Errors, introduced through poor assessment of physical measurement or because of inconsistent or inappropriate standard operating procedures for collecting, processing, storing or analysing haematological and biochemistry analytes, have a negative impact on the power of association studies using the collected data. A dataset from UK Biobank was used to evaluate the impact of pre-analytical variability on the power of association studies.
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality and, whilst smoking remains the single most important risk factor, COPD risk is heritable. Of 26 independent genomic regions showing association with lung function in genome-wide association studies, eleven have been reported to show association with airflow obstruction. Although the main risk factor for COPD is smoking, some individuals are observed to have a high forced expired volume in 1 second (FEV1) despite many years of heavy smoking. We hypothesised that these "resistant smokers" may harbour variants which protect against lung function decline caused by smoking and provide insight into the genetic determinants of lung health. We undertook whole exome re-sequencing of 100 heavy smokers who had healthy lung function given their age, sex, height and smoking history and applied three complementary approaches to explore the genetic architecture of smoking resistance. Firstly, we identified novel functional variants in the "resistant smokers" and looked for enrichment of these novel variants within biological pathways. Secondly, we undertook association testing of all exonic variants individually with two independent control sets. Thirdly, we undertook gene-based association testing of all exonic variants. Our strongest signal of association with smoking resistance for a non-synonymous SNP was for rs10859974 (P = 2.34 × 10(-4)) in CCDC38, a gene which has previously been reported to show association with FEV1/FVC, and we demonstrate moderate expression of CCDC38 in bronchial epithelial cells. We identified an enrichment of novel putatively functional variants in genes related to cilia structure and function in resistant smokers. Ciliary function abnormalities are known to be associated with both smoking and reduced mucociliary clearance in patients with COPD. We suggest that genetic influences on the development or function of cilia in the bronchial epithelium may affect growth of cilia or the extent of damage caused by tobacco smoke.
We hypothesized that improved diaphragmatic neuromechanical coupling during inspiratory loading is not sufficient to prevent alveolar hypoventilation and task failure, and that the latter results primarily from central-output inhibition of the diaphragm and air hunger rather than contractile fatigue. Eighteen subjects underwent progressive inspiratory loading. By task failure all developed hypercapnia. Tidal transdiaphragmatic pressure (?Pdi) and diaphragmatic electrical activity (?EAdi) increased during loading - the former more than the latter; thus, neuromechanical coupling (?Pdi/?EAdi) increased during loading. Progressive increase in extra-diaphragmatic muscle contribution to tidal breathing, expiratory muscle recruitment, and decreased end-expiratory lung volume contributed to improved neuromechanical coupling. At task failure, subjects experienced intolerable breathing discomfort, at which point mean ?EAdi was 74.9±4.9% of maximum, indicating that the primary mechanism of hypercapnia was submaximal diaphragmatic recruitment. Contractile fatigue was an inconsistent finding. In conclusion, hypercapnia during acute loading primarily resulted from central-output inhibition of the diaphragm suggesting that acute loading responses are controlled by the cortex rather than bulbopontine centers.
Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.
Because the diaphragm is essential for survival, we wondered if it might be less vulnerable to the long-lasting effects of fatigue than limb muscles. Using a recently introduced magnetic probe to activate the phrenic nerves, we followed the evolution of twitch transdiaphragmatic pressure after inducing fatigue in healthy volunteers. Twenty-four hours after its induction, diaphragmatic fatigue had not fully recovered. Findings from this study later served as the foundation for incorporating a once-daily, T-tube-trial arm into a randomized controlled trial of techniques for ventilator weaning in intensive care unit patients and also influenced the design of a controlled trial of the weaning of tracheostomy patients who required prolonged ventilation. The research methodology was later employed to determine whether low-frequency fatigue is responsible for weaning failure. Employing a further modification of the technique--twitch airway pressure--it became evident that respiratory muscle weakness is a greater problem than fatigue in ventilated patients. Twitch airway pressure is now being used to document the prevalence and consequences of ventilator-induced respiratory muscle weakness. Our study--which began with a circumscribed, simple question--has yielded dividends in unforeseen directions, illustrating the fruitfulness of research into basic physiological mechanisms.
