746,626 single-nucleotide polymorphisms (SNPs) were tested for association with BMI after adjustment for age, gender, disease status, and population structure. Sixty high scoring SNPs that showed nominal association in both GWAS cohorts were further replicated in 3,274 additional subjects in four replication cohorts and a meta-analysis was computed. Meta-analysis of 4,989 subjects revealed five SNPs (rs6794092, rs268972, rs2033195, rs815611, and rs6088887) at four loci showing consistent associations in both GWAS (P < 0.0001) and replication cohorts (P < 0.05) with combined P values range from 2.4 × 10(-6) to 5 × 10(-5). These loci are located near PP13439-TMEM212, CDH12, MFAP3-GALNT10, and FER1L4 and had effect sizes between 0.091 and 0.167 s.d. unit (or 0.67-1.24 kg/m(2)) of BMI for each copy of the effect allele. Our findings suggest the presence of novel loci potentially associated with adiposity in African Americans. Further replication and meta-analysis in African Americans and other populations will shed light on the role of these loci in different ethnic populations.
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Meta-analysis of genome-wide linkage scans for renal function traits.
Nephrol. Dial. Transplant.
PUBLISHED: 05-28-2011
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Several genome scans have explored the linkage of chronic kidney disease phenotypes to chromosomic regions with disparate results. Genome scan meta-analysis (GSMA) is a quantitative method to synthesize linkage results from independent studies and assess their concordance.
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The impact of FADS genetic variants on ?6 polyunsaturated fatty acid metabolism in African Americans.
BMC Genet.
PUBLISHED: 05-20-2011
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Arachidonic acid (AA) is a long-chain omega-6 polyunsaturated fatty acid (PUFA) synthesized from the precursor dihomo-gamma-linolenic acid (DGLA) that plays a vital role in immunity and inflammation. Variants in the Fatty Acid Desaturase (FADS) family of genes on chromosome 11q have been shown to play a role in PUFA metabolism in populations of European and Asian ancestry; no work has been done in populations of African ancestry to date.
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Relationships between calcified atherosclerotic plaque and bone mineral density in African Americans with type 2 diabetes.
J. Bone Miner. Res.
PUBLISHED: 03-26-2011
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Inverse relationships have been reported between bone mineral density (BMD) and calcified atherosclerotic plaque (CP). This suggests these processes may be related. We examined relationships between BMD and CP in 753 African Americans with type 2 diabetes from 664 families, accounting for the effects of modifiable cardiovascular disease (CVD) risk factors. Association analyses were performed using generalized estimating equations (GEEs) to assess cross-sectional relationships between computed tomography-determined measures of thoracic and lumbar vertebral volumetric BMD (vBMD) and CP in the coronary and carotid arteries and infrarenal aorta. Significant inverse associations were seen between thoracic and lumbar vBMD and CP in all three vascular beds in unadjusted analyses. A fully adjusted model accounting for age, sex, body mass index, systolic blood pressure, low-density lipoprotein cholesterol, C-reactive protein, hemoglobin A(1c), smoking, and hormone-replacement therapy revealed significant inverse associations between thoracic vBMD and CP in coronary and carotid arteries and aorta, whereas lumbar vBMD was associated with CP in coronary artery and aorta. Inverse associations exist between vertebral BMD and calcified atherosclerotic plaque in African-American men and women with type 2 diabetes. This relationship was independent of conventional CVD risk factors and supports the hypothesis that bone metabolism and atherosclerotic plaque mineralization are related processes.
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Coronary calcium score and prediction of all-cause mortality in diabetes: the diabetes heart study.
Diabetes Care
PUBLISHED: 03-11-2011
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In diabetes, it remains unclear whether the coronary artery calcium (CAC) score provides additional information about total mortality risk beyond traditional risk factors.
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Correlates of coronary artery calcified plaque in blacks and whites with type 2 diabetes.
Ann Epidemiol
PUBLISHED: 03-05-2011
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To examine whether the relationship between cardiovascular disease risk factors and coronary artery calcification (CAC) is modified by race among those with diabetes.
