Hemizygous Deletion on Chromosome 3p26.1 Is Associated with Heavy Smoking among African American Subjects in the COPDGene Study.

Ferdouse Begum,John E Hokanson,James D Crapo,Ingo Ruczinski,Robert B Scharpf,Jacqueline B Hetmanski,Margaret M Parker,Terri H Beaty,Edwin K Silverman,Michael H Cho,Sharon M Lutz,Huiping Zhang

doi:10.1371/journal.pone.0164134

Abstract

Many well-powered genome-wide association studies have identified genetic determinants of self-reported smoking behaviors and measures of nicotine dependence, but most have not considered the role of structural variants, such as copy number variation (CNVs), influencing these phenotypes. Here, we included 2,889 African American and 6,187 non-Hispanic White subjects from the COPDGene cohort (http://www.copdgene.org) to carefully investigate the role of polymorphic CNVs across the genome on various measures of smoking behavior. We identified a CNV component (a hemizygous deletion) on chromosome 3p26.1 associated with two quantitative phenotypes related to smoking behavior among African Americans. This polymorphic hemizygous deletion is significantly associated with pack-years and cigarettes smoked per day among African American subjects in the COPDGene study. We sought evidence of replication in African Americans from the population based Atherosclerosis Risk in Communities (ARIC) study. While we observed similar CNV counts, the extent of exposure to cigarette smoking among ARIC subjects was quite different and the smaller sample size of heavy smokers in ARIC severely limited statistical power, so we were unable to replicate our findings from the COPDGene cohort. But meta-analyses of COPDGene and ARIC study subjects strengthened our association signal. However, a few linkage studies have reported suggestive linkage to the 3p26.1 region, and a few genome-wide association studies (GWAS) have reported markers in the gene (GRM7) nearest to this 3p26.1 area of polymorphic deletions are associated with measures of nicotine dependence among subjects of European ancestry.

Highlights

Cigarette smoking is the leading environmental risk factor for many chronic diseases including chronic obstructive pulmonary disease (COPD), coronary artery disease and several common cancers [1, 2]
This study focuses on testing for association between polymorphic copy number variants (CNVs) and different phenotypes reflecting smoking behavior in a sample of adult smokers drawn from the COPDGene study, a large study of current and former smokers including both non-Hispanic White (NHW) and African American (AA) adults with at least 10 pack-years exposure to cigarette smoking
We performed stratified analysis in NHW (n = 6,187) and AA (n = 2,889) subjects separately, but we only found genome-wide significant evidence of association between polymorphic CNVs on chromosome 3p26.1 and smoking behavior among African American subjects, where these CNVs are far more polymorphic

Summary

Introduction

Cigarette smoking is the leading environmental risk factor for many chronic diseases including chronic obstructive pulmonary disease (COPD), coronary artery disease and several common cancers [1, 2]. To undertand the genetic underpinning of this complex phenotype, several large-scale GWAS have been conducted on quantitative measures of smoking behavior, but the majority of studies included subjects of European ancestry, there have been a few studies of African-American and Asian populations. These previous studies have identified multiple genetic loci significantly associated with smoking behaviors [4,5,6,7,8,9]. Because CNVs are based on estimated deletions/amplifications, inferences based on significant association tests can be more tenuous, they can still identify genes potentially influencing complex phenotypes, such as quantitative measures of smoking behavior

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Results

Conclusion