This report summarizes current physiological and technical knowledge on esophageal pressure (Pes) measurements in patients receiving mechanical ventilation. The respiratory changes in Pes are representative of changes in pleural pressure. The difference between airway pressure (Paw) and Pes is a valid estimate of transpulmonary pressure. Pes helps determine what fraction of Paw is applied to overcome lung and chest wall elastance. Pes is usually measured via a catheter with an air-filled thin-walled latex balloon inserted nasally or orally. To validate Pes measurement, a dynamic occlusion test measures the ratio of change in Pes to change in Paw during inspiratory efforts against a closed airway. A ratio close to unity indicates that the system provides a valid measurement. Provided transpulmonary pressure is the lung-distending pressure, and that chest wall elastance may vary among individuals, a physiologically based ventilator strategy should take the transpulmonary pressure into account. For monitoring purposes, clinicians rely mostly on Paw and flow waveforms. However, these measurements may mask profound patient-ventilator asynchrony and do not allow respiratory muscle effort assessment. Pes also permits the measurement of transmural vascular pressures during both passive and active breathing. Pes measurements have enhanced our understanding of the pathophysiology of acute lung injury, patient-ventilator interaction, and weaning failure. The use of Pes for positive end-expiratory pressure titration may help improve oxygenation and compliance. Pes measurements make it feasible to individualize the level of muscle effort during mechanical ventilation and weaning. The time is now right to apply the knowledge obtained with Pes to improve the management of critically ill and ventilator-dependent patients.
Chronic obstructive pulmonary disease (COPD) independently associates with an increased risk of coronary artery disease (CAD), but it has not been fully investigated whether this co-morbidity involves shared pathophysiological mechanisms. To identify potential common pathways across the two diseases, we tested all recently published single nucleotide polymorphisms (SNPs) associated with human lung function (spirometry) for association with carotid intima-media thickness (cIMT) in 3,378 subjects with multiple CAD risk factors, and for association with CAD in a case-control study of 5,775 CAD cases and 7,265 controls. SNPs rs2865531, located in the CFDP1 gene, and rs9978142, located in the KCNE2 gene, were significantly associated with CAD. In addition, SNP rs9978142 and SNP rs3995090 located in the HTR4 gene, were associated with average and maximal cIMT measures. Genetic risk scores combining the most robustly spirometry-associated SNPs from the literature were modestly associated with CAD, (odds ratio (OR) (95% confidence interval (CI95)?= 1.06 (1.03, 1.09); P-value = 1.5 × 10(-4), per allele). In conclusion, our study suggests that some genetic loci implicated in determining human lung function also influence cIMT and susceptibility to CAD. The present results should help elucidate the molecular underpinnings of the co-morbidity observed across COPD and CAD.
Lung function measures are heritable, predict mortality and are relevant in diagnosis of chronic obstructive pulmonary disease (COPD). COPD and asthma are diseases of the airways with major public health impacts and each have a heritable component. Genome-wide association studies of SNPs have revealed novel genetic associations with both diseases but only account for a small proportion of the heritability. Complex copy number variation may account for some of the missing heritability. A well-characterised genomic region of complex copy number variation contains beta-defensin genes (DEFB103, DEFB104 and DEFB4), which have a role in the innate immune response. Previous studies have implicated these and related genes as being associated with asthma or COPD. We hypothesised that copy number variation of these genes may play a role in lung function in the general population and in COPD and asthma risk. We undertook copy number typing of this locus in 1149 adult and 689 children using a paralogue ratio test and investigated association with COPD, asthma and lung function. Replication of findings was assessed in a larger independent sample of COPD cases and smoking controls. We found evidence for an association of beta-defensin copy number with COPD in the adult cohort (OR?=?1.4, 95%CI:1.02-1.92, P?=?0.039) but this finding, and findings from a previous study, were not replicated in a larger follow-up sample(OR?=?0.89, 95%CI:0.72-1.07, P?=?0.217). No robust evidence of association with asthma in children was observed. We found no evidence for association between beta-defensin copy number and lung function in the general populations. Our findings suggest that previous reports of association of beta-defensin copy number with COPD should be viewed with caution. Suboptimal measurement of copy number can lead to spurious associations. Further beta-defensin copy number measurement in larger sample sizes of COPD cases and children with asthma are needed.
Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes, and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57,412 individuals of European descent from 22 cohorts collaborating with the NHLBIs Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20 to 80. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ?50,000 cosmopolitan tagged SNPs across ?2,100 cardiovascular-related genes. Each trait was modeled as a function of age, study site, and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P<2.4x10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (?±SE,0.048±0.008, P=7.7x10(-9)) as was rs7302703-G in HOXC10 (?=0.044±0.008, P=2.9x10(-7)) and rs936108-C in PEMT (?=0.035±0.007, P=1.9x10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A near SHC1 (?=0.10±0.02, P=1.9x10(-6)), and rs1037575-A in ATBDB4 (?=0.046±0.01, P=2.2x10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.
Neurally adjusted ventilatory assist operates through recordings of electrical activity of the diaphragm (EAdi). Barwing and colleagues found increases in EAdi in weaning-failure patients, although the values were not significantly different from weaning-success patients. Future studies will need to carefully control for the considerable biological noise evident in EAdi recordings.
An emergent strain (ribotype 027) of Clostridium difficile infection (CDI) has been implicated in epidemics worldwide. Organizational factors such as bed occupancy have been associated with an increased incidence of CDI; however, the data are sparse, and the association has not been widely demonstrated. We investigated the association of bed occupancy and CDI within a large hospital organization in the United Kingdom.
Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of ? = -0.068 g/L per minor allele (P = 1.20*10(-12)). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1-5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.
Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD.We assessed the association of lung function with 2,100 genes selected for cardiovascular diseases among 20,077 European-Americans and 6,900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with percent emphysema, and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with FEV1/FVC and percent emphysema.We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10(-6)) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10(-7)). Both SNPs flank the gene for apolipoprotein M (apoM), a component of HDL. Both replicated in an independent cohort. SNPs in a second gene related to apoM and HDL, PCSK9, were associated with FEV1/FVC among African-Americans. rs707974 was associated with percent emphysema among European-Americans and African-Americans, and APOM expression was related to FEV1/FVC and percent emphysema. Higher HDL levels were associated with lower FEV1/FVC and greater percent emphysema.These findings suggest a novel role for the APOM/HDL pathway in the pathogenesis of COPD and emphysema.
The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.
Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.
Generation Scotland: Scottish Family Health Study (GS:SFHS) is a family-based biobank of 24,000 participants with rich phenotype and DNA available for genetic research. This paper describes the laboratory results from genotyping 32 single nucleotide polymorphisms (SNPs) on DNA from over 10,000 participants who attended GS:SFHS research clinics. The analysis described here was undertaken to test the quality of genetic information available to researchers. The success rate of each marker genotyped (call rate), minor allele frequency and adherence to Mendelian inheritance are presented. The few deviations in marker transmission in the 925 parent-child trios analysed were assessed as to whether they were likely to be miscalled genotypes, data or sample handling errors, or pedigree inaccuracies including non-paternity.
Patients requiring prolonged mechanical ventilation (>21 days) are commonly weaned at long-term acute care hospitals (LTACHs). The most effective method of weaning such patients has not been investigated.
Genome-Wide Association Study (GWAS) meta-analyses have identified a strong association signal for lung function, which maps to a region on 4q24 containing two oppositely transcribed genes: glutathione S-transferase, C-terminal domain containing (GSTCD) and integrator complex subunit 12 (INTS12). Both genes were found to be expressed in a range of human airway cell types. The promoter regions and transcription start sites were determined in mRNA from human lung and a novel splice variant was identified for each gene. We obtained the following evidence for GSTCD and INTS12 co-regulation and expression: (i) correlated mRNA expression was observed both via Q-PCR and in a lung expression quantitative trait loci (eQTL) study, (ii) induction of both GSTCD and INTS12 mRNA expression in human airway smooth muscle cells was seen in response to TGF?1, (iii) a lung eQTL study revealed that both GSTCD and INTS12 mRNA levels positively correlate with percent predicted FEV1, and (iv) FEV1 GWAS associated SNPs in 4q24 were found to act as an eQTL for INTS12 in a number of tissues. In fixed sections of human lung tissue, GSTCD protein expression was ubiquitous, whereas INTS12 expression was predominantly in epithelial cells and pneumocytes. During human fetal lung development, GSTCD protein expression was observed to be highest at the earlier pseudoglandular stage (10-12 weeks) compared with the later canalicular stage (17-19 weeks), whereas INTS12 expression levels did not alter throughout these stages. Knowledge of the transcriptional and translational regulation and expression of GSTCD and INTS12 provides important insights into the potential role of these genes in determining lung function. Future work is warranted to fully define the functions of INTS12 and GSTCD.
