Contributions
Abstract: P454
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Environmental risk factors
Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We utilized separate-sample Mendelian Randomization (MR) to estimate the causal effect of body mass index (BMI) on MS susceptibility. For non-Hispanic Caucasian members of Kaiser Permanente, Northern California (1,104 MS cases and 10,536 controls) and a replication dataset from Sweden (5,133 MS cases and 4,718 controls), a weighted genetic risk score (GRS) was constructed using 97 variants previously established to predict BMI. Models were adjusted for birth year, sex, education, smoking, ancestry, and genetic predictors of MS including HLA-DRB1*15:01 and 110 non-HLA variants. We also examined this relationship in non-Hispanic white pediatric MS cases and controls from over 15 sites across the U.S. (total sample size: 394 MS cases, 10,875 controls). Adjusted MR estimates suggested higher genetically induced BMI predicted greater MS susceptibility in adult KPNC and Swedish datasets (odds ratio [OR] = 1.13, 95% CI 1.04, 1.22 and OR=1.09, 95% CI 1.03, 1.15, respectively). A significant causal association between BMI GRS and pediatric MS was also demonstrated (OR = 1.20, 95% CI 1.06, 1.36; p=0.004) after adjusting for sex, ancestry, HLA-DRB1*15:01, and 110 non-HLA MS risk variants. Although the mechanism remains unclear, these findings support a causal effect of increased BMI on MS and suggest a role for inflammatory pathways.
Disclosure:
L.F. Barcellos: nothing to disclose
M. Gianfrancesco: nothing to disclose
X. Shao: nothing to disclose
B. Rhead: nothing to disclose
J. Graves is supported by grants from the NMSS, Race to Erase MS, Biogen and Genentech.
A. Waldman: is supported by grants from the NIH (K23NS069806) and Biogen Idec.
T. Lotze: nothing to disclose
T. Schreiner: nothing to disclose
A. Belman: nothing to disclose
B. Greenberg: nothing to disclose
B. Weinstock-Guttman: nothing to disclose
G. Aaen: nothing to disclose
J.M. Tillema: nothing to disclose
J. Hart: nothing to disclose
J. Ness: nothing to disclose
Y. Harris: nothing to disclose
J. Rubin: nothing to disclose
M. Candee: nothing to disclose
L. Krupp: nothing to disclose
M. Gorman: nothing to disclose
L. Benson: nothing to disclose
M. Rodrigue: nothing to disclose
T. Chitnis: nothing to disclose
S. Mar: nothing to disclose
I. Kahn: nothing to disclose
J. Rose has research support from VA, NMSS, Guthy Jackson Charitable Foundation, Arrien Pharmaceuticals, Teva Neuroscience, Biogen and AbbVie.
S. Roalstad: nothing to disclose
T.C. Casper: nothing to disclose
L. Shen: nothing to disclose
H. Quach: nothing to disclose
C. Metayer: nothing to disclose
M. Glymour: nothing to disclose
S. Walter: nothing to disclose
A. Hubbard: nothing to disclose
I. Jónsdóttir: nothing to disclose
K. Stefansson: nothing to disclose
P. Strid: nothing to disclose
J. Hillert has received honoraria for serving on advisory boards for BiogenIdec and Novartis and speaker"s fees from BiogenIdec, Merck-Serono, Bayer-Schering, Teva and Sanofi-Aventis, and has served as principle investigator for projects, or received unrestricted research support from, BiogenIdec, Merck-Serono, TEVA, Sanofi-Aventis, Novartis and Bayer-Schering and his MS research is funded by the Swedish Research Council.
A. Hedstrom: nothing to disclose
T. Olsson has received lecture and/or advisory board honoraria, and unrestricted MS research grants from Astrazeneca, Biogen, Novartis , Allmiral and Genzyme.
