Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA.
Cancer Epidemiol Biomarkers Prev. 2011 Dec;20(12):2603-9. doi: 10.1158/1055-9965.EPI-11-0749. Epub 2011 Oct 25.
Genetic variants located at 15q25, including those in the cholinergic receptor nicotinic cluster (CHRNA5) have been implicated in both lung cancer risk and nicotine dependence in recent genome-wide association studies. Among these variants, a 22-bp insertion/deletion, rs3841324 showed the strongest association with CHRNA5 mRNA expression levels. However the influence of rs3841324 on lung cancer risk has not been studied in depth.
We have, therefore, evaluated the association of rs3841324 genotypes with lung cancer risk in a case-control study of 624 Caucasian subjects with lung cancer and 766 age- and sex-matched cancer-free Caucasian controls. We also evaluated the joint effects of rs3841324 with single-nucleotide polymorphisms (SNP) rs16969968 and rs8034191 in the 15q25 region that have been consistently implicated in lung cancer risk.
We found that the homozygous genotype with both short alleles (SS) of rs3841324 was associated with a decreased lung cancer risk in female ever smokers relative to the homozygous wild-type (LL) and heterozygous (LS) genotypes combined in a recessive model [OR(adjusted) = 0.55, 95% confidence interval (CI), 0.31-0.89, P = 0.0168]. There was no evidence for a sex difference in the association between this variant and cigarettes smoked per day (CPD). Diplotype analysis of rs3841324 with either rs16969968 or rs8034191 showed that these polymorphisms influenced the lung cancer risk independently.
This study has shown a sex difference in the association between the 15q25 variant rs3841324 and lung cancers. Further research is warranted to elucidate the mechanisms underlying these observations.
位于 15q25 的遗传变异，包括胆碱能受体烟碱簇（CHRNA5）中的变异，在最近的全基因组关联研究中与肺癌风险和尼古丁依赖都有关。在这些变异中，22 个碱基对的插入/缺失，rs3841324 与 CHRNA5 mRNA 表达水平的相关性最强。然而，rs3841324 对肺癌风险的影响尚未深入研究。
因此，我们在一项包括 624 例白种人肺癌患者和 766 例年龄和性别匹配的无癌症白种人对照的病例对照研究中，评估了 rs3841324 基因型与肺癌风险的关联。我们还评估了 rs3841324 与 15q25 区域中一直与肺癌风险相关的单核苷酸多态性（SNP）rs16969968 和 rs8034191 的联合效应。
我们发现，与 rs3841324 的两个短等位基因（SS）纯合基因型相比，在女性曾吸烟者中，隐性模型下 rs3841324 的纯合野生型（LL）和杂合型（LS）基因型的组合与肺癌风险降低相关[OR（调整）=0.55，95%置信区间（CI），0.31-0.89，P=0.0168]。在该变异与每天吸烟量（CPD）之间的关联中，没有证据表明存在性别差异。rs3841324 与 rs16969968 或 rs8034191 的双等位基因分析表明，这些多态性独立影响肺癌风险。
本研究表明，15q25 变异 rs3841324 与肺癌之间的关联存在性别差异。需要进一步研究阐明这些观察结果的机制。