A repolarization abnormality manifested as T-wave alternans (TWA) in electrocardiogram (ECG) predicts cardiovascular mortality. A common variant in the NOS1AP gene is associated with mortality and QT interval duration, possibly in a gender-specific manner, but data is lacking on potential association with TWA. This study tested association between rs10494366 in NOS1AP and both TWA and 4-year mortality.
Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied.
Presence of left ventricular hypertrophy on an ECG (ECG-LVH) is widely assessed clinically and provides prognostic information in some settings. There is evidence for significant heritability of ECG-LVH. We conducted a large-scale gene-centric association analysis of 4 commonly measured indices of ECG-LVH.
Genome-wide association studies (GWAS) have provided new insights into the molecular mechanisms of lung function and lung diseases. GWAS, and studies that build upon their findings, will continue to provide evidence aimed at advancing understanding of lung disease. This paper summarises the key features of a GWAS, references some recent findings and discusses how the chest physician can interpret the validity and utility of future GWAS and related studies.
Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (?140?mm?Hg systolic blood pressure or? ?90?mm?Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
The prevalence of depression in chronic obstructive pulmonary disease (COPD) is greater than in the general population, but the mechanism is unknown. Depression has been linked mechanistically to testosterone deficiency, and testosterone deficiency (hypogonadism) affects many men with COPD. Accordingly, we hypothesized that significant depressive symptoms would be associated with hypogonadism in men with COPD. The hypothesis was tested in a prospective cross-sectional investigation of 104 men (FEV1 = 43 ± 1% predicted (± SE)), 36 of whom had significant depressive symptoms (Geriatric Depression Scale score or GDS ? 11). Hypogonadism was present in 14 patients with GDS ? 11 (39%) and in 21 with GDS < 11 (31%; p = 0.41). The independent association between depressive symptoms and gonadal state was evaluated after adjusting for potential confounders: combined severity of lung disease and functional impairment (BODE-index), co-morbidities (Charlson co-morbidity-Index), age, active smoking, education, and marital status. After controlling for confounding variables, multivariable logistic-regression analysis revealed that only BODE-index (odds ratio 1.40; p = 0.003), lack of companion (2.73; p = 0.045) and younger age (0.93; p = 0.021) were independently associated with depressive symptoms. In a secondary analysis, patients were stratified into those with severe depressive symptoms (GDS ? 19) and those with mild depressive symptoms (GDS 11-18). Prevalence of hypogonadism was greater in first group than in the second (62% vs. 26%; p = 0.036). After controlling for confounders, however, gonadal state was not associated with severe depressive symptoms. Similarly, gonadal state was not associated with mood and motivation subscale scores of the GDS. In conclusion, presence of significant depressive symptoms was not associated with hypogonadism in men with COPD.
Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
A simulated cricket batting innings was developed to replicate the physical demands of scoring a century during One-Day International cricket. The simulated innings requires running-between-the-wickets across six 5-over stages, each of 21 min duration. To validate whether the simulated batting innings is reflective of One-Day International batting, movement patterns were collected using a global positioning system (GPS) and compared with previous research. In addition, indicators of physical strain were recorded (heart rate, jump heights, sweat loss, tympanic temperature). Nine club cricketers (mean ± s: age 20 ± 3 years; body mass 79.5 ± 7.9 kg) performed the simulated innings outdoors. There was a moderate trend for distance covered in the simulated innings to be less than that during One-Day batting (2171 ± 157 vs. 2476 ± 631 m · h?¹; effect size = 0.78). This difference was largely explained by a strong trend for less distance covered walking in the simulated innings than in One-Day batting (1359 ± 157 vs. 1604 ± 438 m · h?¹; effect size = 1.61). However, there was a marked trend for distance covered both striding and sprinting to be greater in the simulated innings than in One-Day batting (effect size > 1.2). Practically, the simulated batting innings may be used for match-realistic physical training and as a research protocol to assess the demands of prolonged, high-intensity cricket batting.
Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
Recent genetic epidemiology studies have been dominated by genome-wide association (GWA) studies using single nucleotide polymorphisms (SNPs). However, a form of structural genomic variation, termed copy number variation (CNV), is also widespread throughout the human genome, and can be highly polymorphic between individuals. Such variation has long been shown, through candidate gene studies using low-throughput molecular biology techniques, to have direct consequences on human health and variation. Many studies have now sought to extensively characterise this variation on a genome-wide scale and, increasingly, attempts are being made to identify associations between CNV and human disease. Although many of the study design issues that have been described for SNP GWA studies are also relevant for CNV GWA studies, CNV studies also present their own unique set of challenges and considerations. New microarray-based technologies are enabling more accurate mapping of CNVs, and CNV maps of the human genome are being regularly refined with increasing resolution. The study of CNV and its effects on human health and disease therefore present a dynamic and exciting challenge for researchers in the field of genetic epidemiology.
Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium).
Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
Plasma levels of high-density lipoprotein cholesterol (HDL-C) are known to be heritable, but only a fraction of the heritability is explained. We used a high-density genotyping array containing single-nucleotide polymorphisms (SNPs) from HDL-C candidate genes selected on known biology of HDL-C metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging SNPs and included low-frequency nonsynonymous SNPs.
Early repolarization (ER), defined by J-point elevation in 12-lead ECG, was recently associated with increased risk for idiopathic ventricular fibrillation and cardiovascular mortality. The determinants of ER are unknown. We investigated its heritability in a large, family-based cohort.
HDL cholesterol (HDL-C) is an established marker of cardiovascular risk with significant genetic determination. However, HDL particles are not homogenous, and refined HDL phenotyping may improve insight into regulation of HDL metabolism. We therefore assessed HDL particles by NMR spectroscopy and conducted a large-scale candidate gene association analysis.
Genetic determinants of blood pressure are poorly defined. We undertook a large-scale, gene-centric analysis to identify loci and pathways associated with ambulatory systolic and diastolic blood pressure. We measured 24-hour ambulatory blood pressure in 2020 individuals from 520 white European nuclear families (the Genetic Regulation of Arterial Pressure of Humans in the Community Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array, which contains ? 50 000 single nucleotide polymorphisms in >2000 cardiovascular candidate loci. We found a strong association between rs13306560 polymorphism in the promoter region of MTHFR and CLCN6 and mean 24-hour diastolic blood pressure; each minor allele copy of rs13306560 was associated with 2.6 mm Hg lower mean 24-hour diastolic blood pressure (P = 1.2 × 10??). rs13306560 was also associated with clinic diastolic blood pressure in a combined analysis of 8129 subjects from the Genetic Regulation of Arterial Pressure of Humans in the Community Study, the CoLaus Study, and the Silesian Cardiovascular Study (P=5.4 × 10??). Additional analysis of associations between variants in gene ontology-defined pathways and mean 24-hour blood pressure in the Genetic Regulation of Arterial Pressure of Humans in the Community Study showed that cell survival control signaling cascades could play a role in blood pressure regulation. There was also a significant overrepresentation of rare variants (minor allele frequency: < 0.05) among polymorphisms showing at least nominal association with mean 24-hour blood pressure indicating that a considerable proportion of its heritability may be explained by uncommon alleles. Through a large-scale gene-centric analysis of ambulatory blood pressure, we identified an association of a novel variant at the MTHFR/CLNC6 locus with diastolic blood pressure and provided new insights into the genetic architecture of blood pressure.
Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
Clinicians have long been aware that substantial lung injury results when mechanical ventilation imposes too much stress on the pulmonary parenchyma. Evidence is accruing that substantial injury may also result when the ventilator imposes too little stress on the respiratory muscles. Through adjustment of ventilator settings and administration of pharmacotherapy, the respiratory muscles may be rendered almost (or completely) inactive. Research in animals has shown that diaphragmatic inactivity produces severe injury and atrophy of muscle fibers. Human data have recently revealed that 18 to 69 hours of complete diaphragmatic inactivity associated with mechanical ventilation decreased the cross-sectional areas of diaphragmatic fibers by half or more. The atrophic injury seems to result from increased oxidative stress leading to activation of protein-degradation pathways. Scientific understanding of ventilator-induced respiratory muscle injury has not reached the stage where meaningful controlled trials can be done, and thus, it is not possible to give concrete recommendations for patient management. In the meantime, clinicians are advised to select ventilator settings that avoid both excessive patient effort and excessive respiratory muscle rest. The contour of the airway pressure waveform on a ventilator screen provides the most practical indication of patient effort, and clinicians are advised to pay close attention to the waveform as they titrate ventilator settings. Research on ventilator-induced respiratory muscle injury is in its infancy and portends to be an exciting area to follow.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.
