A Genome-Wide Association Study In COPD Identifies A Susceptibility Locus On Chromosome 19q13

Abstract

The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genomewide significant locus on chromosome 19q13 (rs7937, OR 5 0.74, P 5 2.9 3 10 29 ). Genotyping this single * Molecular Genetics, 2012, Vol. 21, No. 4 947-957 doi:10.1093/hmg/ddr524 Advance Access published on November 11, 2011nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P 5 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV 1 (P 5 0.08 and 0.04) and severe (GOLD 3&4) COPD (P 5 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.

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

“…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).…”

“…All differential methylation results for CpG sites annotated to 8 genes found in genome-wide significant loci from previous COPD and emphysema GWAS 8,9,11,12 were extracted and filtered at b-diff thresholds of 1% and 5% to create 2 subsets of results. The P-values for all results in these 2 subsets were examined to assess the overall significance of the associations involving CpG sites annotated to these GWAS genes.…”

“…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).…”

Chronic Obstructive Pulmonary Disease: Official diagnosis and treatment guidelines of the Czech Pneumological and Phthisiological Society; a novel phenotypic approach to COPD with patient-oriented care

“…Apart from active smoking, which is responsible for 70-80% of cases of COPD onset, the following are also generally considered risk factors: environmental tobacco smoke -ETS, cannabis smoking, cigar, pipe or water pipe smoking; prolonged exposure to industrial pollution, longterm inhalation of vehicle exhaust, burnt fossil fuel and biomass fumes, low weight at birth and frequent infections during childhood 29,30 . The development of the disease is determined by the specific interaction between genetic and epigenetic factors, and effects of the environment 31,32 .…”

Chronic Obstructive Pulmonary Disease Genetics: A Review of the Past and a Look Into the Future

“…23 They imputed missing genotypes in each cohort against the 1000 Genomes Project data, allowing better combination of the genetic information from each cohort. Along with previously identified regions (CHRNA3/5/IREB2, HHIP and FAM13A), they additionally identified variants from a novel region on 19q13 as significantly associated with COPD.…”