Hancock, D.B. et al. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat. Genet. 42, 45-52

Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
Nature Genetics (Impact Factor: 29.35). 12/2009; 42(1):45-52. DOI: 10.1038/ng.500
Source: PubMed


Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV(1)) and its ratio to forced vital capacity (FEV(1)/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV(1)/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV(1) (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 x 10(-8)) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.

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    • "Single nucleotide polymorphisms (SNPs) attaining genome-wide significance in four recent GWA studies for either FEV1 or the ratio of FEV1 to FVC [13], [14], [15], [16] were selected for cross-reference analysis with CAD susceptibility and cIMT. In particular, we selected 26 lead SNPs, representing 26 loci robustly associated with spirometry measures, through a literature search (Table 1). "
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    ABSTRACT: 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.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "Several GWAS have now been conducted in COPD and several genes have been found to be associated with the development of this condition, the most common and strongly associated being HHIP (hedgehog-interacting protein) (30), CHRNA3 (cholinergic receptor, nicotinic, alpha 3) (30), IREB2 (iron responsive element binding protein 2) (10), and FAM13A (family with sequence similarity 13, member A) (8). CHRNA3 has been demonstrated to be associated with smoking intensity (30) and all show an association with FEV1/FVC (16, 30) but, to the best of our knowledge, there are no studies investigating associations with exacerbation frequency or other key phenotypes in COPD. In studies like the one reported here, where the frequency of the rs2227744A allele in infrequent exacerbators was found to be similar to that observed in the general population (Whitehall II and ELSA healthy controls), and the effect of the SNP on a subgroup of cases was diluted and masked, a comparison between all COPD cases (including both frequent and infrequent exacerbators) and healthy controls would potentially fail to show an association between PAR-1 and susceptibility to COPD. "
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    ABSTRACT: Proteinase activated receptor-1 (PAR-1) plays a key role in mediating the interplay between coagulation and inflammation in response to injury. The aim of this study was to investigate the role of the promoter SNP rs2227744G>A in modulating PAR-1/F2R gene expression in the context of chronic obstructive pulmonary disease (COPD) and COPD exacerbations. The function of the rs2227744G>A SNP was investigated using reporter gene assays. The frequency of the polymorphism in the UK population was assessed by genotyping 8579 healthy individuals from the Whitehall II and ELSA cohorts. The rs2227744G>A SNP was genotyped in a carefully phenotyped cohort of 203 COPD cases and matched controls. The results were further replicated in two different COPD cohorts. The minor allele of the rs2227744G>A polymorphism was found to increase F2R expression by 2.6-fold (p<0.001). The rs2227744G>A SNP was not significantly associated with COPD, or with lung function, in all cohorts. The minor allele of the SNP was found to be associated with protection from frequent exacerbations (p=0.04) in the cohort of COPD patients for which exacerbation frequency was available. Considering exacerbations as a continuous variable, the presence of the minor allele was associated with a significantly lower COPD exacerbation rate (3.03 vs 1.98 exacerbations/year, MWU p=0.04). Taken together these data do not support a role for the rs2227744G>A F2R polymorphism in the development of COPD but suggest a protective role for this polymorphism from frequent exacerbations. Studies in separate cohorts to replicate these findings are warranted.
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    • "The Institutional Review Board at Cornell University and the Health ABC Publications Committee approved the use of Health ABC data for this study. The Framingham Heart Study (FHS) cohort (n = 7,694; includes individuals from the original, offspring, and third generation cohorts) [17] served as a replication cohort for cross-sectional SNP—lung function associations discovered in Health ABC European-Americans (Additional file 2 for further details on both cohort studies). The Institutional Review Board at the Boston University Medical Campus granted approval for the FHS. "
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    ABSTRACT: Vitamin D is associated with lung health in epidemiologic studies, but mechanisms mediating observed associations are poorly understood. This study explores mechanisms for an effect of vitamin D in lung through an in vivo gene expression study, an expression quantitative trait loci (eQTL) analysis in lung tissue, and a population-based cohort study of sequence variants. Microarray analysis investigated the association of gene expression in small airway epithelial cells with serum 25(OH)D in adult non-smokers. Sequence variants in candidate genes identified by the microarray were investigated in a lung tissue eQTL database, and also in relation to cross-sectional pulmonary function in the Health, Aging, and Body Composition (Health ABC) study, stratified by race, with replication in the Framingham Heart Study (FHS). 13 candidate genes had significant differences in expression by serum 25(OH)D (nominal p < 0.05), and a genome-wide significant eQTL association was detected for SGPP2. In Health ABC, SGPP2 SNPs were associated with FEV1 in both European- and African-Americans, and the gene-level association was replicated in European-American FHS participants. SNPs in 5 additional candidate genes (DAPK1, FSTL1, KAL1, KCNS3, and RSAD2) were associated with FEV1 in Health ABC participants. SGPP2, a sphingosine-1-phosphate phosphatase, is a novel vitamin D-responsive gene associated with lung function. The identified associations will need to be followed up in further studies.
    No preview · Article · Nov 2013 · BMC Medical Genetics
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