Contemporary bioscience sometimes demands vast sample sizes and there is often then no choice but to synthesize data across several studies and to undertake an appropriate pooled analysis. This same need is also faced in health-services and socio-economic research. When a pooled analysis is required, analytic efficiency and flexibility are often best served by combining the individual-level data from all sources and analysing them as a single large data set. But ethico-legal constraints, including the wording of consent forms and privacy legislation, often prohibit or discourage the sharing of individual-level data, particularly across national or other jurisdictional boundaries. This leads to a fundamental conflict in competing public goods: individual-level analysis is desirable from a scientific perspective, but is prevented by ethico-legal considerations that are entirely valid.
Weaning from prolonged mechanical ventilation may be associated with mental discomfort. It is not known whether such discomfort is linked with the development of post-traumatic stress disorder (PTSD). Accordingly, we investigated whether PTSD occurs in patients after weaning from prolonged ventilation. We also determined whether administering a questionnaire would identify patients at risk for developing PTSD.
Helium-oxygen mixtures and pressure-support ventilation have been used to unload the respiratory muscles and increase exercise tolerance in COPD. Considering the different characteristics of these techniques, we hypothesized that helium-oxygen would be more effective in reducing exercise-induced dynamic hyperinflation than pressure-support. We also hypothesized that patients would experience greater increases in respiratory rate and minute ventilation with helium-oxygen than with pressure-support. The hypotheses were tested in ten patients with severe COPD (FEV(1) = 28 ± 3% predicted [mean ± SE]) during constant-load cycling (80% maximal workrate) while breathing 30% oxygen-alone, helium-oxygen, and pressure-support in randomized order. As hypothesized, helium-oxygen had greater impact on dynamic hyperinflation than did pressure-support (end-exercise; p = 0.03). For the most part of exercise, respiratory rate and minute ventilation were greater with helium-oxygen than with pressure-support (p ? 0.008). During the initial phases of exercise, helium-oxygen caused less rib-cage muscle recruitment than did pressure-support (p < 0.03), and after the start of exercise it caused greater reduction in inspiratory reserve volume (p ? 0.02). Despite these different responses, helium-oxygen and pressure-support caused similar increases in exercise duration (oxygen-alone: 6.9 ± 0.8 min; helium-oxygen: 10.7 ± 1.4 min; pressure-support: 11.2 ± 1.6 min; p = 0.003) and similar decreases in inspiratory effort (esophageal pressure-time product), respiratory drive, pulmonary resistance, dyspnea and leg effort (p < 0.03). In conclusion, helium-oxygen reduced exercise-induced dynamic hyperinflation by improving the relationship between hyperinflation and minute ventilation. In contrast, pressure-support reduced hyperinflation solely as a result of lowering ventilation. Helium-oxygen was more effective in reducing exercise-induced dynamic hyperinflation in severe COPD, and was associated with greater increases in respiratory rate and minute ventilation than pressure-support.
Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
In observational studies, analyses of blood pressure (BP) typically require some correction for the use of antihypertensive medications by study participants. Different approaches to correcting for treatment have been compared, but the impact of pharmacogenetic interactions that influence the efficacy of antihypertensive treatments on estimates of genetic main effects has not been considered. This work demonstrates the potential influence of pharmacogenetic interactions in genetic analyses of BP.
We conducted genome-wide association analyses of mean leukocyte telomere length in 2,917 individuals, with follow-up replication in 9,492 individuals. We identified an association with telomere length on 3q26 (rs12696304, combined P = 3.72 x 10(-14)) at a locus that includes TERC, which encodes the telomerase RNA component. Each copy of the minor allele of rs12696304 was associated with an approximately 75-base-pair reduction in mean telomere length, equivalent to approximately 3.6 years of age-related telomere-length attrition.
