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Find video protocols related to scientific articles indexed in Pubmed.
Central blood pressure relates more strongly to retinal arteriolar narrowing than brachial blood pressure: the Nagahama Study.
J. Hypertens.
PUBLISHED: 11-08-2014
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Although central blood pressure (BP) is considered to be more closely associated with large arterial remodeling and cardiovascular outcomes than brachial BP, few studies have investigated these associations with changes in small arteries. As morphological changes in retinal vessels might be associated with cardiovascular outcomes, we conducted a cross-sectional study to investigate the association of central BP with retinal vessel caliber.
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Comprehensive replication of the relationship between myopia-related genes and refractive errors in a large Japanese cohort.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 10-23-2014
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We investigated the association between refractive error in a Japanese population and myopia-related genes identified in two recent large-scale genome-wide association studies.
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Association of serum-free Fatty Acid level with reduced reflection pressure wave magnitude and central blood pressure: the nagahama study.
Hypertension
PUBLISHED: 09-08-2014
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Central blood pressure (BP) has been suggested to be a better predictor of cardiovascular disease risk than brachial BP. Given that central BP and arterial waveform are both influenced by insulin resistance, major initiators of insulin resistance, such as serum-free fatty acid (FFA), are suspected of potentially being involved in central hemodynamics. To confirm that insulin signaling is an important modulator of central hemodynamics, we investigated this hypothesis in a large-scale general population. Brachial BP and radial arterial waveform were measured simultaneously in 9393 middle-aged to elderly individuals. The augmentation index was calculated from the radial waveform as the ratio of the height of the late systolic peak to that of the first peak. Central systolic BP was defined as the absolute pressure of the late systolic peak of the waveform. Differences in central and brachial pulse pressure (PP) were considered to represent PP amplification. PP amplification differed significantly among serum FFA level quartiles (Q1, 7.8±5.3; Q2, 8.6±5.0; Q3, 9.3±5.7; Q4, 10.3±6.1 mm Hg; P<0.001), and the maximum difference in combination with diabetes mellitus status was 4.9 mm Hg. Multivariate analysis adjusted for major covariates indicated that higher serum FFA was an independent determinant for higher PP amplification (?=0.145, P<0.001) and lower augmentation index (?=-0.122, P<0.001) and central systolic BP (?=-0.044, P<0.001), whereas the association between FFA and PP amplification significantly decreased (?=0.022, P<0.001) after further adjustment for augmentation index. Serum FFA is an overlooked factor favorably influencing central hemodynamics. A low-magnitude reflection pressure wave might be involved in this paradoxical relationship.
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An association between anti-nuclear antibody and HLA class II locus and heterogeneous characteristics of staining patterns: The Nagahama Study.
PUBLISHED: 09-03-2014
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Objectives: While anti-nuclear antibody (ANA) is observed in healthy populations as well as in patients with autoimmune diseases such as systemic lupus erythematosus (SLE), detailed genetic background of ANA has remained unclear. The identification of the genetic determinants of ANA in the general population would elucidate the underlying mechanisms of ANA production, and distinguish disease susceptibility genes from ANA production genes. Methods: 9,575 Japanese volunteers were registered and the levels of ANA were quantified with indirect immunofluorescence to analyze correlates. Genetic studies were carried out using 7,148 out of the 9,575 subjects. A genome-wide association study using 3,185 subjects genotyped for 303,506 SNPs, followed by a replication study of 3,963 people was performed. HLA-DRB1 and DQB1 alleles were imputed and associations between ANA positivity and the SNPs or HLA alleles associated with SLE were analyzed. Results: Female and aging were associated with ANA positivity, except for the nucleolar pattern. The T allele of rs2395185 in the HLA locus, in moderate linkage disequilibrium with HLA-DRB1*04:05, was significantly associated with ANA positivity (p=1.3x10(-11) ). The T allele displayed increasing effects on speckled and homogeneous patterns (p?2.2x10(-11) ), but decreasing effects on nucleolar pattern (p=0.0045). The seven SNPs and four HLA-DRB1 alleles associated with SLE did not display significant associations with ANA positivity. Conclusions: rs2395185 linked with HLA-DRB1*04:05 is a genetic determinant of ANA production in the Japanese population. Overlapping of susceptibility loci between SLE and ANA positivity was limited. Nucleolar pattern showed different associations with correlates and the HLA locus from other staining patterns. © 2014 American College of Rheumatology.
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Thermopower of benzenedithiol and C60 molecular junctions with Ni and Au electrodes.
Nano Lett.
PUBLISHED: 08-22-2014
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We have performed thermoelectric measurements of benzenedithiol (BDT) and C60 molecules with Ni and Au electrodes using a home-built scanning tunneling microscope. The thermopower of C60 was negative for both Ni and Au electrodes, indicating the transport of carriers through the lowest unoccupied molecular orbital in both cases, as was expected from the work functions. On the other hand, the Ni-BDT-Ni junctions exhibited a negative thermopower, whereas the Au-BDT-Au junctions exhibited a positive thermopower. First-principle calculations revealed that the negative thermopower of Ni-BDT-Ni junctions is due to the spin-split hybridized states generated by the highest occupied molecular orbital of BDT coupled with s- and d-states of the Ni electrode.
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A genome-wide association study of serum levels of prostate-specific antigen in the Japanese population.
J. Med. Genet.
PUBLISHED: 06-11-2014
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Prostate-specific antigen (PSA) is a useful marker for prostate cancer (PCa) and is widely used for screening of PCa. Previous studies have shown that genetic components influence the levels of PSA, and some of these genetic components would lead to better diagnostic sensitivity and specificity to PCa. However, genetic studies for PSA from Asian countries are limited. Our aim was to identify genetic components influencing PSA levels in the Japanese population using genome-wide association study (GWAS) and to analyse whether genetic components would lead to better screening abilities of PCa.
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Three-dimensional optical coherence tomography evaluation of vascular changes at arteriovenous crossings.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 03-01-2014
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To study the three-dimensional morphologic features of retinal arteriovenous crossings with optical coherence tomography (OCT) and elucidate the vascular changes associated with crossing phenomena as seen on fundus photographs.
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The effects of smoking and shared epitope on the production of ACPA and RF in a Japanese adult population: The Nagahama Study.
Arthritis Care Res (Hoboken)
PUBLISHED: 02-08-2014
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Objective: Anti-citrullinated peptide antibody (ACPA) and rheumatoid factor (RF) are markers to rheumatoid arthritis (RA). Smoking and shared epitope (SE) in HLA-DRB1 are associated with the production of these autoantibodies in RA. Detailed distribution and characterization of ACPA and RF in the general population has remained unclear. We aimed to evaluate positivity of ACPA and RF in a general Japanese population and to detect correlates including genetic components. Methods: ACPA and RF were quantified in 9,804 Japanese volunteers aged from 30 to 75. Logistic regression analyses were performed to evaluate the effects of candidates of correlates on the autoantibody positivity. Genome-wide association study (GWAS) was performed using 394,239 SNPs for 3,170 participants, and HLA-DRB1 alleles were imputed based on the GWAS data. Results: 1.7% and 6.4% of subjects were positive for ACPA and RF, respectively, and the two showed a significant correlation (p=2.0x10(-23) ). Old age was associated with ACPA positivity (p=0.00062). Sex, smoking, SE, and other candidates of correlates did not have significant effects. Interaction between smoking and SE positivity was not apparent, but smoking showed a significant association with high levels of ACPA (p=0.0019). Conclusions: ACPA and RF could be detected in 1.7% and 6.4% of the Japanese adult population without RA, respectively. ACPA and RF were suggested to share mechanisms even in healthy populations. Old age was associated with increasing ACPA positivity. While positivity of ACPA and RF was not associated with SE and smoking, an association between high ACPA and smoking was observed. © 2014 American College of Rheumatology.
