Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease

Abstract

Rationale: Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome-wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility.Objectives: To identify coding variants associated with COPD.Methods: We tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts.Measurements and Main Results: We included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 3 10 214 ) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 3 10 26 ) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 3 10 28 ) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM. Conclusions:In an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis.

Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

“…Analysis of only European ancestry (Supplementary Table 4) and only African ancestry (Supplementary Table 5 and Supplementary Figure 3) Stage 1 cohorts showed no unique association signals. Of the 22 genome-wide significant loci described in our study, 9 have been previously described as genome- (or exome-) wide significant in studies of COPD 13,16–19 : HHIP , CHRNA5 , HTR4 , FAM13A , RIN3 , TGFB2 , GSTCD-NPNT , CYP2A6 , and IL27 - CCDC101 . The remaining 13 loci have not been previously associated with COPD at genome- (or exome-) wide significance.…”

“…In contrast, we found no evidence of a strong eQTL signal or co-localization at our other two novel loci. At 3q21, EEFSEC is a potential candidate, as it is a paralog of TUFM , a top blood and lung eQTL gene for the 16p11.2/ IL27 COPD susceptibility locus 19 , recently part of a novel COPD-related pathway involving NLRX1 30–32 . At 10q22, pulmonary surfactant-associated protein D ( SFTPD ) is the most likely candidate, as it is highly expressed in pneumocytes 27 , and sftpd (−/−) mice develop pulmonary emphysema 33 .…”

Targeted high-throughput sequencing of candidate genes for chronic obstructive pulmonary disease

“…The direction of effect is the same for both SNPs, with the minor alleles associated with reduced expression of CHRNA5 . Also recently, rs16969968 was found to be the most significantly associated variant in an exome array analysis in a study including more than 6,100 COPD cases and 6,000 control subjects across five cohorts [31]. …”

Integrated transcriptomic correlation network analysis identifies COPD molecular determinants

“…Notably, the list of 61 switch genes includes SPP1 that encodes adiponectin, which has been suggested as a protein biomarker for COPD [Suh 2018] and TUFM, which is probably the best candidate within a strong COPD GWAS region on chromosome 16 [Hobbs 2016].…”