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Genome-wide association scan for survival on dialysis in African-Americans with type 2 diabetes.
Am. J. Nephrol.
PUBLISHED: 03-04-2011
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African-Americans (AAs) with diabetes have high incidence rates of end-stage renal disease (ESRD) with associated high mortality. Genetic factors modulating the risk of mortality on dialysis are poorly understood.
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Buffy coat specimens remain viable as a DNA source for highly multiplexed genome-wide genetic tests after long term storage.
J Transl Med
PUBLISHED: 03-02-2011
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Blood specimen collection at an early study visit is often included in observational studies or clinical trials for analysis of secondary outcome biomarkers. A common protocol is to store buffy coat specimens for future DNA isolation and these may remain in frozen storage for many years. It is uncertain if the DNA remains suitable for modern genome wide association (GWA) genotyping.
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Genetic mapping of vascular calcified plaque loci on chromosome 16p in European Americans from the diabetes heart study.
Ann. Hum. Genet.
PUBLISHED: 02-12-2011
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A linkage peak for carotid artery calcified plaque (CarCP) on chromosome 16p (LOD 4.39 at 8.4 cM) in families with type 2 diabetes mellitus (T2DM) from the Diabetes Heart Study (DHS) has been refined. Fine mapping encompassed 104 single-nucleotide polymorphisms (SNPs) in 937 subjects from 315 families; including 45 SNPs in six candidate genes (CACNA1H, SEPX1, ABCA3, IL32, SOCS1, CLEC16A). Linkage and association analyses using variance components analysis adjusting for age, gender, body mass index (BMI), and diabetes status refined the CarCP linkage into two distinct peaks (LODs: 3.89 at 6.9 cM and 4.86 at 16.0 cM). Evidence of linkage for coronary calcified plaque (LOD: 2.27 at 19 cM) and a vascular calcification principle component (LOD: 3.71 at 16.0 cM) was also observed. The strongest evidence for association with CarCP was observed with SNPs in the A2BP1 gene region (rs4337300 P= 0.005) with modest evidence of association with SNPs in CACNA1H (P= 0.010-0.033). Bayesian quantitative trait nucleotide (BQTN) analysis identified a SNP, rs1358489, with either a functional effect on CarCP or in linkage disequilibrium (LD) with a functional SNP. This study refined the 16p region contributing to vascular calcification. The causal variants remain to be identified, but results are consistent with a linkage peak that is due to multiple common variants, though rare variants cannot be excluded.
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Clinical efficacy and safety evaluation of tailoring iron chelation practice in thalassaemia patients from Asia-Pacific: a subanalysis of the EPIC study of deferasirox.
Int. J. Hematol.
PUBLISHED: 02-09-2011
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Although thalassaemia is highly prevalent in the Asia-Pacific region, clinical data on efficacy and safety profiles of deferasirox in patients from this region are rather limited. Recently, data from the multicentre Evaluation of Patients Iron Chelation with Exjade (EPIC) study in 1744 patients with different anaemias has provided an opportunity to analyse 1115 thalassaemia patients, of whom 444 patients were from five countries in the Asia-Pacific region (AP) for whom thalassaemia management and choice of iron chelators were similar. Compared to the rest of the world (ROW), baseline clinical data showed that the AP group appeared to be more loaded with iron (3745.0 vs. 2822.0 ng/ml) and had a higher proportion on deferoxamine monotherapy prior to the study (82.9 vs. 58.9%). Using a starting deferasirox dose based on transfusional iron intake and tailoring it to individual patient response, clinical efficacy based on serum ferritin reduction in AP and ROW thalassaemia patients was similar. Interestingly, the AP group developed a higher incidence of drug-related skin rash compared to ROW (18.0 vs. 7.2%), which may indicate different pharmacogenetic backgrounds in the two populations. Our analysis confirms that, with appropriate adjustment of dose, deferasirox can be clinically effective across different regions, with manageable side effects.