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Identification of citrullinated cellular fibronectin in synovial fluid from patients with rheumatoid arthritis.
Mod Rheumatol
PUBLISHED: 02-05-2014
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Cellular fibronectin (cFn) has been implicated in the pathogenesis of rheumatoid arthritis (RA), and we previously demonstrated the presence of citrullinated cFn in rheumatoid synovial tissues. The present study aimed to investigate whether citrullinated cFn can be detected in the plasma or synovial fluid of RA patients.
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Airflow limitation in smokers is associated with arterial stiffness: the Nagahama Study.
Atherosclerosis
PUBLISHED: 01-10-2014
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Pathophysiological mechanisms of associations between airflow limitation (AL) and arterial stiffness remain unclear. One factor that might affect both AL and arterial stiffness is habitual smoking. The aim of this study is to investigate a possible interaction of smoking on the association between AL and arterial stiffness.
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Genetics of rheumatoid arthritis contributes to biology and drug discovery.
Yukinori Okada, Di Wu, Gosia Trynka, Towfique Raj, Chikashi Terao, Katsunori Ikari, Yuta Kochi, Koichiro Ohmura, Akari Suzuki, Shinji Yoshida, Robert R Graham, Arun Manoharan, Ward Ortmann, Tushar Bhangale, Joshua C Denny, Robert J Carroll, Anne E Eyler, Jeffrey D Greenberg, Joel M Kremer, Dimitrios A Pappas, Lei Jiang, Jian Yin, Lingying Ye, Ding-Feng Su, Jian Yang, Gang Xie, Ed Keystone, Harm-Jan Westra, Tonu Esko, Andres Metspalu, Xuezhong Zhou, Namrata Gupta, Daniel Mirel, Eli A Stahl, Dorothée Diogo, Jing Cui, Katherine Liao, Michael H Guo, Keiko Myouzen, Takahisa Kawaguchi, Marieke J H Coenen, Piet L C M van Riel, Mart A F J van de Laar, Henk-Jan Guchelaar, Tom W J Huizinga, Philippe Dieudé, Xavier Mariette, S Louis Bridges, Alexandra Zhernakova, René E M Toes, Paul P Tak, Corinne Miceli-Richard, So-Young Bang, Hye-Soon Lee, Javier Martín, Miguel A González-Gay, Luis Rodriguez-Rodriguez, Solbritt Rantapää-Dahlqvist, Lisbeth Arlestig, Hyon K Choi, Yoichiro Kamatani, Pilar Galán, Mark Lathrop, , Steve Eyre, John Bowes, Anne Barton, Niek de Vries, Larry W Moreland, Lindsey A Criswell, Elizabeth W Karlson, Atsuo Taniguchi, Ryo Yamada, Michiaki Kubo, Jun S Liu, Sang-Cheol Bae, Jane Worthington, Leonid Padyukov, Lars Klareskog, Peter K Gregersen, Soumya Raychaudhuri, Barbara E Stranger, Philip L De Jager, Lude Franke, Peter M Visscher, Matthew A Brown, Hisashi Yamanaka, Tsuneyo Mimori, Atsushi Takahashi, Huji Xu, Timothy W Behrens, Katherine A Siminovitch, Shigeki Momohara, Fumihiko Matsuda, Kazuhiko Yamamoto, Robert M Plenge.
Nature
PUBLISHED: 01-07-2014
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A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ?10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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Large-scale East-Asian eQTL mapping reveals novel candidate genes for LD mapping and the genomic landscape of transcriptional effects of sequence variants.
PLoS ONE
PUBLISHED: 01-01-2014
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Profiles of sequence variants that influence gene transcription are very important for understanding mechanisms that affect phenotypic variation and disease susceptibility. Using genotypes at 1.4 million SNPs and a comprehensive transcriptional profile of 15,454 coding genes and 6,113 lincRNA genes obtained from peripheral blood cells of 298 Japanese individuals, we mapped expression quantitative trait loci (eQTLs). We identified 3,804 cis-eQTLs (within 500 kb from target genes) and 165 trans-eQTLs (>500 kb away or on different chromosomes). Cis-eQTLs were often located in transcribed or adjacent regions of genes; among these regions, 5' untranslated regions and 5' flanking regions had the largest effects. Epigenetic evidence for regulatory potential accumulated in public databases explained the magnitude of the effects of our eQTLs. Cis-eQTLs were often located near the respective target genes, if not within genes. Large effect sizes were observed with eQTLs near target genes, and effect sizes were obviously attenuated as the eQTL distance from the gene increased. Using a very stringent significance threshold, we identified 165 large-effect trans-eQTLs. We used our eQTL map to assess 8,069 disease-associated SNPs identified in 1,436 genome-wide association studies (GWAS). We identified genes that might be truly causative, but GWAS might have failed to identify for 148 out of the GWAS-identified SNPs; for example, TUFM (P?=?3.3E-48) was identified for inflammatory bowel disease (early onset); ZFP90 (P?=?4.4E-34) for ulcerative colitis; and IDUA (P?=?2.2E-11) for Parkinson's disease. We identified four genes (P<2.0E-14) that might be related to three diseases and two hematological traits; each expression is regulated by trans-eQTLs on a different chromosome than the gene.
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Twisted gastrulation, a BMP antagonist, exacerbates podocyte injury.
PLoS ONE
PUBLISHED: 01-01-2014
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Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7) in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1), a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs) and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury.
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An Integrative Study of the Genetic, Social and Environmental Determinants of Chronic Kidney Disease Characterized by Tubulointerstitial Damages in the North Central Region of Sri Lanka.
J Occup Health
PUBLISHED: 12-18-2013
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Objectives: Previous investigations on chronic kidney disease of unknown etiology characterized by tubulointerstitial damages (CKDu) in the North Central Region (NCR) of Sri Lanka have supported the involvement of social, environmental and genetic factors in its pathogenesis. Methods: We conducted a social-environmental-and-genetic epidemiology study on a male population in NCR to investigate the genetic and environmental contributors. We recruited 311 case-series patients and 504 control candidates. Of the 504 control candidates, 218 (43%) were eliminated because of the presence of hypertension, proteinuria, high HBA1c, high serum creatinine or high alpha-1 microglobulin in urine. Results and Discussion: None of 18 metals measured (µg/l) in urine, including Cd, As and Pb, showed significantly higher concentrations in cases compared with controls. As speciation results showed that 75-80% of total urinary As was in the form of arsenobetaine, which is non-toxic to humans. None of the metal concentrations in drinking water samples exceeded guideline values. A genome-wide association study (GWAS) was conducted to determine the genetic contributors. The GWAS yielded a genome-wide significant association with CKDu for a single nucleotide polymorphism (SNP; rs6066043; P=5.23×10(-9) in quantitative trait locus analysis; P=3.73×10(-8) in dichotomous analysis) in SLC13A3 (sodium-dependent dicarboxylate transporter member 3). The population attributable fraction and odds ratio for this SNP were 50% and 2.13. Genetic susceptibility was identified as the major risk factor for CKDu. However, 43% of the apparently healthy male population suffers from non-communicable diseases, suggesting their possible influence on CKDu progression.
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Association between ZIC2, RASGRF1, and SHISA6 genes and high myopia in Japanese subjects.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 10-24-2013
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We investigated the association of genetic variations, which were identified recently in a large-scale genome-wide association study (GWAS) to confer risk of refractive error and common myopia in Caucasians, with high myopia in Japanese subjects.
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Association between the cholesteryl ester transfer protein gene and polypoidal choroidal vasculopathy.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 08-17-2013
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To determine whether genetic variants in the lipid-associated genes are related to the risk of developing polypoidal choroidal vasculopathy (PCV) in a Japanese population.