I. Kockum has received honoraria for lecture from Merck Serono.
C. Schaefer: nothing to disclose
E. Waubant: nothing to disclose
L. Alfredsson: nothing to disclose
Abstract: P454
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Environmental risk factors
Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We utilized separate-sample Mendelian Randomization (MR) to estimate the causal effect of body mass index (BMI) on MS susceptibility. For non-Hispanic Caucasian members of Kaiser Permanente, Northern California (1,104 MS cases and 10,536 controls) and a replication dataset from Sweden (5,133 MS cases and 4,718 controls), a weighted genetic risk score (GRS) was constructed using 97 variants previously established to predict BMI. Models were adjusted for birth year, sex, education, smoking, ancestry, and genetic predictors of MS including HLA-DRB1*15:01 and 110 non-HLA variants. We also examined this relationship in non-Hispanic white pediatric MS cases and controls from over 15 sites across the U.S. (total sample size: 394 MS cases, 10,875 controls). Adjusted MR estimates suggested higher genetically induced BMI predicted greater MS susceptibility in adult KPNC and Swedish datasets (odds ratio [OR] = 1.13, 95% CI 1.04, 1.22 and OR=1.09, 95% CI 1.03, 1.15, respectively). A significant causal association between BMI GRS and pediatric MS was also demonstrated (OR = 1.20, 95% CI 1.06, 1.36; p=0.004) after adjusting for sex, ancestry, HLA-DRB1*15:01, and 110 non-HLA MS risk variants. Although the mechanism remains unclear, these findings support a causal effect of increased BMI on MS and suggest a role for inflammatory pathways.
Disclosure:
L.F. Barcellos: nothing to disclose
M. Gianfrancesco: nothing to disclose
X. Shao: nothing to disclose
B. Rhead: nothing to disclose
J. Graves is supported by grants from the NMSS, Race to Erase MS, Biogen and Genentech.
A. Waldman: is supported by grants from the NIH (K23NS069806) and Biogen Idec.
T. Lotze: nothing to disclose
T. Schreiner: nothing to disclose
A. Belman: nothing to disclose
B. Greenberg: nothing to disclose
B. Weinstock-Guttman: nothing to disclose
G. Aaen: nothing to disclose
J.M. Tillema: nothing to disclose
J. Hart: nothing to disclose
J. Ness: nothing to disclose
Y. Harris: nothing to disclose
J. Rubin: nothing to disclose
M. Candee: nothing to disclose
L. Krupp: nothing to disclose
M. Gorman: nothing to disclose
L. Benson: nothing to disclose
M. Rodrigue: nothing to disclose
T. Chitnis: nothing to disclose
S. Mar: nothing to disclose
I. Kahn: nothing to disclose
J. Rose has research support from VA, NMSS, Guthy Jackson Charitable Foundation, Arrien Pharmaceuticals, Teva Neuroscience, Biogen and AbbVie.
S. Roalstad: nothing to disclose
T.C. Casper: nothing to disclose
L. Shen: nothing to disclose
H. Quach: nothing to disclose
C. Metayer: nothing to disclose
M. Glymour: nothing to disclose
S. Walter: nothing to disclose
A. Hubbard: nothing to disclose
I. Jónsdóttir: nothing to disclose
K. Stefansson: nothing to disclose
P. Strid: nothing to disclose
J. Hillert has received honoraria for serving on advisory boards for BiogenIdec and Novartis and speaker"s fees from BiogenIdec, Merck-Serono, Bayer-Schering, Teva and Sanofi-Aventis, and has served as principle investigator for projects, or received unrestricted research support from, BiogenIdec, Merck-Serono, TEVA, Sanofi-Aventis, Novartis and Bayer-Schering and his MS research is funded by the Swedish Research Council.
A. Hedstrom: nothing to disclose
T. Olsson has received lecture and/or advisory board honoraria, and unrestricted MS research grants from Astrazeneca, Biogen, Novartis , Allmiral and Genzyme.
I. Kockum has received honoraria for lecture from Merck Serono.
C. Schaefer: nothing to disclose
E. Waubant: nothing to disclose
L. Alfredsson: nothing to disclose