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Differential effects of MYH9 and APOL1 risk variants on FRMD3 Association with Diabetic ESRD in African Americans.
PLoS Genet.
PUBLISHED: 02-04-2011
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Single nucleotide polymorphisms (SNPs) in MYH9 and APOL1 on chromosome 22 (c22) are powerfully associated with non-diabetic end-stage renal disease (ESRD) in African Americans (AAs). Many AAs diagnosed with type 2 diabetic nephropathy (T2DN) have non-diabetic kidney disease, potentially masking detection of DN genes. Therefore, genome-wide association analyses were performed using the Affymetrix SNP Array 6.0 in 966 AA with T2DN and 1,032 non-diabetic, non-nephropathy (NDNN) controls, with and without adjustment for c22 nephropathy risk variants. No associations were seen between FRMD3 SNPs and T2DN before adjusting for c22 variants. However, logistic regression analysis revealed seven FRMD3 SNPs significantly interacting with MYH9-a finding replicated in 640 additional AA T2DN cases and 683 NDNN controls. Contrasting all 1,592 T2DN cases with all 1,671 NDNN controls, FRMD3 SNPs appeared to interact with the MYH9 E1 haplotype (e.g., rs942280 interaction p-value?=?9.3E?? additive; odds ratio [OR] 0.67). FRMD3 alleles were associated with increased risk of T2DN only in subjects lacking two MYH9 E1 risk haplotypes (rs942280 OR?=?1.28), not in MYH9 E1 risk allele homozygotes (rs942280 OR?=?0.80; homogeneity p-value?=?4.3E??). Effects were weaker stratifying on APOL1. FRMD3 SNPS were associated with T2DN, not type 2 diabetes per se, comparing AAs with T2DN to those with diabetes lacking nephropathy. T2DN-associated FRMD3 SNPs were detectable in AAs only after accounting for MYH9, with differential effects for APOL1. These analyses reveal a role for FRMD3 in AA T2DN susceptibility and accounting for c22 nephropathy risk variants can assist in detecting DN susceptibility genes.
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Association of PNPLA3 with non-alcoholic fatty liver disease in a minority cohort: the Insulin Resistance Atherosclerosis Family Study.
Liver Int.
PUBLISHED: 01-13-2011
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Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition, particularly among Hispanic Americans. A genetic variant in PNPLA3 (rs738409) has been identified as a strong predictor of hepatic fat content.
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RGS6 variants are associated with dietary fat intake in Hispanics: the IRAS Family Study.
Obesity (Silver Spring)
PUBLISHED: 01-13-2011
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Recently, a genome-wide association scan was completed in the IRAS (Insulin Resistance Atherosclerosis Study) Family Study (IRASFS) Hispanic-American cohort. Multiple single-nucleotide polymorphisms (SNPs) in the G-protein signaling 6 (RGS6) gene were found to be associated with adiposity phenotypes. RGS6 has shown downstream antagonistic interplay with opioid receptors, targets of fatty/sugary food agonists. The possibility that RGS6 promotes tolerance and tachyphylaxis among the opioid receptor is a plausible pathway for overconsuming fat/sugar-laden food. Therefore, we hypothesized that RGS6 variants are associated with intake of fatty/sugary foods. In 932 Hispanics from San Antonio and San Luis Valley, CO, the following dietary intake variables were assessed using the Block Brief 2000 food frequency questionnaire: total calories, total fat, % calories from fat, % calories from saturated fat, protein, % calories from protein, carbohydrates, % calories from carbohydrates, and daily frequency of servings of fats/oils/sweets. We tested for association between 23 SNPs in RGS6 and dietary intake using a variance components measured genotype approach. All models were adjusted for gender, recruitment site, admixture, BMI, and age. Using an additive genetic model, rs1402064 was associated with higher intake of fats/oils/sweets, total calories, total fat and saturated fat (P = 0.0007, 0.026, 0.023, and 0.024). SNPs rs847330 and rs847354 were associated with higher intake of fats/oils/sweets (P = 0.002 and 0.018), total fat (P = 0.040 and 0.048) and saturated fat (P = 0.044 and 0.041). Finally, rs769148 was associated with higher intake of fats/oils/sweets (P = 0.002). RGS6 is a new candidate gene for adiposity traits that may be associated with a behavioral tendency toward fat-laden food intake.
