Causal Effect of Genetic Variants Associated with Body Mass Index on Multiple Sclerosis Susceptibility

Milena A. Gianfrancesco, M. Maria Glymour, Stefan Walter, Brooke Rhead, Xiaorong Shao, Ling Shen, Hong Quach, Alan Hubbard, Ingileif Jónsdóttir, Kári Stefánsson, Pernilla Strid, Jan Hillert, Anna Hedström, Tomas Olsson, Ingrid Kockum, Catherine Schaefer, Lars Alfredsson, Lisa F. Barcellos

Rannsóknarafurð: Framlag til fræðitímaritsGreinritrýni

25 Tilvitnanir (Scopus)

Útdráttur

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.

Upprunalegt tungumálEnska
Síður (frá-til)162-171
Síðufjöldi10
FræðitímaritAmerican Journal of Epidemiology
Bindi185
Númer tölublaðs3
DOI
ÚtgáfustaðaÚtgefið - 1 feb. 2017

Athugasemd

Funding Information:
This work was supported by the National Institute of Neurological Disorders and Stroke (grants R01 NS049510, R01 NS0495103, and F31 NS093832); the National Institute of Allergy and Infectious Diseases (grants R01 AI 076544 and RC2 AG036607); the Robert Wood Johnson Foundation; the Wayne and Gladys Valley Foundation; the Ellison Medical Foundation; the AFA Foundation; the Knut and Alice Wallenberg Foundation; the Swedish Brain Foundation; the Margareta af Ugglas Foundation; European Union Seventh Framework Programme NEURINOX (grant 2012-278611); the Swedish Medical Research Council (grant 521-2012-2917 to L.A.); and the Swedish Research Council for Health, Working Life, and Welfare (including grants 2012-0325 and 2015-00195 to L.A.).

Publisher Copyright:
© 2017 The Author.

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