Pulmonary function is an easily measurable and reliable index of the physiological state of the lungs and airways 1 . Pulmonary function also predicts mortality in the general population, even among people who have never smoked (never-smokers) who have only modestly reduced pulmonary function and no respiratory symptoms 2,3 . The peak level of pulmonary function attained in early adulthood and its subsequent decline with age are likely influenced by genetic and environmental factors. Tobacco smoking is a major environmental cause of accelerated decline in pulmonary function with age. Other inhaled pollutants also appear to contribute. Familial aggregation studies suggest a genetic contribution to lung function, with heritability estimates exceeding 40% 4,5 , but little is known about the specific genetic factors involved. A relatively uncommon deficiency of α1-antitrypsin is the only established genetic risk factor for accelerated decline in pulmonary function and for development of chronic obstructive pulmonary disease (COPD), especially in smokers 4,6 . However, α1-antitrypsin accounts for little of the population variability in pulmonary function 4 . Candidate gene studies suggest that other genetic variants may influence the time course of pulmonary function and its decline in relation to smoking, but these putative genetic risk factors remain unknown 4 .Forced expiratory volume in the first second (FEV 1 ) and its ratio to forced vital capacity (FEV 1 /FVC) are two clinically relevant pulmonary function measures. Although both FEV 1 and FVC are influenced by lung size and can be reduced by restrictive lung diseases, obstructive lung disease leads to proportionately greater reduction in FEV 1 than FVC. Therefore, reduced FEV 1 /FVC, an indicator of airflow obstruction that is independent of lung size, is the primary criterion for defining an obstructive ventilatory defect 1 . Whereas low FEV 1 /FVC indicates the presence of airflow obstruction, FEV 1 is used to classify the severity and follow the progression of obstructive lung disease over time 5,7,8 .The first genome-wide association study (GWAS) for pulmonary function evaluating 70,987 SNPs in about 1,220 Framingham Heart Study (FHS) participants revealed no genome-wide significant loci 9 . Recently, a GWAS of FEV 1 /FVC using 2,540,223 SNPs in 7,691 FHS participants identified several SNPs on chromosome 4q31 near HHIP with genome-wide significance 10 . A GWAS of COPD 11 also implicated the HHIP region along with CHRNA3-CHRNA5 on chromosome 15, a region previously associated with nicotine dependence 12,13 .We conducted meta-analyses of GWAS results for a cross-sectional analysis of pulmonary function (FEV 1 /FVC and FEV 1 ) in 20,890 individuals of European ancestry from four Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium 14 studies: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), FHS and Rotterdam Study (RS-I and RS-II). Given that cigarette smoking is a major risk factor for pulmonary fun...
Pulmonary function measures reflect respiratory health and predict mortality, and are used in the diagnosis of chronic obstructive pulmonary disease (COPD). We tested genome-wide association with the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in 48,201 individuals of European ancestry, with follow-up of 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 (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.
QT interval duration reflecting myocardial repolarization on the electrocardiogram is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of 3 genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study. We observed associations at P < 5×10−8 with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and Mendelian Long QT Syndromes. Associations at five novel loci included 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RIFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4–6.5% of variation in QT interval. Identifying the causal variants and defining their impact on myocardial repolarization may add incrementally to the prevention of sudden cardiac death and drug-induced arrhythmias.
QRS interval on the electrocardiogram reflects ventricular depolarization and conduction time, and is a risk factor for mortality, sudden death, and heart failure. We performed a genome-wide association meta-analysis in 40,407 European-descent individuals from 14 studies, with further genotyping in 7170 additional Europeans, and identified 22 loci associated with QRS duration (P < 5 × 10−8). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors, and calcium-handling proteins, but also point to novel biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a gene at our most significant locus, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.
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