Abstract

Multiple genome-wide and targeted association studies reveal a significant association of variants in the CHRNA5-CHRNA3-CHRNB4 (CHRNA5/A3/B4) gene cluster on chromosome 15 with nicotine dependence. The subjects examined in most of these studies had a European origin. However, considering the distinct linkage disequilibrium patterns in European and other ethnic populations, it would be of tremendous interest to determine whether such associations could be replicated in populations of other ethnicities, such as Asians. In this study, we performed comprehensive association and interaction analyses for 32 single-nucleotide polymorphisms (SNPs) in CHRNA5/A3/B4 with smoking initiation (SI), smoking quantity (SQ), and smoking cessation (SC) in a Korean sample (N = 8,842). We found nominally significant associations of 7 SNPs with at least one smoking-related phenotype in the total sample (SI: P = 0.015∼0.023; SQ: P = 0.008∼0.028; SC: P = 0.018∼0.047) and the male sample (SI: P = 0.001∼0.023; SQ: P = 0.001∼0.046; SC: P = 0.01). A spectrum of haplotypes formed by three consecutive SNPs located between rs16969948 in CHRNA5 and rs6495316 in the intergenic region downstream from the 5′ end of CHRNB4 was associated with these three smoking-related phenotypes in both the total and the male sample. Notably, associations of these variants and haplotypes with SC appear to be much weaker than those with SI and SQ. In addition, we performed an interaction analysis of SNPs within the cluster using the generalized multifactor dimensionality reduction method and found a significant interaction of SNPs rs7163730 in LOC123688, rs6495308 in CHRNA3, and rs7166158, rs8043123, and rs11072793 in the intergenic region downstream from the 5′ end of CHRNB4 to be influencing SI in the male sample. Considering that fewer than 5% of the female participants were smokers, we did not perform any analysis on female subjects specifically. Together, our detected associations of variants in the CHRNA5/A3/B4 cluster with SI, SQ, and SC in the Korean smoker samples provide strong evidence for the contribution of this cluster to the etiology of SI, ND, and SC in this Asian population.

Highlights

  • There are about 1.3 billion smokers worldwide, and the mortality burden from tobacco use has been estimated to exceed 6 million annually [1]

  • We found that the A allele of rs951266 in CHRNA5 was nominally significantly associated with smoking initiation (SI) (P = 0.023; odds ratio [OR] = 1.32; 95% confidence interval [CI]: = 1.04, 1.67) and smoking quantity (SQ) (P = 0.008; OR = 1.48; 95% CI: 1.11, 1.98), and the G allele of rs11072768 in CHRNB4 was nominally significantly associated with SI (P = 0.015; OR = 1.14; 95% CI: 1.03, 1.27), SQ (P = 0.028; OR = 1.17; 95% CI: 1.02, 1.34), and smoking cessation (SC) (P = 0.018; OR = 1.16; 95% CI: 1.03, 1.31)

  • We examined genetic associations and epistatic variants in CHRNA5/A3/B4 with SI, SQ, and SC in the total and male samples

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Summary

Introduction

There are about 1.3 billion smokers worldwide, and the mortality burden from tobacco use has been estimated to exceed 6 million annually [1]. In Korea, male smoking prevalence is among the highest in the world [2]. The number of deaths attributable to smoking-related diseases in Korea is about 35,000 each year, and the economic loss from premature death from smoking-related diseases exceeded 3 trillion won (approximately US $2.5 billion) in the year 2000 [3]. Nicotine is the psychoactive substance in tobacco that causes addiction. Many of those who want to quit smoking do not seek treatment but are unable to quit on their own [4]. Evidence for moderate heritabilities of smoking initiation (SI), nicotine dependence (ND), and smoking cessation (SC) has led to intensive efforts to identify susceptibility loci for these complex behavioral phenotypes [5,6,7,8]

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