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Vascular Endothelial Growth Factor Gene and the Response to Anti-Vascular Endothelial Growth Factor Treatment for Choroidal Neovascularization in High Myopia.
Ophthalmology
PUBLISHED: 06-20-2013
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To investigate the association between the vascular endothelial growth factor (VEGF) gene polymorphism and the response to anti-VEGF treatment for choroidal neovascularization (CNV) in highly myopic eyes.
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Genome-wide association study of the genetic factors related to confectionery intake: Potential roles of the ADIPOQ gene.
Obesity (Silver Spring)
PUBLISHED: 05-29-2013
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Objective: The excessive consumption of confectionery might have adverse effects on human health. To screen genetic factors associated with confectionery-intake frequency, a genome-wide association study (GWAS) in Japan was conducted. Design and Methods: For the discovery phase (stage 1), we conducted a GWAS of 939 noncancer patients in a cancer hospital. Additive models were used to test associations between genotypes of approximately 500,000 single-nucleotide polymorphisms (SNPs) and the confectionery-intake score (based on intake frequency). We followed-up association signals with P < 1 × 10(-5) and minor allele frequency >0.01 in stage 1 by genotyping the SNPs of 4,491 participants in a cross-sectional study within a cohort (replication phase [stage 2]). Results: We identified 12 SNPs in stage 1 that were potentially related to confectionery intake. In stage 2, this association was replicated for one SNP (rs822396; P = 0.049 for stage 2 and 4.2 × 10(-5) for stage 1+2) in intron 1 of the ADIPOQ gene, which encodes the adipokine adiponectin. Conclusions: Given the biological plausibility and previous relevant findings, the association of an SNP in the ADIPOQ gene with a preference for confectionery is worthy of follow-up and provides a good working hypothesis for experimental testing.
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Association of longer QT interval with arterial waveform and lower pulse pressure amplification: the Nagahama Study.
Am. J. Hypertens.
PUBLISHED: 04-18-2013
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Central systolic blood pressure (cSBP) has been postulated to correlate closely with cardiovascular risk. Identifying factors associated with cSBP is therefore important. Prolonged QT interval is known to be associated with cardiovascular outcomes and might also be associated with the arterial waveform and cSBP. We investigated the possible associations between electrocardiogram wave interval and cSBP in general population samples.
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PLD4 as a novel susceptibility gene for systemic sclerosis in a Japanese population.
Arthritis Rheum.
PUBLISHED: 04-12-2013
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Systemic sclerosis (SSc) is an autoimmune disease for which multiple susceptibility genes have been reported. Genome-wide association studies have shown that large numbers of susceptibility genes are shared among autoimmune diseases. Recently, our group identified 9 novel susceptibility genes associated with rheumatoid arthritis (RA) in a Japanese population. The aim of this study was to elucidate whether the 18 genes that displayed associations or suggestive associations for RA in our previous study are associated with SSc in Japanese.
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Two susceptibility loci to Takayasu arteritis reveal a synergistic role of the IL12B and HLA-B regions in a Japanese population.
Am. J. Hum. Genet.
PUBLISHED: 03-23-2013
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Takayasu arteritis (TAK) is an autoimmune systemic vasculitis of unknown etiology. Although previous studies have revealed that HLA-B*52:01 has an effect on TAK susceptibility, no other genetic determinants have been established so far. Here, we performed genome scanning of 167 TAK cases and 663 healthy controls via Illumina Infinium Human Exome BeadChip arrays, followed by a replication study consisting of 212 TAK cases and 1,322 controls. As a result, we found that the IL12B region on chromosome 5 (rs6871626, overall p = 1.7 × 10(-13), OR = 1.75, 95% CI 1.42-2.16) and the MLX region on chromosome 17 (rs665268, overall p = 5.2 × 10(-7), OR = 1.50, 95% CI 1.28-1.76) as well as the HLA-B region (rs9263739, a proxy of HLA-B*52:01, overall p = 2.8 × 10(-21), OR = 2.44, 95% CI 2.03-2.93) exhibited significant associations. A significant synergistic effect of rs6871626 and rs9263739 was found with a relative excess risk of 3.45, attributable proportion of 0.58, and synergy index of 3.24 (p ? 0.00028) in addition to a suggestive synergistic effect between rs665268 and rs926379 (p ? 0.027). We also found that rs6871626 showed a significant association with clinical manifestations of TAK, including increased risk and severity of aortic regurgitation, a representative severe complication of TAK. Detection of these susceptibility loci will provide new insights to the basic mechanisms of TAK pathogenesis. Our findings indicate that IL12B plays a fundamental role on the pathophysiology of TAK in combination with HLA-B(?)52:01 and that common autoimmune mechanisms underlie the pathology of TAK and other autoimmune disorders such as psoriasis and inflammatory bowel diseases in which IL12B is involved as a genetic predisposing factor.
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Increased aortic wave reflection and smaller pulse pressure amplification in smokers and passive smokers confirmed by urinary cotinine levels: the Nagahama Study.
Int. J. Cardiol.
PUBLISHED: 03-17-2013
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Central blood pressure (cSBP) is suggested to be a better predictor of cardiovascular risk than brachial BP. Although brachial BP levels among smokers have been reported to be the same or somewhat lower than those in nonsmokers, it is suggested that smoking might have a substantial impact on cSBP.
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Common and distinct clinical features in adult patients with anti-aminoacyl-tRNA synthetase antibodies: heterogeneity within the syndrome.
PLoS ONE
PUBLISHED: 02-27-2013
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To identify similarities and differences in the clinical features of adult Japanese patients with individual anti-aminoacyl-tRNA synthetase antibodies (anti-ARS Abs).
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Application of permanents of square matrices for DNA identification in multiple-fatality cases.
BMC Genet.
PUBLISHED: 02-15-2013
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DNA profiling is essential for individual identification. In forensic medicine, the likelihood ratio (LR) is commonly used to identify individuals. The LR is calculated by comparing two hypotheses for the sample DNA: that the sample DNA is identical or related to a reference DNA, and that it is randomly sampled from a population. For multiple-fatality cases, however, identification should be considered as an assignment problem, and a particular sample and reference pair should therefore be compared with other possibilities conditional on the entire dataset.
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Three groups in the 28 joints for rheumatoid arthritis synovitis--analysis using more than 17,000 assessments in the KURAMA database.
PLoS ONE
PUBLISHED: 02-12-2013
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Rheumatoid arthritis (RA) is a joint-destructive autoimmune disease. Three composite indices evaluating the same 28 joints are commonly used for the evaluation of RA activity. However, the relationship between, and the frequency of, the joint involvements are still not fully understood. Here, we obtained and analyzed 17,311 assessments for 28 joints in 1,314 patients with RA from 2005 to 2011 from electronic clinical chart templates stored in the KURAMA (Kyoto University Rheumatoid Arthritis Management Alliance) database. Affected rates for swelling and tenderness were assessed for each of the 28 joints and compared between two different sets of RA patients. Correlations of joint symptoms were analyzed for swellings and tenderness using kappa coefficient and eigen vectors by principal component analysis. As a result, we found that joint affected rates greatly varied from joint to joint both for tenderness and swelling for the two sets. Right wrist joint is the most affected joint of the 28 joints. Tenderness and swellings are well correlated in the same joints except for the shoulder joints. Patients with RA tended to demonstrate right-dominant joint involvement and joint destruction. We also found that RA synovitis could be classified into three categories of joints in the correlation analyses: large joints with wrist joints, PIP joints, and MCP joints. Clustering analysis based on distribution of synovitis revealed that patients with RA could be classified into six subgroups. We confirmed the symmetric joint involvement in RA. Our results suggested that RA synovitis can be classified into subgroups and that several different mechanisms may underlie the pathophysiology in RA synovitis.
