Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia, United States of America.
PLoS One. 2010 Aug 16;5(8):e12183. doi: 10.1371/journal.pone.0012183.
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 approximately 0.023; SQ: P = 0.008 approximately 0.028; SC: P = 0.018 approximately 0.047) and the male sample (SI: P = 0.001 approximately 0.023; SQ: P = 0.001 approximately 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.
多个全基因组和靶向关联研究表明，15 号染色体上 CHRNA5-CHRNA3-CHRNB4（CHRNA5/A3/B4）基因簇中的变异与尼古丁依赖显著相关。这些研究中的大多数研究对象都有欧洲血统。然而，考虑到欧洲和其他种族群体之间明显不同的连锁不平衡模式，确定这些关联是否可以在其他种族群体（如亚洲人）中复制，将具有巨大的意义。在这项研究中，我们对韩国样本（N=8842）中的 CHRNA5/A3/B4 中的 32 个单核苷酸多态性（SNP）与吸烟起始（SI）、吸烟量（SQ）和戒烟（SC）进行了综合关联和交互分析。我们发现，在总样本中，有 7 个 SNP 与至少一种与吸烟相关的表型具有显著的关联（SI：P=0.015 到 0.023；SQ：P=0.008 到 0.028；SC：P=0.018 到 0.047），在男性样本中也有同样的结果（SI：P=0.001 到 0.023；SQ：P=0.001 到 0.046；SC：P=0.01）。位于 CHRNA5 上的 rs16969948 和 CHRNB4 5'端下游基因间区的 rs6495316 之间的三个连续 SNP 形成的一系列单倍型与总样本和男性样本中的这三个与吸烟相关的表型有关。值得注意的是，与 SC 相关的这些变体和单倍型的关联似乎比与 SI 和 SQ 的关联弱得多。此外，我们使用广义多因子降维方法对簇内的 SNP 进行了交互分析，发现 rs7163730 位于 LOC123688 中的 SNP、rs6495308 位于 CHRNA3 中的 SNP 以及 rs7166158、rs8043123 和 rs11072793 位于 CHRNB4 5'端下游基因间区中的 SNP 之间存在显著的交互作用，影响男性样本中的 SI。由于女性参与者中吸烟者的比例不到 5%，我们没有对女性参与者进行专门的分析。总之，我们在韩国吸烟者样本中检测到 CHRNA5/A3/B4 簇中的变异与 SI、SQ 和 SC 的关联，为该簇对亚洲人群中 SI、ND 和 SC 的病因学的贡献提供了有力的证据。
