Common and rare variants genetic association analysis of cigarettes per day among ever smokers in COPD cases and controls

Common and rare variants genetic association analysis of cigarettes per day among ever smokers in... Abstract Introduction Cigarette smoking is a major environmental risk factor for many diseases, including chronic obstructive pulmonary disease (COPD). There are shared genetic influences on cigarette smoking and COPD. Genetic risk factors for cigarette smoking in cohorts enriched for COPD are largely unknown. Methods We performed genome-wide association analyses for average cigarettes per day (CPD) across the COPDGene Non-Hispanic White (NHW) (n=6,659) and African American (AA) (n=3,260), GenKOLS (n=1,671), and ECLIPSE (n=1,942) cohorts. In addition, we performed exome array association analyses across the COPDGene NHW and AA cohorts. We considered analyses across the entire cohort and stratified by COPD case-control status. Results We identified genome-wide significant associations for CPD on chromosome 15q25 across all cohorts (lowest p=1.78x10-15), except in the COPDGene AA cohort alone. Previously reported associations on chromosome 19 had suggestive and directionally consistent associations (RAB4 p=1.95x10-6; CYP2A7 p=7.50x10-5; CYP2B6 4.04x10-4). When we stratified by COPD case-control status, single nucleotide polymorphisms (SNPs) in chromosome 15q25 were nominally associated in both NHW COPD cases (Beta=0.11, p=5.58x10-4) and controls (Beta=0.12, p=3.86x10-5). For the gene-based exome array association analysis of rare variants, there were no exome-wide significant associations. For these previously replicated associations, the most significant results were among COPDGene NHW subjects for CYP2A7 (p=5.2x10-4). Conclusions In a large genome-wide association study of both common variants and a gene-based association of rare coding variants in ever smokers, we found genome-wide significant associations on chromosome 15q25 with CPD for common variants, but not for rare coding variants. These results were directionally consistent among COPD cases and controls. IMPLICATIONS We examined both common and rare coding variants associated with CPD in a large population of heavy smokers with and without COPD of NHW and AA descent. We replicated genome-wide significant associations on chromosome 15q25 with CPD for common variants among NHW subjects, but not for rare variants. We demonstrated for the first time that common variants on chromosome 15q25 associated with CPD are similar among COPD cases and controls. Previously reported associations on chromosome 19 showed suggestive and directionally consistent associations among common variants (RAB4, CYP2A7, and CYP2B6) and for rare variants (CYP2A7) among COPDGene NHW subjects. While the genetic effect sizes for these SNPs on chromosome 15q25 are modest, we show that this creates a substantial smoking burden over the lifetime of a smoker. © The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nicotine and Tobacco Research Oxford University Press

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Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
ISSN
1462-2203
eISSN
1469-994X
D.O.I.
10.1093/ntr/nty095
Publisher site
See Article on Publisher Site

Abstract

Abstract Introduction Cigarette smoking is a major environmental risk factor for many diseases, including chronic obstructive pulmonary disease (COPD). There are shared genetic influences on cigarette smoking and COPD. Genetic risk factors for cigarette smoking in cohorts enriched for COPD are largely unknown. Methods We performed genome-wide association analyses for average cigarettes per day (CPD) across the COPDGene Non-Hispanic White (NHW) (n=6,659) and African American (AA) (n=3,260), GenKOLS (n=1,671), and ECLIPSE (n=1,942) cohorts. In addition, we performed exome array association analyses across the COPDGene NHW and AA cohorts. We considered analyses across the entire cohort and stratified by COPD case-control status. Results We identified genome-wide significant associations for CPD on chromosome 15q25 across all cohorts (lowest p=1.78x10-15), except in the COPDGene AA cohort alone. Previously reported associations on chromosome 19 had suggestive and directionally consistent associations (RAB4 p=1.95x10-6; CYP2A7 p=7.50x10-5; CYP2B6 4.04x10-4). When we stratified by COPD case-control status, single nucleotide polymorphisms (SNPs) in chromosome 15q25 were nominally associated in both NHW COPD cases (Beta=0.11, p=5.58x10-4) and controls (Beta=0.12, p=3.86x10-5). For the gene-based exome array association analysis of rare variants, there were no exome-wide significant associations. For these previously replicated associations, the most significant results were among COPDGene NHW subjects for CYP2A7 (p=5.2x10-4). Conclusions In a large genome-wide association study of both common variants and a gene-based association of rare coding variants in ever smokers, we found genome-wide significant associations on chromosome 15q25 with CPD for common variants, but not for rare coding variants. These results were directionally consistent among COPD cases and controls. IMPLICATIONS We examined both common and rare coding variants associated with CPD in a large population of heavy smokers with and without COPD of NHW and AA descent. We replicated genome-wide significant associations on chromosome 15q25 with CPD for common variants among NHW subjects, but not for rare variants. We demonstrated for the first time that common variants on chromosome 15q25 associated with CPD are similar among COPD cases and controls. Previously reported associations on chromosome 19 showed suggestive and directionally consistent associations among common variants (RAB4, CYP2A7, and CYP2B6) and for rare variants (CYP2A7) among COPDGene NHW subjects. While the genetic effect sizes for these SNPs on chromosome 15q25 are modest, we show that this creates a substantial smoking burden over the lifetime of a smoker. © The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Nicotine and Tobacco ResearchOxford University Press

Published: May 15, 2018

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