Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis

Abstract

Background The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. Methods Genome-wide association analysis in COPDGene (non-Hispanic whites and African-Americans) was combined with existing data from the ECLIPSE, NETT/NAS, and GenKOLS (Norway) studies. Analyses were performed both using all moderate-to-severe cases and the subset of severe cases. Top loci not previously described as genome-wide significant were genotyped in the ICGN study, and results combined in a joint meta-analysis. Findings Analysis of a total of 6,633 moderate-to-severe cases and 5,704 controls confirmed association at three known loci: CHRNA3/CHRNA5/IREB2, FAM13A, and HHIP (10−12 < P < 10−14), and also showed significant evidence of association at a novel locus near RIN3 (overall P, including ICGN = 5•4×10−9). In the severe COPD analysis (n=3,497), the effects at two of three previously described loci were significantly stronger; we also identified two additional loci previously reported to affect gene expression of MMP12 and TGFB2 (overall P = 2•6x10−9 and 8•3×10−9). RIN3 and TGFB2 expression levels were reduced in a set of Lung Tissue Research Consortium COPD lung tissue samples compared with controls. Interpretation In a genome-wide study of COPD, we confirmed associations at three known loci and found additional genome-wide significant associations with moderate-to-severe COPD near RIN3 and with severe COPD near MMP12 and TGFB2. Genetic variants, apart from alpha-1 antitrypsin deficiency, increase the risk of COPD. Our analysis of severe COPD suggests additional genetic variants may be identified by focusing on this subgroup. Funding National Heart, Lung, and Blood Institute; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; US Department of Veterans Affairs.

DNA methylation profiling in human lung tissue identifies genes associated with COPD

“…This yielded 3 sites annotated to 2 of the GWAS genes at a 10% FDR (DLC1 and TGFB2); 11,12 no differentially methylated CpG sites were identified at a 5% FDR. Using more liberal criteria of 1% difference in methylation revealed 17 sites annotated to 5 of the GWAS genes significant at a 10% FDR (FAM13A, Figure 2.…”

“…We integrated the genome-wide significant loci identified in previous COPD genome-wide association studies, 8,9,11,12 with the differential methylation results after filtering for minimal differences in methylation (b-diff) (3,260 sites, b-diff > 5% and 44,662 sites; b-diff > 1%). We observed nominal (FDR < 10%) evidence of differential methylation in the threshold COPD GWAS genes FAM13A, HHIP, DLC1, TGFB2, and RIN3 (Supplemental Tables S4 and S5).…”

“…Genetic association studies have identified loci at genome-wide significance; genes nearest to these loci (GWAS genes) include IREB2 in the 15q25 locus (CHRNA3/5, IREB2), HHIP in the 4q31 locus, and FAM13A in the 4q22 locus. [8][9][10] Recently, RIN3, MMP12, and TGFB2 were identified as likely COPD genes 11 and GWAS of CT emphysema 12 identified DLC1 and AGER. Information regarding DNA methylation in the regions surrounding these loci is limited, particularly in lung tissue from subjects with COPD; in normal lung tissue, 4 2 CpG sites (cg24631222 and cg04882995) were found to be significantly associated with lung cancer GWAS SNPs in the 15q25.1 locus (CHRNA5, CHRNA3, CHRNB4).…”

Translating Lung Function Genome-Wide Association Study (GWAS) Findings

“…with COPD diagnosis. SNPs with the lowest P values studied (P ≤ 1 x 10 -9 ) were in or near to FAM13A (Cho et al, 2010;Cho et al, 2012;Cho et al, 2014;J. H. Lee et al, 2014), HHIP Van Durme et al, 2010), Cholinergic Receptor, Nicotinic, Alpha 3 (Neuronal) (CHRNA3) Pillai et al, 2009), ACN9…”

A Decade of National Heart, Lung, and Blood Institute Programs Supporting COPD Research and Education

“…28 Over 65 articles resulting from the COPDGene® study have been published or are currently in press, and these address a range of topics, from new CT-based biomarkers for disease phenotype 29 and acute exacerbations 30 to genome-wide identification of risk loci for severe COPD. 31 COPDGene® has sparked over 140 ancillary study proposals, at least 10 of which have been awarded NIH funding. Recently, NHLBI competitively renewed COPDGene® to study the progression of the disease at 5 years and to undertake whole-exome sequencing of the participants' genomes.…”