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An association analysis of HLA-DRB1 with systemic lupus erythematosus and rheumatoid arthritis in a Japanese population: effects of *09:01 allele on disease phenotypes.
Rheumatology (Oxford)
PUBLISHED: 02-12-2013
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Objective. To re-evaluate the roles of HLA-DRB1 alleles in susceptibility to SLE and RA and their effects on autoantibody status in large-scale Japanese cohorts. Methods. A total of 656 SLE, 2410 RA and 911 control subjects, who were all Japanese, were genotyped for HLA-DRB1 alleles using sequence-specific oligonucleotide probes. The association of alleles with disease susceptibility was tested by logistic regression analysis and by the relative predispositional effect method. The association with autoantibody status was examined by the standard ?(2) test. Results. HLA-DRB1*15:01, *09:01, *08:02 and *04:01 were significantly associated with SLE susceptibility, while shared epitope (SE) alleles and DRB1*09:01 were associated with RA susceptibility. The compound heterozygote of DRB1*09:01/*15:01 conferred an increased risk for SLE compared with the homozygotes for DRB1*09:01 and *15:01 and was associated with earlier onset of disease, whereas the compound effect of DRB1-SE/*09:01 was not clear in RA. DRB1*09:01 was significantly associated with the appearance of anti-Sm antibody in SLE as well as ACPA in RA, while protectively associated with anti-dsDNA antibody in SLE. No significant interaction was observed between DRB1*09:01 and smoking status for the appearance of ACPA, unlike that observed in SE alleles in RA. Conclusion. We identified HLA-DRB1 alleles associated with SLE and RA in a Japanese population and demonstrated a shared susceptibility of DRB1*09:01 between the diseases as well as its effect on autoantibody production.
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Interferon regulatory factor 5 polymorphisms in sarcoidosis.
Mod Rheumatol
PUBLISHED: 01-04-2013
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Interferon regulatory factor 5 (IRF5) gene polymorphisms are associated with susceptibility to autoimmune diseases. The aim of this study is to determine the roles of IRF5 single-nucleotide polymorphisms (SNPs) in sarcoidosis.
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Insulin-like growth factor 1 is not associated with high myopia in a large Japanese cohort.
Mol. Vis.
PUBLISHED: 01-01-2013
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To investigate whether genetic variations in the insulin-like growth factor 1 (IGF-1) gene are associated with high myopia in Japanese.
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Population model-based inter-diplotype similarity measure for accurate diplotype clustering.
J. Comput. Biol.
PUBLISHED: 12-09-2011
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Classification of the individuals genotype data is important in various kinds of biomedical research. There are many sophisticated clustering algorithms, but most of them require some appropriate similarity measure between objects to be clustered. Hence, accurate inter-diplotype similarity measures are always required for classification of diplotypes. In this article, we propose a new accurate inter-diplotype similarity measure that we call the population model-based distance (PMD), so that we can cluster individuals with diplotype SNPs data (i.e., unphased-diplotypes) with higher accuracies. For unphased-diplotypes, the allele sharing distance (ASD) has been the standard to measure the genetic distance between the diplotypes of individuals. To achieve higher clustering accuracies, our new measure PMD makes good use of a given appropriate population model which has never been utilized in the ASD. As the population model, we propose to use an hidden Markov model (HMM)-based model. We call the PMD based on the model the HHD (HIT HMM-based Distance). We demonstrate the impact of the HHD on the diplotype classification through comprehensive large-scale experiments over the genome-wide 8930 data sets derived from the HapMap SNPs database. The experiments revealed that the HHD enables significantly more accurate clustering than the ASD.
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Spatiotemporal measurement of tumor oxygenation reveals repeat hypoxic phenomenon in mice.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 08-29-2011
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Tumor hypoxia is considered a potential therapeutic problem because it reduces the effects of radiation therapy. Clinical experience has shown that long-term tumor oxygenation cannot be achieved with oxygen inhalation, but the mechanisms behind this phenomenon remain unknown. In this study, we designed an optical system for evaluating spatiotemporal changes in tissue oxygen tension (pO(2)) by phosphorescence quenching. The system can measure continuous changes in pO(2) at a fixed point and can also perform two-dimensional mapping of pO(2) in any part of the tumor tissue. We implanted tumor tissue in a dorsal skinfold chamber of C57BL/6 mice and observed tumor growth. After the tumor attained a diameter of 2 mm, the mice received oxygen inhalation and pO(2) was measured. Tumor pO(2) increased after inhalation but the oxygen level was not maintained despite continuous inhalation of pure oxygen; the tumor returned to a hypoxic state. These results mimic the clinical experience of oxygen inhalation treatment in radiation therapy. Our system reproduces the repeat hypoxic phenomenon in a murine tumor model and can be used to determine the mechanisms of oxygen metabolism in tumors.
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A large-scale association study identified multiple HLA-DRB1 alleles associated with ACPA-negative rheumatoid arthritis in Japanese subjects.
Ann. Rheum. Dis.
PUBLISHED: 08-27-2011
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HLA-DRB1 is associated with rheumatoid arthritis (RA). However, it has recently been suggested that HLA-DRB1 is only associated with patients with RA who have anticitrullinated peptide/protein antibodies (ACPA), which are specific to RA.
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A polymorphism of the POLG2 gene is genetically associated with the invasiveness of urinary bladder cancer in Japanese males.
J. Hum. Genet.
PUBLISHED: 07-07-2011
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Urinary bladder cancer (UBC) is a common cancer with male predominance. Pathologically it is classified into two distinct tumor entities related to the risk of patients. The low-grade tumors with relatively well-differentiated tumor histology (G1 and G2) at stage Ta are non-invasive and pose a minimal risk, whereas high-grade tumors (G2 and G3) with stages T1 to T4 are aggressive with invasion, and therefore, pose a serious risk for the patients. DNA repair and metabolic process genes may have major roles in cancer progression and development. To identify genes associated with invasiveness of UBC, we have extensively genotyped 802 single nucleotide polymorphisms in 114 genes related to DNA repair mechanisms and metabolic processes. A genetic association study was performed between non-invasive (G1 and G2 with Ta) and invasive (G2 and G3 with T1 to T4) groups of Japanese UBC patients. We found that rs17650301 in POLG2 showed marked difference in genotype distribution between the two groups in males (P=6.93 × 10(-4)), which was further confirmed in an independent sample set (overall P=1.67 × 10(-4)). We also found by an in silico analysis that the risk allele of rs17650301 increased the transcription of POLG2. In conclusion, rs17650301 is a good candidate marker for UBC invasiveness in Japanese males.
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The FOXE1 and NKX2-1 loci are associated with susceptibility to papillary thyroid carcinoma in the Japanese population.
J. Med. Genet.
PUBLISHED: 07-05-2011
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FOXE1 and NKX2-1 are two known genetic risk factors for the predisposition to sporadic papillary thyroid carcinoma (PTC) in Europeans, but their association in other ethnicities is still unknown.
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The human AIRE gene at chromosome 21q22 is a genetic determinant for the predisposition to rheumatoid arthritis in Japanese population.
Hum. Mol. Genet.
