INTRODUCTION Tobacco smoke exposure is an established risk factor for multiple sclerosis (MS), yet how it confers risk is not known. Evidence from observational studies suggests nicotine may be a protective component. Animal studies further support this hypothesis, demonstrating nicotine's protective effect in MS is mediated by the presence and absence of α7 and α9 nicotinic acetylcholine receptors (nAChRs), respectively. OBJECTIVE To determine if variation in the genes encoding α7 and α9 nAChRs (cholinergic receptor nicotinic alpha 7 (CHRNA7) and alpha 9 (CHRNA9)) will modify MS risk conferred by tobacco smoking. METHODS A multi-stage gene-environment (G×E) framework was utilized, including a case-control analysis (286 cases, 176 controls) with haplotype- and gene-based analyses, followed by an extension case-only (1053 cases) analysis for overlapping variants. RESULTS The results suggest that CHRNA7 and CHRNA9 modifies MS risk conferred by tobacco smoke, where risk among smokers was increased in carriers of the minor CHRNA9 haplotype and in non-carriers the minor CHRNA7 haplotype. The findings are consistent with the pharmacology of these receptors and animal studies of MS. CONCLUSION This study implicates novel processes in MS initiation and demonstrate the need for further G×E studies to advancing our understanding of the missing heritability of MS.

中文翻译：

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烟碱乙酰胆碱受体α7和α9改变烟草烟雾导致多发性硬化症的风险


引言 烟草烟雾暴露是多发性硬化症 (MS) 的既定危险因素，但其如何带来风险尚不清楚。观察性研究的证据表明尼古丁可能是一种保护性成分。动物研究进一步支持了这一假设，证明尼古丁对 MS 的保护作用分别是由 α7 和 α9 烟碱乙酰胆碱受体 (nAChR) 的存在和缺失介导的。目的 确定编码 α7 和 α9 nAChR（胆碱能受体烟碱 α 7 (CHRNA7) 和 α 9 (CHRNA9)）的基因变异是否会改变吸烟带来的多发性硬化症风险。方法 采用多阶段基因环境 (G×E) 框架，包括病例对照分析（286 例病例，176 例对照）以及基于单倍型和基因的分析，然后是仅扩展病例分析（1053 例）重叠变体的分析。结果结果表明，CHRNA7 和 CHRNA9 改变了烟草烟雾带来的 MS 风险，其中次要 CHRNA9 单倍型携带者和非次要 CHRNA7 单倍型携带者中吸烟者的风险增加。这些发现与这些受体的药理学和多发性硬化症的动物研究一致。结论 这项研究揭示了 MS 发生的新过程，并证明需要进一步的 G×E 研究，以增进我们对 MS 缺失遗传性的理解。