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Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans: the NHLBI CARe Project.
PLoS Genet.
PUBLISHED: 01-07-2011
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Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia.
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Genomewide linkage scan for diabetic renal failure and albuminuria: the FIND study.
Am. J. Nephrol.
PUBLISHED: 01-04-2011
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Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals.
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A genome-wide association study for diabetic nephropathy genes in African Americans.
Kidney Int.
PUBLISHED: 12-08-2010
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A genome-wide association study was performed using the Affymetrix 6.0 chip to identify genes associated with diabetic nephropathy in African Americans. Association analysis was performed adjusting for admixture in 965 type 2 diabetic African American patients with end-stage renal disease (ESRD) and in 1029 African Americans without type 2 diabetes or kidney disease as controls. The top 724 single nucleotide polymorphisms (SNPs) with evidence of association to diabetic nephropathy were then genotyped in a replication sample of an additional 709 type 2 diabetes-ESRD patients and 690 controls. SNPs with evidence of association in both the original and replication studies were tested in additional African American cohorts consisting of 1246 patients with type 2 diabetes without kidney disease and 1216 with non-diabetic ESRD to differentiate candidate loci for type 2 diabetes-ESRD, type 2 diabetes, and/or all-cause ESRD. Twenty-five SNPs were significantly associated with type 2 diabetes-ESRD in the genome-wide association and initial replication. Although genome-wide significance with type 2 diabetes was not found for any of these 25 SNPs, several genes, including RPS12, LIMK2, and SFI1 are strong candidates for diabetic nephropathy. A combined analysis of all 2890 patients with ESRD showed significant association SNPs in LIMK2 and SFI1 suggesting that they also contribute to all-cause ESRD. Thus, our results suggest that multiple loci underlie susceptibility to kidney disease in African Americans with type 2 diabetes and some may also contribute to all-cause ESRD.
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Review of the Diabetes Heart Study (DHS) family of studies: a comprehensively examined sample for genetic and epidemiological studies of type 2 diabetes and its complications.
Rev Diabet Stud
PUBLISHED: 11-10-2010
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The Diabetes Heart Study (DHS) is a genetic and epidemiological study of 1,443 European American and African American participants from 564 families with multiple cases of type 2 diabetes. Initially, participants were comprehensively examined for measures of subclinical cardiovascular disease (CVD) including computed tomography measurement of vascular calcified plaque, ultrasound imaging of carotid artery wall thickness, and electrocardiographic intervals. Subsequent studies have investigated the relationship between bone mineral density and vascular calcification, measures of adiposity, and biomarkers. Ongoing studies are carrying out an extensive evaluation of cerebrovascular disease using magnetic resonance imaging and cognitive assessment. A second, parallel study, the African American DHS, has expanded the sample of African Americans to investigate marked racial differences in subclinical CVD between European Americans and African Americans. Studies in development will evaluate the impact of social stress during the lifecourse on CVD risk, and the prevalence of gastroparesis in this diabetes enriched sample. In addition, the ongoing high mortality rate in DHS participants provides novel insights into the increased risks for type 2 diabetes affected individuals. A comprehensive genetic analysis of the sample is underway using the genome-wide association study (GWAS) approach. Data from this GWAS survey will complement prior family-based linkage data in the analysis of genetic contributors to the wide range of traits in the sample. To our knowledge the DHS family of studies has created the most comprehensively examined sample of individuals with type 2 diabetes yet available, and represents a unique resource for the study people with type 2 diabetes. The aim of this review is to provide a collective overview of the major results from the DHS family of studies, and relate them to the larger body of biomedical investigations of diabetes and its complications.