PUBLISHED: 04-19-2011
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Rheumatoid arthritis (RA) is a typical complex trait and the major cause of chronic inflammation worldwide. Although multiple genetic loci have been shown for their association with the onset of RA, they cover only a part of its genetic components and are largely ethnicity-specific. To identify novel genetic factors related to the predisposition and prognosis of RA in Japanese, we conducted a large-scale genome-wide association (GWA) study. We performed a GWA analysis by scanning the genome of 1247 RA cases and 1486 controls for 277 420 single nucleotide polymorphisms (SNPs), followed by replication analysis using two independent sample sets consisting of 1865 cases and 1623 controls, and 2303 cases and 3380 controls. We identified two SNPs, rs2075876 and rs760426, in intron of the autoimmune regulator AIRE gene at chromosome 21q22 that showed strong associations with the disease (P= 3.6 × 10(-9) and P= 4.4 × 10(-8), respectively). Rs1800250, in exon7 of AIRE, was in strong linkage disequilibrium (r(2)= 0.94) with rs2075876 and introduced an amino acid alteration (S278R) in the SAND domain of the AIRE protein. In silico analysis showed the decreased transcription of AIRE by the risk allele of rs2075876 compared with the alternative allele (P= 6.8 × 10(-5)). No correlation was observed between the rs2075876 genotype and quantitative traits reflecting the progression of RA. As AIRE is a key molecule which regulates the expression and presentation of self-antigens in thymic negative selection, its downregulation by genetic polymorphisms may result in the survival of auto-reactive T cells to trigger auto-inflammation in RA.
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catena-Poly[[[tetra-kis-(cyanido-?C)tungstate(IV)]-di-?-cyanido-?C:N-bis-[diaqua-(2,2-bipyridyl-?N,N)manganese(II)]-di-?-cyanido-?N:C] hexa-hydrate].
Acta Crystallogr Sect E Struct Rep Online
PUBLISHED: 03-26-2011
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The polymeric title compound, {[Mn(II) (2)W(IV)(CN)(8)(C(10)H(8)N(2))(2)(H(2)O)(4)]·6H(2)O}(n), has a one-dimensional cyanide-bridged Mn(II)-W(IV) bimetallic assembly. The coordination geometry of the W(IV) atom is eight-coordinate square-anti-prismatic and that of each of the Mn(II) atoms is six-coordinate distorted octa-hedral. Two pairs of CN ligands of W(CN)(8) are bridged to two Mn(II) atoms, the remaining CN ligands being terminal. Each Mn(II) atom is additionally coordinated by a bidentate 2,2-bipyridyl ligand and two water mol-ecules. The crystal structure is stabilized by O-H?O and O-H?N hydrogen bonds.
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Genetic variants in pigment epithelium-derived factor influence response of polypoidal choroidal vasculopathy to photodynamic therapy.
Ophthalmology
PUBLISHED: 03-24-2011
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To investigate whether photodynamic therapy (PDT) outcomes of polypoidal choroidal vasculopathy (PCV) are related to baseline clinical characteristics, smoking history, or genetic factors by analyzing the retreatment-free period after the first PDT.
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Association between the SERPING1 gene and age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese.
PLoS ONE
PUBLISHED: 03-17-2011
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Recently, a complement component 1 inhibitor (SERPING1) gene polymorphism was identified as a novel risk factor for age-related macular degeneration (AMD) in Caucasians. We aimed to investigate whether variations in SERPING1 are associated with typical AMD or with polypoidal choroidal vasculopathy (PCV) in a Japanese population.
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Myelin basic protein as a novel genetic risk factor in rheumatoid arthritis--a genome-wide study combined with immunological analyses.
PLoS ONE
PUBLISHED: 03-10-2011
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Rheumatoid arthritis (RA) is a major cause of adult chronic inflammatory arthritis and a typical complex trait. Although several genetic determinants have been identified, they account for only a part of the genetic susceptibility. We conducted a genome-wide association study of RA in Japanese using 225,079 SNPs genotyped in 990 cases and 1,236 controls from two independent collections (658 cases and 934 controls in collection1; 332 cases and 302 controls in collection2), followed by replication studies in two additional collections (874 cases and 855 controls in collection3; 1,264 cases and 948 controls in collection4). SNPs showing p<0.005 in the first two collections and p<10(-4) by meta-analysis were further genotyped in the latter two collections. A novel risk variant, rs2000811, in intron2 of the myelin basic protein (MBP) at chromosome 18q23 showed strong association with RA (p?=?2.7×10(-8), OR 1.23, 95% CI: 1.14-1.32). The transcription of MBP was significantly elevated with the risk allele compared to the alternative allele (p<0.001). We also established by immunohistochemistry that MBP was expressed in the synovial lining layer of RA patients, the main target of inflammation in the disease. Circulating autoantibody against MBP derived from human brain was quantified by ELISA between patients with RA, other connective tissue diseases and healthy controls. As a result, the titer of anti-MBP antibody was markedly higher in plasma of RA patients compared to healthy controls (p<0.001) and patients with other connective tissue disorders (p<0.001). ELISA experiment using citrullinated recombinant MBP revealed that a large fraction of anti-MBP antibody in RA patients recognized citrullinated MBP. This is the first report of a genetic study in RA implicating MBP as a potential autoantigen and its involvement in pathogenesis of the disease.
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A trans-ethnic genetic study of rheumatoid arthritis identified FCGR2A as a candidate common risk factor in Japanese and European populations.
Mod Rheumatol
PUBLISHED: 02-28-2011
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Rheumatoid arthritis (RA) is a common systemic autoimmune disease and its onset and prognosis are controlled by genetic, immunological, and environmental factors. The HLA locus, particularly HLA-DRB1, is its strongest genetic risk determinant across ethnicities. Several other genes, including PTPN22 and PADI4, show modest association with RA. However, they cover only a part of its genetic components and their relative contribution is different between populations. To identify novel genetic determinants, we took a candidate gene approach in a trans-ethnic manner. After critical selection of 169 genes based on their immunological function, we performed SNP discovery of these genes by the resequencing of exons and surrounding areas using European and Japanese DNAs. We then generated a panel of 1,509 SNPs for case-control association study in both populations. The DerSimonian-Laird test for meta-analysis, using the combined results of the two populations, identified rs7551957 at the 5-flanking region of the low-affinity Fc-gamma receptor IIa (FCGR2A) gene as the strongest candidate for the association (p = 8.6 × 10(-5), odds ratio = 1.58 with 95%CI 1.25-1.99). Suggestive signals were also obtained for three SNPs in the dihydropyrimidine dehydrogenase (DPYD) gene (rs6685859; p = 1.3 × 10(-4), rs7550959; p = 1.5 × 10(-4) and rs7531138; p = 1.7 × 10(-4)) and an intronic SNP, rs2269310, of the erythrocytic spectrin beta (SPTB) gene (p = 7.9 × 10(-4)).
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Association of elastin gene polymorphism to age-related macular degeneration and polypoidal choroidal vasculopathy.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 01-01-2011
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To see if there is an association in Japanese between elastin gene (ELN) polymorphisms and neovascular age-related macular degeneration (AMD) or its subtypes, typical AMD (tAMD) and polypoidal choroidal vasculopathy (PCV).
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Association of 15q14 and 15q25 with high myopia in Japanese.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 01-01-2011
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To investigate whether there are associations of genetic variations in chromosome 15q14 and 15q25, recently shown to confer risk of refractive error and myopia in Caucasians, with high myopia in Japanese.
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PADI4 polymorphism predisposes male smokers to rheumatoid arthritis.
Ann. Rheum. Dis.
PUBLISHED: 11-09-2010
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To elucidate the differential role of peptidyl arginine deiminase 4 (PADI4) polymorphism in rheumatoid arthritis (RA) between Asian and European populations, possible gene-environmental interactions among the PADI4 polymorphism, sex and smoking status were analysed.
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POSH promotes cell survival in Drosophila and in human RASF cells.
FEBS Lett.
PUBLISHED: 10-04-2010
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In Drosophila, Eiger, a tumor necrosis factor ? (TNF?) superfamily ligand, induces cell death by activating the c-Jun N-terminal kinase (JNK) pathway. Here, we report that overexpression of Plenty of SH3s (POSH) suppresses Eiger-induced cell death and produces highly deformed tissues. These results imply that high levels of POSH protect tissues from cell death. In humans, rheumatoid arthritis synovial fibroblasts (RASF) are generally resistant to apoptosis. We show that POSH is expressed at relatively high levels in RASF, and its reduction by RNAi sensitizes these cells to Fas-mediated apoptosis. Thus, we demonstrate that POSH promotes cell survival in Drosophila and in human RASF.
