Haplotypes with copy number and single nucleotide polymorphisms in CYP2A6 locus are associated with smoking quantity in a Japanese population

PLoS One. 2012;7(9):e44507. doi: 10.1371/journal.pone.0044507. Epub 2012 Sep 25.

Abstract

Smoking is a major public health problem, but the genetic factors associated with smoking behaviors are not fully elucidated. Here, we have conducted an integrated genome-wide association study to identify common copy number polymorphisms (CNPs) and single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) in Japanese smokers (N = 17,158). Our analysis identified a common CNP with a strong effect on CPD (rs8102683; P=3.8 x 10(-42)) in the 19q13 region, encompassing the CYP2A6 locus. After adjustment for the associated CNP, we found an additional associated SNP (rs11878604; P=9.7 x 10(-30)) located 30 kb downstream of the CYP2A6 gene. Imputation of the CYP2A6 locus revealed that haplotypes underlying the CNP and the SNP corresponded to classical, functional alleles of CYP2A6 gene that regulate nicotine metabolism and explained 2% of the phenotypic variance of CPD (ANOVA F-test P=9.5 x 10(-52)). These haplotypes were also associated with smoking-related diseases, including lung cancer, chronic obstructive pulmonary disease and arteriosclerosis obliterans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Analysis of Variance
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Cytochrome P-450 CYP2A6
  • DNA Copy Number Variations*
  • Female
  • Gene Frequency
  • Genetic Loci*
  • Genetic Variation
  • Genome-Wide Association Study
  • Haplotypes
  • Humans
  • Japan / epidemiology
  • Male
  • Nicotine / metabolism
  • Polymorphism, Single Nucleotide*
  • Smoking / epidemiology
  • Smoking / genetics*
  • Smoking / metabolism

Substances

  • Nicotine
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A6 protein, human
  • Cytochrome P-450 CYP2A6

Grant support

This work was conducted as a part of the BioBank Japan Project, which is supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.