Nicotinic acetylcholine receptors α7 and α9 modifies tobacco smoke risk for multiple sclerosis

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 alpha 7 and alpha 9 nicotinic acetylcholine receptors (nAChRs), respectively. Objective: To determine if variation in the genes encoding alpha 7 and alpha 9 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 (GxE) 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 thatCHRNA7andCHRNA9modifies MS risk conferred by tobacco smoke, where risk among smokers was increased in carriers of the minorCHRNA9haplotype and in non-carriers the minorCHRNA7haplotype. 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 GxE studies to advancing our understanding of the missing heritability of MS.