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Development of an autonomously replicating linear vector of the yeast Cryptococcus humicola by using telomere-like sequence repeats.
Appl. Microbiol. Biotechnol.
PUBLISHED: 10-03-2010
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The yeast Cryptococcus humicola has several attractive properties for practical applications such as in bioremediation and as a source of industrially useful enzymes and compounds. We have developed an autonomously replicating vector of C. humicola to improve its properties. We initially tried to isolate an autonomously replicating sequence (ARS) from genomic DNA by transformation using a genomic DNA library. We obtained a candidate plasmid vector harboring an ARS that gave high transformation efficiency. Southern blot analysis of transformants revealed the autonomous replication of the introduced vector in some transformants. However, the vector was not only variously altered in length but also linearized. PCR analysis indicated that a telomere-like sequence repeat (TTAGGGGG)( n ) was added to the termini of linearized vector. Thus, we constructed an autonomously replicating linear vector having ten repeats of the telomere-like sequence at both ends. The vector transformed the yeast cells with high transformation efficiency (3230 CFU/?g of DNA), which was approximately 25-fold higher than that of a control vector lacking the repeats, and was autonomously replicated at a roughly constant size. The copy number was estimated to be less than one copy, and Ura(+) mitotic stability varied widely among the transformants and was related to plasmid segregation efficiency.
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Anti-citrullinated peptide antibody-negative RA is a genetically distinct subset: a definitive study using only bone-erosive ACPA-negative rheumatoid arthritis.
Rheumatology (Oxford)
PUBLISHED: 09-09-2010
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ACPA is a highly specific marker for RA. It was recently reported that ACPA can be used to classify RA into two disease subsets, ACPA-positive and ACPA-negative RA. ACPA-positive RA was found to be associated with the HLA-DR shared epitope (SE), but ACPA negative was not. However, the suspicion remained that this result was caused by the ACPA-negative RA subset containing patients with non-RA diseases. We examined whether this is the case even when possible non-RA ACPA-negative RA patients were excluded by selecting only patients with bone erosion.
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Estimation of P-value of MAX test with double triangle diagram for 2 x 3 SNP case-control tables.
Genet. Epidemiol.
PUBLISHED: 09-07-2010
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Single nucle otide polymorphisms (SNPs) are the most popular markers in genetic epidemiology. Multiple tests have been applied to evaluate genetic effect of SNPs, such as Pearsons test with two degrees of freedom, three tests with one degree of freedom (chi(2) tests for dominant and recessive modes and Cockran-Armitage trend test for additive mode) as well as MAX3 test and MAX test, which are combination of four tests mentioned earlier. Because MAX test is a combination of Pearsons test of two degrees of freedom and two tests of one degree of freedom, the probability density function (pdf) of MAX statistics does not match pdf of chi(2) distribution of either one or two degrees of freedom. In order to calculate P-value of MAX test, we introduced a new diagram, Double Triangle Diagram, which was an extension of de Finetti diagram in population genetics which characterized all of the tests for 2 x 3 tables. In the diagram the contour lines of MAX statistics were consisted of elliptic curves and two tangent lines to the ellipses in the space. We normalized the ellipses into regular circles and expressed P-value of MAX test in an integral form. Although a part of the integral was not analytically solvable, it was calculable with arbitrary accuracy by dividing the area under pdf into finite rectangles. We confirmed that P-values from our method took uniform distribution from 0 to 1 in three example marginal count sets and concluded that our method was appropriate to give P-value of MAX test for 2 x 3 tables.
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Joint effect of cigarette smoking and CFH and LOC387715/HTRA1 polymorphisms on polypoidal choroidal vasculopathy.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 08-04-2010
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To investigate whether the major genetic and environmental risk factors of age-related macular degeneration (AMD)-CFH Y402H and LOC387715 A69S and cigarette smoking-are also associated with polypoidal choroidal vasculopathy (PCV) and whether the associations of CFH Y402H and LOC387715 A69S with PCV are modified by smoking.
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CFH and ARMS2 variations in age-related macular degeneration, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 06-23-2010
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To seek an association in Japanese individuals between the CFH polymorphisms Y402H and I62V and the ARMS2 polymorphism A69S and age-related macular degeneration (AMD) or its three subtypes: typical (t)AMD, polypoidal choroidal vasculopathy (PCV), and retinal angiomatous proliferation (RAP).
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Isolation and identification of persistent chlorinated organophosphorus flame retardant-degrading bacteria.
Appl. Environ. Microbiol.
PUBLISHED: 06-04-2010
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Tris(2-chloroethyl) and tris(1,3-dichloro-2-propyl) phosphates are chlorinated persistent flame retardants that have recently emerged as environmental pollutants. Two bacterial strains that can degrade the compounds when they are the sole phosphorus sources have been isolated and identified as members of the sphingomonads. The strains can be useful for the bioremediation of environments contaminated with these compounds.
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Single-nucleotide polymorphisms in the promoter region of matrix metalloproteinase-1, -2, and -3 in Japanese with high myopia.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 04-30-2010
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Polymorphisms in the promoter regions of matrix metalloproteinase (MMP) genes can cause variations in the expression of the MMP genes in the sclera that can lead to a greater susceptibility to axial elongation of the eye. The purpose of this study was to determine whether functional single-nucleotide polymorphisms (SNPs) in the MMP1, -2, and -3 promoter regions are associated with high myopia in the Japanese.
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The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl.
Hum. Mol. Genet.
PUBLISHED: 03-29-2010
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Papillary thyroid cancer (PTC) among individuals exposed to radioactive iodine in their childhood or adolescence is a major internationally recognized health consequence of the Chernobyl accident. To identify genetic determinants affecting individual susceptibility to radiation-related PTC, we conducted a genome-wide association study employing Belarusian patients with PTC aged 0-18 years at the time of accident and age-matched Belarusian control subjects. Two series of genome scans were performed using independent sample sets, and association with radiation-related PTC was evaluated. Meta-analysis by the Mantel-Haenszel method combining the two studies identified four SNPs at chromosome 9q22.33 showing significant associations with the disease (Mantel-Haenszel P: mhp = 1.7 x 10(-9) to 4.9 x 10(-9)). The association was further reinforced by a validation analysis using one of these SNP markers, rs965513, with a new set of samples (overall mhp = 4.8 x 10(-12), OR = 1.65, 95% CI: 1.43-1.91). Rs965513 is located 57-kb upstream to FOXE1, a thyroid-specific transcription factor with pivotal roles in thyroid morphogenesis and was recently reported as the strongest genetic risk marker of sporadic PTC in European populations. Of interest, no association was obtained between radiation-related PTC and rs944289 (mhp = 0.17) at 14p13.3 which showed the second strongest association with sporadic PTC in Europeans. These results show that the complex pathway underlying the pathogenesis may be partly shared by the two etiological forms of PTC, but their genetic components do not completely overlap each other, suggesting the presence of other unknown etiology-specific genetic determinants in radiation-related PTC.
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Ethnogenetic heterogeneity of rheumatoid arthritis-implications for pathogenesis.
Nat Rev Rheumatol
PUBLISHED: 03-16-2010
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Autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus are generally considered multifactorial-that is, they involve both genetic and environmental factors. Technical advances in human genetics over the past 5 years have enabled the survey of the entire human genome for disease susceptibility genes and have contributed to a greater understanding of the molecular mechanisms underlying autoimmunity. Among the genetic predisposition factors identified to date, some variants have been found to be restricted to specific ethnic groups, which might reflect migration history and the natural selection that shaped genetic variation in these populations. Other genetic factors could also have exerted different magnitudes of risk for the disease among the different populations, which might be explained by their interactions with other genetic and environmental factors. These pieces of evidence suggest that substantial heterogeneity exists in the genetics underlying autoimmunity among different ethnic populations. This Review discusses the genetic heterogeneity in autoimmunity, with a focus on rheumatoid arthritis, between Asian and European populations. In addition to the most-studied and well-characterized gene HLA-DRB1, we will also describe examples of the gene-environment interactions between PADI4 and smoking, and the gene-gene interactions between PTPN22 and FCRL3.
