Contributions
Abstract: P452
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Environmental risk factors
Background: Low serum levels of 25-hydroxyvitamin D (25(OH)D) are associated with a higher risk of multiple sclerosis (MS) and with greater MS activity and disease progression. However, a causal relationship between 25(OH)D and MS has not been firmly established.
Methods: We conducted Mendelian randomization analyses using three single nucleotide polymorphisms found to be associated with serum 25(OH)D level in a genome-wide association study (Ahn et al., 2010) to estimate the causal effect of low 25(OH)D on MS susceptibility. We constructed the instrumental variable (IV) by computing a weighted genetic score for variants associated with increasing 25(OH)D levels in serum, using the estimated effect of each risk variant: rs2282679-C, in an intron of GC; rs2060793-G, upstream of CYP2R1; and rs3829251-A, in an intron of NADSYN1. We analyzed the effect of the IV on MS susceptibility in two separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, ancestry, self-reported body mass index at age 18-20, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles, the strongest genetic risk factor for MS.
Results: The genetic score for increasing levels of 25(OH)D was associated with a decreased risk of MS in both populations. In White, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the causal odds ratio (OR) was 0.79 (p=0.04, 95% CI: 0.64-0.99). In members of a Swedish population from the EIMS and GEMS MS case-control studies (6,335 cases and 5,762 controls), the causal OR was 0.86 (p=0.03, 95% CI: 0.76-0.98). A meta-analysis of the two populations gave a combined causal OR of 0.85 (p=0.003, 95% CI: 0.76-0.94).
Conclusion: These results provide evidence that low serum 25(OH)D concentrations are a cause, rather than a result, of MS, independent of established risk factors.
*These authors contributed equally.
Disclosure:
B. Rhead: nothing to disclose
M. Bäärnhielm: nothing to disclose
M. Gianfrancesco: nothing to disclose
A. Mok: nothing to disclose
X. Shao: nothing to disclose
H. Quach: nothing to disclose
L. Shen: nothing to disclose
C. Schaefer: nothing to disclose
J. Link has received research support from Neuro Sweden.
A. Gyllenberg has received funding from the Swedish NEURO foundation 2014-2015.
A.K. Hedström: nothing to disclose
T. Olsson has received lecture and/or advisory board honoraria, and unrestricted MS research grant support from Biogen, Novartis, Genzyme and Merck. He has received academic grant support from the Swedish research Council, the AFA foundation, the Knut and Alice Wallenberg foundation and the Swedish Brain foundation.
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. His MS research is funded by the Swedish Research Council.
I. Kockum has received speaker honoraria from Merck. Has received research support from the “100års fonden”, NHR foundation and Swedish childhood diabetes foundation.
L. Alfredsson receives research support from the Swedish Medical Research Council (521-2012-2917) and Swedish Research Council for Health, Working Life and Welfare (2012-0325 and 2015-00195) and the Swedish Brain Foundation; received speaker honoraria from Teva.
L.F. Barcellos: nothing to disclose
Abstract: P452
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Environmental risk factors
Background: Low serum levels of 25-hydroxyvitamin D (25(OH)D) are associated with a higher risk of multiple sclerosis (MS) and with greater MS activity and disease progression. However, a causal relationship between 25(OH)D and MS has not been firmly established.
Methods: We conducted Mendelian randomization analyses using three single nucleotide polymorphisms found to be associated with serum 25(OH)D level in a genome-wide association study (Ahn et al., 2010) to estimate the causal effect of low 25(OH)D on MS susceptibility. We constructed the instrumental variable (IV) by computing a weighted genetic score for variants associated with increasing 25(OH)D levels in serum, using the estimated effect of each risk variant: rs2282679-C, in an intron of GC; rs2060793-G, upstream of CYP2R1; and rs3829251-A, in an intron of NADSYN1. We analyzed the effect of the IV on MS susceptibility in two separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, ancestry, self-reported body mass index at age 18-20, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles, the strongest genetic risk factor for MS.
Results: The genetic score for increasing levels of 25(OH)D was associated with a decreased risk of MS in both populations. In White, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the causal odds ratio (OR) was 0.79 (p=0.04, 95% CI: 0.64-0.99). In members of a Swedish population from the EIMS and GEMS MS case-control studies (6,335 cases and 5,762 controls), the causal OR was 0.86 (p=0.03, 95% CI: 0.76-0.98). A meta-analysis of the two populations gave a combined causal OR of 0.85 (p=0.003, 95% CI: 0.76-0.94).
Conclusion: These results provide evidence that low serum 25(OH)D concentrations are a cause, rather than a result, of MS, independent of established risk factors.
*These authors contributed equally.
Disclosure:
B. Rhead: nothing to disclose
M. Bäärnhielm: nothing to disclose
M. Gianfrancesco: nothing to disclose
A. Mok: nothing to disclose
X. Shao: nothing to disclose
H. Quach: nothing to disclose
L. Shen: nothing to disclose
C. Schaefer: nothing to disclose
J. Link has received research support from Neuro Sweden.
A. Gyllenberg has received funding from the Swedish NEURO foundation 2014-2015.
A.K. Hedström: nothing to disclose
T. Olsson has received lecture and/or advisory board honoraria, and unrestricted MS research grant support from Biogen, Novartis, Genzyme and Merck. He has received academic grant support from the Swedish research Council, the AFA foundation, the Knut and Alice Wallenberg foundation and the Swedish Brain foundation.
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. His MS research is funded by the Swedish Research Council.
I. Kockum has received speaker honoraria from Merck. Has received research support from the “100års fonden”, NHR foundation and Swedish childhood diabetes foundation.
L. Alfredsson receives research support from the Swedish Medical Research Council (521-2012-2917) and Swedish Research Council for Health, Working Life and Welfare (2012-0325 and 2015-00195) and the Swedish Brain Foundation; received speaker honoraria from Teva.
L.F. Barcellos: nothing to disclose