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Resequencing and analysis of variation in the TCF7L2 gene in African Americans suggests that SNP rs7903146 is the causal diabetes susceptibility variant.
Diabetes
PUBLISHED: 10-27-2010
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Variation in the transcription factor 7-like 2 (TCF7L2) locus is associated with type 2 diabetes across multiple ethnicities. The aim of this study was to elucidate which variant in TCF7L2 confers diabetes susceptibility in African Americans.
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Rapid microwave-assisted chemical cleavage - mass spectrometric method for the identification of hemoglobin variants in blood.
Anal. Chem.
PUBLISHED: 10-11-2010
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A sensitive, rapid analytical method has been developed for the characterization of human hemoglobin disorders with very small volumes (<1 ?L) of blood. As an alternative to conventional enzymatic digestion, a site-specific chemical cleavage method has been established using 0.05% formic acid under microwave-irradiation conditions for short time intervals, for example, less than 10 min. Peptide analysis was performed by MALDI TOF MS and capillary liquid chromatographic ESI MS/MS. The cleavage of the hemoglobin chains with formic acid occurred at either side or at both sides (C- and N-terminal) of aspartic acid residues, but preferentially N-terminally. The method has been applied to blood samples from hemoglobin S carrier heterozygotes and hemoglobin S thalassaemia compound heterozygotes with a reduced expression level of hemoglobin S. Both MALDI TOF MS and ESI MS/MS analysis allowed the identification of the hemoglobin S "signature" peptide. This alternative method of sample preparation is compatible with MS techniques and is expected to significantly contribute to the further development of rapid, robust, reproducible and sensitive analytical methods in proteomics and biomedical diagnostics where protein variant characterization is a crucial factor for biomarker discovery and disease identification.
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Ethnic differences in the relationship between pericardial adipose tissue and coronary artery calcified plaque: African-American-diabetes heart study.
J. Clin. Endocrinol. Metab.
PUBLISHED: 09-01-2010
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Calcified atherosclerotic plaque (CP) is less prevalent and less severe in African-Americans (AA), relative to European Americans (EA). Because pericardial adipose tissue (PAT) is associated with CP in the neighboring coronary arteries, we explored ethnic-specific relationships between PAT and CP.
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The apolipoprotein L1 (APOL1) gene and nondiabetic nephropathy in African Americans.
J. Am. Soc. Nephrol.
PUBLISHED: 08-05-2010
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Mapping by admixture linkage disequilibrium (LD) detected strong association between nonmuscle myosin heavy chain 9 gene (MYH9) variants on chromosome 22 and nondiabetic nephropathy in African Americans. MYH9-related variants were posited to be the probable, but not necessarily the definitive, causal variants as a result of impressive statistical evidence of association, renal expression, and a role in autosomal dominant MYH9 disorders characterized by progressive glomerulosclerosis (Epstein and Fechtner syndromes). Dense mapping within MYH9 revealed striking LD patterns and racial variation in risk allele frequencies, suggesting population genetic factors such as selection may be operative in this region. Genovese and colleagues examined large chromosomal regions adjacent to MYH9 using genome-wide association methods and non-HapMap single nucleotide polymorphisms identified in Yoruba from the 1000 Genomes project. Statistically stronger associations were detected between two independent sequence variants in the Apolipoprotein L1 gene (APOL1) and nondiabetic nephropathy in African Americans, with odds ratios of 10.5 in idiopathic FSGS and 7.3 in hypertension-attributed ESRD. These kidney disease risk variants likely rose to high frequency in Africa because they confer resistance to trypanosomal infection and protect from African sleeping sickness. Risk variants in MYH9 and APOL1 are in strong LD, and the genetic risk that was previously attributed to MYH9 may reside, in part or in whole, in APOL1, although more complex models of risk cannot be excluded. This association likely explains racial disparities in nondiabetic nephropathy as a result of the high prevalence of risk alleles in individuals of African ancestry.
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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.