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Regulatory polymorphisms in EGR2 are associated with susceptibility to systemic lupus erythematosus.
Hum. Mol. Genet.
PUBLISHED: 03-01-2010
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Systemic lupus erythematosus (SLE) is an autoimmune disease induced by the combinations of environmental and genetic factors. Recently, mice in which the early growth response 2 (EGR2) gene, a zinc-finger transcription factor, is conditionally knocked out in CD2(+) T cells have been shown to develop a lupus-like autoimmune disease. Here, we evaluated if polymorphisms in the EGR2 gene influence SLE susceptibility in humans. We first analyzed the effect of SNPs in the EGR2 region on EGR2 expression, and a significant positive correlation with expression was identified in an SNP located at the 5 flanking region of EGR2 (rs10761670, R=0.23, P=0.00072). We then performed a case-control association study using three sets of SLE cohorts by genotyping 14 tag SNPs in the EGR2 gene region. A peak of association with SLE susceptibility was observed for rs10761670 [Pooled: OR = 1.23 (95% CI 1.10-1.37), P=0.00023). This SNP was also associated with susceptibility to rheumatoid arthritis (RA) [OR = 1.15 (95% CI 1.05-1.26), P = 0.0019), suggesting that EGR2 is a common risk factor for SLE and RA. Among the SNPs in complete linkage disequilibrium with rs10761670 (r(2) = 1.0), two SNPs (rs1412554 and rs1509957) affected the binding of transcription factors and transcriptional activity in vitro, suggesting that they may be candidates of causal regulatory variants in this region. Therefore, EGR2 is a genetic risk factor for SLE, in which increased gene expression may contribute to SLE pathogenesis.
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The association of a nonsynonymous single-nucleotide polymorphism in TNFAIP3 with systemic lupus erythematosus and rheumatoid arthritis in the Japanese population.
Arthritis Rheum.
PUBLISHED: 01-30-2010
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Genome-wide association (GWA) studies in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Caucasian populations have independently identified risk variants in and near the tumor necrosis factor alpha (TNFalpha)-induced protein 3 gene (TNFAIP3), which is crucial for the regulation of TNF-mediated signaling and Toll-like receptor signaling. The aim of this study was to assess the role of TNFAIP3 in the development of SLE and RA in Japanese subjects.
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A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility.
Nat. Genet.
PUBLISHED: 01-19-2010
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Rheumatoid arthritis is a common autoimmune disease with a complex genetic etiology. Here, through a genome-wide association study of rheumatoid arthritis, we identified a polymorphism in CCR6, the gene encoding chemokine (C-C motif) receptor 6 (a surface marker for Th17 cells) at 6q27, that was associated with rheumatoid arthritis susceptibility and was validated in two independent replication cohorts from Japan (rs3093024, a total of 7,069 individuals with rheumatoid arthritis (cases) and 20,727 controls, overall odds ratio = 1.19, P = 7.7 x 10(-19)). We identified a triallelic dinucleotide polymorphism of CCR6 (CCR6DNP) in strong linkage disequilibrium with rs3093024 that showed effects on gene transcription. The CCR6DNP genotype was correlated with the expression level of CCR6 and was associated with the presence of interleukin-17 (IL-17) in the sera of subjects with rheumatoid arthritis. Moreover, CCR6DNP was associated with susceptibility to Graves and Crohns diseases. These results suggest that CCR6 is critically involved in IL-17-driven autoimmunity in human diseases.
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Contribution of a haplotype in the HLA region to anti-cyclic citrullinated peptide antibody positivity in rheumatoid arthritis, independently of HLA-DRB1.
Arthritis Rheum.
PUBLISHED: 12-02-2009
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To examine the risk of anti-cyclic citrullinated peptide (anti-CCP) antibody positivity in rheumatoid arthritis (RA) patients carrying certain haplotypes in the HLA region.
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FCRL3, an autoimmune susceptibility gene, has inhibitory potential on B-cell receptor-mediated signaling.
J. Immunol.
PUBLISHED: 10-22-2009
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A polymorphism that up-regulates the expression of Fc receptor-like 3 (FCRL3) gene has recently been described as predisposing for several human autoimmune diseases. FCRL3 is preferentially expressed on B cells and is unique in displaying both an ITAM and an ITIM in the cytosolic domain, suggesting signaling functions. Herein, we show that FCRL3 potentially inhibits BCR-mediated signaling, using murine FcgammaRIIB/human FCRL3 chimeric protein. Coligation of the chimeric protein with BCR leads to phosphorylation of tyrosine residues in the cytosolic domain. This coligation inhibits cell tyrosine phosphorylation and calcium mobilization in addition to activation-induced cell death mediated by BCR signaling. Mutational analysis showed the tyrosine residues in two potential ITIMs at 662 and 692 offer the main contributions to this inhibition, which is further supported by strong associations of SH-2 domain-containing phosphatases with the following phosphotyrosine motifs: SHIP with the ITIM-like motif at 662; and SHP-1 and -2 with the canonical ITIM at 692. These results, together with previous genetic data, suggest that augmented inhibition of BCR-mediated signaling by FCRL3 with the disease-risk genotype alter the activation threshold and promote tolerance breakdown in B cells.
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Diaroyl tellurides: synthesis, structure and NBO analysis of (2-MeOC6H4CO)2Te--comparison with its sulfur and selenium isologues. The first observation of [MgBr][R(C=Te)O] salts.
Molecules
PUBLISHED: 06-03-2009
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A series of aromatic diacyl tellurides were prepared in moderate to good yields by the reactions of sodium orpotassium arenecarbotelluroates with acyl chlorides in acetonitrile. X-ray structure analyses and theoretical calculations of 2-methoxybenzoic anhydride and bis(2-methoxybenzoyl) sulfide, selenide and telluride were carried out. The two 2-MeOC(6)H(4)CO moieties of bis(2-methoxybenzoyl) telluride are nearly planar and the two methoxy oxygen atoms intramolecularly coordinate to the central tellurium atom from both side of C(11)-Te(11)-C(22) plane. In contrast, the oxygen and sulfur isologues (2-MeOC(6)H(4)CO)(2)E (E = O, S), show that one of the two methoxy oxygen atoms contacts with the oxygen atom of the carbonyl group connected to the same benzene ring. The structure of di(2-methoxybenzoyl) selenide which was obtained by MO calculation resembles that of tellurium isologues rather than the corresponding oxygen and sulfur isologues. The reactions of di(aroyl) tellurides with Grignard reagents lead to the formation of tellurocarboxylato magnesium complexes [MgBr][R(C=Te)O].
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A genome-wide association analysis identified a novel susceptible locus for pathological myopia at 11q24.1.
PLoS Genet.
PUBLISHED: 05-26-2009
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Myopia is one of the most common ocular disorders worldwide. Pathological myopia, also called high myopia, comprises 1% to 5% of the general population and is one of the leading causes of legal blindness in developed countries. To identify genetic determinants associated with pathological myopia in Japanese, we conducted a genome-wide association study, analyzing 411,777 SNPs with 830 cases and 1,911 general population controls in a two-stage design (297 cases and 934 controls in the first stage and 533 cases and 977 controls in the second stage). We selected 22 SNPs that showed P-values smaller than 10(-4) in the first stage and tested them for association in the second stage. The meta-analysis combining the first and second stages identified an SNP, rs577948, at chromosome 11q24.1, which was associated with the disease (P = 2.22x10(-7) and OR of 1.37 with 95% confidence interval: 1.21-1.54). Two genes, BLID and LOC399959, were identified within a 200-kb DNA encompassing rs577948. RT-PCR analysis demonstrated that both genes were expressed in human retinal tissue. Our results strongly suggest that the region at 11q24.1 is a novel susceptibility locus for pathological myopia in Japanese.
