Briggs Farren B S, Acuna Brigid, Shen Ling, Ramsay Patricia, Quach Hong, Bernstein Allan, Bellesis Kalliope H, Kockum Ingrid S, Hedström Anna K, Alfredsson Lars, Olsson Tomas, Schaefer Catherine, Barcellos Lisa F
From the aGenetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, CA; bDivision of Research, Kaiser Permanente, Oakland, CA; cPalm Drive Hospital, Sebastopol, CA; dDepartment of Medicine, Center for Molecular Medicine, Karolinska Institute, Solna, Sweden; eInstitute of Environmental Medicine, Karolinska Institute, Solna, Sweden.
Epidemiology. 2014 Jul;25(4):605-14. doi: 10.1097/EDE.0000000000000089.
Tobacco smoke is an established risk factor for multiple sclerosis (MS). We hypothesized that variation in genes involved in metabolism of tobacco smoke constituents may modify MS risk in smokers.
A three-stage gene-environment investigation was conducted for NAT1, NAT2, and GSTP1 variants. The discovery analysis was conducted among 1588 white MS cases and controls from the Kaiser Permanente Northern California Region HealthPlan (Kaiser). The replication analysis was carried out in 988 white MS cases and controls from Sweden.
Tobacco smoke exposure at the age of 20 years was associated with greater MS risk in both data sets (in Kaiser, odds ratio [OR] = 1.51 [95% confidence interval (CI) = 1.17-1.93]; in Sweden, OR = 1.35 [1.04-1.74]). A total of 42 NAT1 variants showed evidence for interaction with tobacco smoke exposure (P(corrected) < 0.05). Genotypes for 41 NAT1 single nucleotide polymorphisms (SNPs) were studied in the replication data set. A variant (rs7388368C>A) within a dense transcription factor-binding region showed evidence for interaction (Kaiser, OR for interaction = 1.75 [95% CI = 1.19-2.56]; Sweden, OR = 1.62 [1.05-2.49]). Tobacco smoke exposure was associated with MS risk among rs7388368A carriers only; homozygote individuals had the highest risk (A/A, OR = 5.17 [95% CI = 2.17-12.33]).
We conducted a three-stage analysis using two population-based case-control datasets that consisted of a discovery population, a replication population, and a pooled analysis. NAT1 emerged as a genetic effect modifier of tobacco smoke exposure in MS susceptibility.
烟草烟雾是多发性硬化症（MS）的既定风险因素。我们假设参与烟草烟雾成分代谢的基因变异可能会改变吸烟者患MS的风险。
针对NAT1、NAT2和GSTP1变异进行了三阶段基因-环境调查。发现分析在来自北加利福尼亚州凯撒永久医疗集团健康计划（凯撒）的1588名白人MS病例和对照中进行。复制分析在来自瑞典的988名白人MS病例和对照中进行。
在两个数据集中，20岁时接触烟草烟雾均与更高的MS风险相关（在凯撒，比值比[OR]=1.51[95%置信区间（CI）=1.17-1.93]；在瑞典，OR=1.35[1.04-1.74]）。共有42个NAT1变异显示出与烟草烟雾暴露存在相互作用的证据（校正P<0.05）。在复制数据集中研究了41个NAT1单核苷酸多态性（SNP）的基因型。一个位于密集转录因子结合区域内的变异（rs7388368C>A）显示出相互作用的证据（凯撒，相互作用的OR=1.75[95%CI=1.19-2.56]；瑞典，OR=1.62[1.05-2.49]）。仅在rs7388368A携带者中，烟草烟雾暴露与MS风险相关；纯合子个体风险最高（A/A，OR=5.17[95%CI=2.17-12.33]）。
我们使用两个基于人群的病例对照数据集进行了三阶段分析，包括一个发现人群、一个复制人群和一个汇总分析。NAT1成为MS易感性中烟草烟雾暴露的遗传效应修饰因子。