Patients who require mechanical ventilation are at risk of emotional stress because of total dependence on a machine for breathing. The stress may negatively impact ventilator weaning and survival. The purpose of this study was to determine whether depressive disorders in patients being weaned from prolonged mechanical ventilation are linked to weaning failure and decreased survival.
Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n < or = 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < or = 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
The genetic contribution to sporadic amyotrophic lateral sclerosis (ALS) has not been fully elucidated. There are increasing efforts to characterise the role of copy number variants (CNVs) in human diseases; two previous studies concluded that CNVs may influence risk of sporadic ALS, with multiple rare CNVs more important than common CNVs. A little-explored issue surrounding genome-wide CNV association studies is that of post-calling filtering and merging of raw CNV calls. We undertook simulations to define filter thresholds and considered optimal ways of merging overlapping CNV calls for association testing, taking into consideration possibly overlapping or nested, but distinct, CNVs and boundary estimation uncertainty.
Despite the long recognised effects of chromosomal structural abnormalities and completion of the Human Genome Project, much of the structural variation in the genome has gone unrecognised until recently. Deletions and duplications of DNA strands of between a few hundred bp and several million bp-collectively referred to as copy number variants-are now known to be widespread. Since 2007, rigorous and adequately powered genome-wide association studies based on single nucleotide polymorphisms have yielded replicated associations to several common diseases. Some copy number variants explain rare, previously uncharacterised disorders, and they are now expected to explain some of the genetic contribution to common diseases. We review efforts to map copy number variants and discuss present and future prospects for assessment of their relation to human health and disease.
In a group of postoperative patients, Taniguchi and coworkers compared the effect of a computerized system for weaning against manual care. The computerized system involved automatic adjustments to the level of pressure support to achieve a target respiratory rate. Manual care involved adjustments to the level of pressure support to keep the ratio of respiratory frequency to tidal volume below 80. The duration of ventilator weaning was equivalent with the two approaches. The level of pressure support, however, was lower with manual care than with computerized ventilation. The study adds support to the notion that ventilator duration is shortened when weaning is contemplated at the earliest possible time. The findings also emphasize the importance of the Hippocratic dictum that patient outcome is improved when care is individualized rather than delivered according to a protocol.
To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P<1x10(-6). To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842) and QTGEN (n = 13,685). Analysis confirmed the association between common variants near NOS1AP (P = 1.4x10(-83)) and the phospholamban (PLN) gene (P = 1.9x10(-29)). The most associated SNP near NOS1AP (rs12143842) explains 0.82% variance; the SNP near PLN (rs11153730) explains 0.74% variance of QT interval duration. We found no evidence for interaction between these two SNPs (P = 0.99). PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval. These data offer further mechanistic insights into genetic influence on the QT interval which may predispose to life threatening arrhythmias and sudden cardiac death.
It is problematic to withhold therapy in a patient with chronic obstructive pulmonary disease (COPD) who presents with acute respiratory failure so that detailed physiological measurements can be obtained. Accordingly, most information on respiratory muscle activity in patients experiencing acute respiratory failure has been acquired by studying patients who fail a trial of weaning after a period of mechanical ventilation. Such patients experience marked increases in inspiratory muscle load consequent to increases in resistance, elastance, and intrinsic positive end-expiratory pressure. Inspiratory muscle strength is reduced secondary to hyperinflation and possibly direct muscle damage and the release of inflammatory mediators. Most patients recruit both their sternomastoid and expiratory muscles, even though airflow limitation prevents the expiratory muscles from lowering lung volume. Even when acute hypercapnia is present, patients do not exhibit respiratory center depression; indeed, voluntary activation of the diaphragm, in absolute terms, is greater in hypercapnic patients than in normocapnic patients. Instead, the major mechanism of acute hypercapnia is the development of rapid shallow breathing. Despite the marked increase in mechanical load and decreased force-generating capacity of the inspiratory muscles, patients do not develop long-lasting muscle fatigue, at least over the period of a failed weaning trial. Although the disease originates within the lung parenchyma, much of the distress faced by patients with COPD, especially during acute respiratory failure, is caused by the burdens imposed on the respiratory muscles.
Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ? 71,225 European ancestry, N ? 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
The development of acute ventilatory failure represents an inability of the respiratory control system to maintain a level of respiratory motor output to cope with the metabolic demands of the body. The level of respiratory motor output is also the main determinant of the degree of respiratory distress experienced by such patients. As ventilatory failure progresses and patient distress increases, mechanical ventilation is instituted to help the respiratory muscles cope with the heightened workload. While a patient is connected to a ventilator, a physicians ability to align the rhythm of the machine with the rhythm of the patients respiratory centers becomes the primary determinant of the level of rest accorded to the respiratory muscles. Problems of alignment are manifested as failure to trigger, double triggering, an inflationary gas-flow that fails to match inspiratory demands, and an inflation phase that persists after a patients respiratory centers have switched to expiration. With recovery from disorders that precipitated the initial bout of acute ventilatory failure, attempts are made to discontinue the ventilator (weaning). About 20% of weaning attempts fail, ultimately, because the respiratory controller is unable to sustain ventilation and this failure is signaled by development of rapid shallow breathing. Substantial advances in the medical management of acute ventilatory failure that requires ventilator assistance are most likely to result from research yielding novel insights into the operation of the respiratory control system.
Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N?=?50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA?=?)5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA?=?)4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA?=?)1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
MPS encompasses a group of rare lysosomal storage disorders that are associated with the accumulation of glycosaminoglycans (GAG) in organs and tissues. This accumulation can lead to the progressive development of a variety of clinical manifestations. Ear, nose, throat (ENT) and respiratory problems are very common in patients with MPS and are often among the first symptoms to appear. Typical features of MPS include upper and lower airway obstruction and restrictive pulmonary disease, which can lead to chronic rhinosinusitis or chronic ear infections, recurrent upper and lower respiratory tract infections, obstructive sleep apnoea, impaired exercise tolerance, and respiratory failure. This review provides a detailed overview of the ENT and respiratory manifestations that can occur in patients with MPS and discusses the issues related to their evaluation and management.
Most patients with chronic obstructive pulmonary disease (COPD) are middle-aged or older, and by definition all have a chronic illness. Aging and chronic illness decrease sexual interest, sexual function, and testosterone levels. To date, researchers have not simultaneously explored prevalence, risk factors, and impact of sexual dysfunctions on quality of life and survival in men with COPD. We tested three hypotheses: First, sexual dysfunctions, including erectile dysfunction, are highly prevalent and impact negatively the quality of life of those with COPD. Second, gonadal state is a predictor of erectile dysfunction. Third, erectile dysfunction, a potential maker of systemic atherosclerosis, is a risk factor for mortality in men with COPD.
The study of families with rare inherited forms of hypo- and hypertension has been one of the most successful strategies to probe the molecular pathophysiology of blood pressure control and has revealed dysregulation of distal nephron sodium reabsorption to be a common mechanism. Familial Hyperkalaemic Hypertension (FHHt, Gordon Syndrome) is a salt-dependent form of hypertension caused by mutations in regulators of the thiazide-sensitive NaCl cotransporter, NCC, and is effectively treated by thiazide diuretics and/or dietary salt restriction. Variation in at least four genes can cause FHHt, including With No lysine (K) kinases (WNK1 and WNK4), KeLcH-Like3 (KLHL3) and CULlin3 (CUL3). Here we identify novel disease-causing variants in CUL3 and KLHL3 segregating in 63% of pedigrees with previously unexplained FHHt, confirming the importance of these recently-described FHHt genes. We demonstrate conclusively, in two unrelated affected individuals, that rare intronic variants in CUL3 cause skipping of exon 9, as has been proposed. KLHL3 variants all occur in kelch-repeat domains and so are likely to disrupt WNK-complex binding. We found no evidence of plausible disease-causing variants within SLC4A8 (an alternative thiazide-sensitive sodium transporter) in this population. This supports existing evidence that CUL3 and KLHL3 gene products are physiologically important regulators of thiazide-sensitive distal nephron NaCl reabsorption, and hence potentially interesting novel anti-hypertensive drug targets. As a third of our non-WNK FHHt families do not have plausible CUL3 or KLHL3 variants, there are likely to be additional, as yet undiscovered, regulators of thiazide-sensitive pathways.
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