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An optimal dose-effect mode trend test for SNP genotype tables.
Genet. Epidemiol.
PUBLISHED: 04-03-2009
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The genome-wide association studies have improved our understanding of the genetic basis of many complex traits. Two-by-three contingency tables are tested in these studies. The trend test for the additive mode is most often used, which is the test of 1 degree of freedom (df=1) and other tests, such as the genotype test (chi(2) (df=2)) and the chi(2) (df=1) tests for the dominant and recessive modes are also used to increase the power for markers in the non-additive modes. However, any one of them or combination of them is not perfect. We describe the relations among the chi(2) (df=2) test and chi(2) (df=1) tests for the dominant and recessive modes and the trend test for the additive mode and propose a new statistic based on their relations that tests the hypothesis that the disease-susceptible allele has a dose-effect somewhere between the recessive and dominant modes, which corresponds to the optimal dose-effect for the observed data.
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ARMS2 (LOC387715) variants in Japanese patients with exudative age-related macular degeneration and polypoidal choroidal vasculopathy.
Am. J. Ophthalmol.
PUBLISHED: 03-09-2009
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To determine the characteristics of the polymorphisms in the ARMS2 gene in Japanese patients with age-related macular degeneration (AMD) and those with polypoidal choroidal vasculopathy (PCV) and in healthy controls, and also to show possible associations of the polymorphisms with the disease.
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Absence of association between COL1A1 polymorphisms and high myopia in the Japanese population.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 02-07-2009
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The collagen type I alpha 1 (COL1A1) gene was recently reported to be associated with high myopia in the Japanese population. To validate this positive association, the tag single-nucleotide polymorphism (tSNP) approach was used.
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Cloning and expression of carp acetylcholinesterase gene in Pichia pastoris and characterization of the recombinant enzyme.
Protein Expr. Purif.
PUBLISHED: 01-06-2009
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The gene encoding acetylcholinesterase (AChE) was cloned from common carp muscle tissue. The full-length cDNA was 2368 bp that contains a coding region of 1902 bp, corresponding to a protein of 634 amino acids. The deduced amino acid sequence showed a significant homology with those of ichthyic AChEs and several common features among them, including T peptide encoded by exon T in the C-terminus. Three yeast expression vectors were constructed and introduced into the yeast Pichia pastoris. The transformant harboring carp AChE gene lacking exon T most effectively produced AChE activity extracellularly. The replacement of the native signal sequence with the yeast alpha-factor prepro signal sequence rather decreased the production. A decrease in cultivation temperature from 30 to 15 degrees C increased the activity production 32.8-fold. The purified recombinant AChE lacking T peptide, eluted as a single peak with a molecular mass of about 230 kDa on the gel filtration chromatography, exhibited the specific activity of 4970 U/mg. On the SDS-PAGE, three proteins with molecular masses of 73, 54, and 22 kDa were observed. These proteins were N-glycosylated, and their N-terminal sequence showed that the latter two were produced from the former probably by proteolytic cleavage at the C-terminal region. Thus, the recombinant AChE is homotrimer of three identical subunits with 73 kDa. The optimal temperature and pH of the recombinant were comparable to those of the native enzyme purified previously, but the values of kinetic parameters and the sensitivities to substrate inhibition and inhibitors were considerably different between them.
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Genetics of rheumatoid arthritis: underlying evidence of ethnic differences.
J. Autoimmun.
PUBLISHED: 01-03-2009
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A new age has begun in the genetics of rheumatoid arthritis (RA), as genome-wide association studies scanning the human genome have been put into practical use. Among the RA-susceptibility genes identified by genetic studies, HLA-DRB1 gene appears to represent the most major determinant of genetic predisposition to RA. However, inconsistent results of the contributions of non-HLA susceptibility genes have been described, with the exception of a few genes repeatedly associated with RA-susceptibility, such as PTPN22 gene in populations of European ancestry and PADI4 gene in populations of Asian ancestry, revealing the presence of genetic heterogeneity in RA. We review herein recent advances in the genetics of RA and discuss the underlying differences among populations of European and Asian ancestries, taking as examples our previous findings for RA-susceptibility genes in the Japanese population: PADI4; FCRL3; and CD244.
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Patients-to-healthcare workers HIV transmission risk from sharp injuries, Southern Ethiopia.
SAHARA J
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Accidental needlestick injury rate among healthcare workers in Hawassa is extremely high. Epidemiological findings proved the infectious potential of this injury contaminated with a Human Immunodeficiency Virus (HIV)-infected patients blood.
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Association of paired box 6 with high myopia in Japanese.
Mol. Vis.
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The objective of this study was to investigate whether genetic variations in the paired box 6 (PAX6) gene are associated with high myopia in Japanese subjects.
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Peritoneal fibrosis and high transport are induced in mildly pre-injured peritoneum by 3,4-dideoxyglucosone-3-ene in mice.
Perit Dial Int
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Peritoneal dialysis (PD) solution contains high concentrations of glucose and glucose degradation products (GDPs). One of several GDPs--3,4-dideoxyglucosone-3-ene (3,4-DGE)--was recently identified as the most reactive and toxic GDP in PD fluids. In vitro, 3,4-DGE has been shown to induce mesothelial cell damage; however, its role in peritoneal fibrosis in vivo remains unclear. In the present study, we intraperitoneally administered chlorhexidine gluconate (CG) for mild peritoneal injury, and we then injected 3,4-DGE [38 ?mol/L (low concentration) or 145 ?mol/L (high concentration)] 5 times weekly for 4 weeks. Significant thickening of the parietal peritoneal membrane was observed only when treatment with low or high concentrations of 3,4-DGE occurred after CG administration, but not when either CG or 3,4-DGE alone was given. The combination of CG and 3,4-DGE also caused upregulation of messenger RNA expression of transforming growth factor ?1, connective tissue growth factor, fibronectin, collagen type 1 ?1 chain, alpha smooth muscle actin (?-SMA), vascular endothelial growth factor 164, NADPH oxidase 1 and 4, p22phox, p47phox, and gp91phox in peritoneal tissue. Treatment with CG alone was sufficient to cause significant F4/80-positive macrophage infiltration, appearance of ?-SMA-positive cells, and vessel formation in the submesothelial layer. Addition of 3,4-DGE markedly enhanced those changes and induced apoptosis, mainly in leukocytes. The concentration of 3,4-DGE in the abdominal cavity declined more rapidly in CG-treated mice than in PBS-treated mice. Peritoneal membrane permeability determined by peritoneal equilibration test showed high transport conditions in peritoneum treated with both CG and 3,4-DGE. These results indicate that, when mild peritoneal damage is already present, 3,4-DGE causes peritoneal thickening and fibrosis, resulting in deterioration of peritoneal membrane function.
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[Genomic approach to pathophysiology of rheumatoid arthritis].
Clin Calcium
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Genetic studies identified multiple genes and polymorphisms that increase risk to develop rheumatoid arthritis. Genomic approach is characterized with its integrative style using mathematical and statistical models. Its main targets include (1)combinatorial effect of multiple genetic and environmental factors, (2)heterogeneity of pathological states and its individuality, and (3)their chronological heterogeneity. Genomic approach will clarify pathophysiology of various diseases along with the progresses in molecular biology and other researches on individual molecules.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

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.