Gianfrancesco Milena A, Glymour M Maria, Walter Stefan, Rhead Brooke, Shao Xiaorong, Shen Ling, Quach Hong, Hubbard Alan, Jónsdóttir Ingileif, Stefánsson Kári, Strid Pernilla, Hillert Jan, Hedström Anna, Olsson Tomas, Kockum Ingrid, Schaefer Catherine, Alfredsson Lars, Barcellos Lisa F
Genetic Epidemiology and Genomics Lab, Division of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
Department of Epidemiology and Biostatistics, University of California, San Francisco, USA.
Am J Epidemiol. 2017 Feb 1;185(3):162-171. doi: 10.1093/aje/kww120.
Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate that childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We used separate-sample Mendelian randomization to estimate the causal effect of body mass index (BMI) on susceptibility to MS. Using data from non-Hispanic white members of the Kaiser Permanente Medical Care Plan of Northern California (KPNC) (2006-2014; 1,104 cases of MS and 10,536 controls) and a replication data set from Sweden (the Epidemiological Investigation of MS (EIMS) and the Genes and Environment in MS (GEMS) studies, 2005-2013; 5,133 MS cases and 4,718 controls), we constructed a weighted genetic risk score using 97 variants previously established to predict BMI. Results were adjusted for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS. Estimates in KPNC and Swedish data sets suggested that higher genetically induced BMI predicted greater susceptibility to MS (odds ratio = 1.13, 95% confidence interval: 1.04, 1.22 for the KPNC sample; odds ratio = 1.09, 95% confidence interval: 1.03, 1.15 for the Swedish sample). Although the mechanism remains unclear, to our knowledge, these findings support a causal effect of increased BMI on susceptibility to MS for the first time, and they suggest a role for inflammatory pathways that characterize both obesity and the MS disease process.
多发性硬化症（MS）是一种具有遗传和环境风险因素的自身免疫性疾病。最近的研究表明，儿童期和青少年肥胖会使患MS的风险加倍，但这种关联可能反映的是未测量的混杂因素，而非肥胖的因果效应。我们使用独立样本孟德尔随机化方法来估计体重指数（BMI）对MS易感性的因果效应。利用北加利福尼亚凯撒永久医疗保健计划（KPNC）中未受西班牙裔影响的白人成员的数据（2006 - 2014年；1104例MS病例和10536例对照）以及来自瑞典的一个重复数据集（MS的流行病学调查（EIMS）和MS中的基因与环境（GEMS）研究，2005 - 2013年；5133例MS病例和4718例对照），我们使用先前确定的97个预测BMI的变体构建了一个加权遗传风险评分。结果针对出生年份、性别、教育程度、吸烟状况、血统以及MS的遗传预测因素进行了调整。KPNC和瑞典数据集中的估计表明，更高的遗传诱导BMI预示着对MS的易感性更高（优势比 = 1.13，95%置信区间：KPNC样本为1.04，1.22；瑞典样本为优势比 = 1.09，95%置信区间：1.03，1.15）。尽管机制尚不清楚，但据我们所知，这些发现首次支持了BMI升高对MS易感性的因果效应，并且表明了炎症途径在肥胖和MS疾病过程中的作用。
