Gianfrancesco Milena A, Stridh Pernilla, Rhead Brooke, Shao Xiaorong, Xu Edison, Graves Jennifer S, Chitnis Tanuja, Waldman Amy, Lotze Timothy, Schreiner Teri, Belman Anita, Greenberg Benjamin, Weinstock-Guttman Bianca, Aaen Gregory, Tillema Jan M, Hart Janace, Caillier Stacy, Ness Jayne, Harris Yolanda, Rubin Jennifer, Candee Meghan, Krupp Lauren, Gorman Mark, Benson Leslie, Rodriguez Moses, Mar Soe, Kahn Ilana, Rose John, Roalstad Shelly, Casper T Charles, Shen Ling, Quach Hong, Quach Diana, Hillert Jan, Bäärnhielm Maria, Hedstrom Anna, Olsson Tomas, Kockum Ingrid, Alfredsson Lars, Metayer Catherine, Schaefer Catherine, Barcellos Lisa F, Waubant Emmanuelle
From the Division of Epidemiology, School of Public Health (M.A.G., X.S., E.X., H.Q., D.Q., C.M., L.F.B.), and Computational Biology Graduate Group (B.R.), University of California, Berkeley; Department of Clinical Neuroscience and Center for Molecular Medicine (P.S.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Neurology (J.S.G., E.W.) and Regional Pediatric MS Center, Neurology (J.H., S.C.), University of California, San Francisco; Partners Pediatric Multiple Sclerosis Center (T.C.), Massachusetts General Hospital for Children, Boston; Division of Neurology (A.W.), Children's Hospital of Philadelphia, PA; Blue Bird Circle Multiple Sclerosis Center (T.L.), Baylor College of Medicine, Houston, TX; Children's Hospital Colorado (T.S.), University of Colorado, Denver; Lourie Center for Pediatric Multiple Sclerosis (A.B., L.K.), Stony Brook Children's Hospital, NY; Department of Neurology (B.G.), University of Texas Southwestern, Dallas; Pediatric Multiple Sclerosis Center (B.W.-G.), Jacobs Neurological Institute, SUNY Buffalo, NY; Pediatric MS Center at Loma Linda University Children's Hospital (G.A.), CA; Mayo Clinic's Pediatric Multiple Sclerosis Center (J.M.T., M.R.), Rochester, MN; University of Alabama Center for Pediatric-onset Demyelinating Disease (J.N., Y.H.), Children's Hospital of Alabama, Birmingham; Department of Pediatric Neurology (J.R.), Northwestern Feinberg School of Medicine, Chicago, IL; Primary Children's Hospital (M.C.), University of Utah, Salt Lake City; Boston Children's Hospital (M.G., L.B.), MA; Pediatric-onset Demyelinating Diseases and Autoimmune Encephalitis Center (S.M.), St. Louis Children's Hospital, Washington University School of Medicine, MO; Children's National Medical Center (I.K.), Washington, DC; Departments of Neurology (J.R.) and Pediatrics (S.R., T.C.C.), University of Utah School of Medicine, Salt Lake City; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Oakland, CA; Institute of Environmental Medicine (J.H., M.B., A.H., T.O., I.K., L.A.), Karolinska Institutet; Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Stockholm, Sweden; and Research Program on Genes, Environment and Health (C.S.), Kaiser Permanente, Oakland, CA.
Neurology. 2017 Apr 25;88(17):1623-1629. doi: 10.1212/WNL.0000000000003849. Epub 2017 Mar 29.
To utilize Mendelian randomization to estimate the causal association between low serum vitamin D concentrations, increased body mass index (BMI), and pediatric-onset multiple sclerosis (MS) using genetic risk scores (GRS).
We constructed an instrumental variable for vitamin D (vitD GRS) by computing a GRS for 3 genetic variants associated with levels of 25(OH)D in serum using the estimated effect of each risk variant. A BMI GRS was also created that incorporates the cumulative effect of 97 variants associated with BMI. Participants included non-Hispanic white individuals recruited from over 15 sites across the United States (n = 394 cases, 10,875 controls) and Sweden (n = 175 cases, 5,376 controls; total n = 16,820).
Meta-analysis findings demonstrated that a vitD GRS associated with increasing levels of 25(OH)D in serum decreased the odds of pediatric-onset MS (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.55, 0.94; = 0.02) after controlling for sex, genetic ancestry, , and over 100 non-human leukocyte antigen MS risk variants. A significant association between BMI GRS and pediatric disease onset was also demonstrated (OR 1.17, 95% CI 1.05, 1.30; = 0.01) after adjusting for covariates. Estimates for each GRS were unchanged when considered together in a multivariable model.
We provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS.
利用孟德尔随机化方法，使用遗传风险评分（GRS）来估计低血清维生素D浓度、体重指数（BMI）增加与儿童期多发性硬化症（MS）之间的因果关联。
我们通过使用每个风险变异体的估计效应，计算与血清25(OH)D水平相关的3个基因变异体的GRS，构建了维生素D的工具变量（vitD GRS）。还创建了一个BMI GRS，该评分纳入了与BMI相关的97个变异体的累积效应。参与者包括从美国15个以上地点招募的非西班牙裔白人个体（n = 394例，10,875例对照）和瑞典个体（n = 175例，5,376例对照；总计n = 16,820）。
荟萃分析结果表明，在控制了性别、遗传血统、以及100多个非人类白细胞抗原MS风险变异体后，与血清中25(OH)D水平升高相关的vitD GRS降低了儿童期MS的发病几率（优势比[OR] 0.72，95%置信区间[CI] 0.55，0.94；P = 0.02）。在调整协变量后，也证明了BMI GRS与儿童疾病发病之间存在显著关联（OR 1.17，95% CI 1.05，1.30；P = 0.01）。在多变量模型中一起考虑时，每个GRS的估计值不变。
我们提供的证据支持维生素D水平降低和BMI增加对儿童期MS易感性的独立因果效应。
