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Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study.

Mokry LE, Ross S, Ahmad OS, Forgetta V, Smith GD, Leong A, Greenwood CM, Thanassoulis G, Richards JB - PLoS Med. (2015)

Bottom Line: We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10-12).MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7-2.5; p = 7.7 × 10-12; I2 = 63%, 95% CI: 0%-88%).While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely.

View Article: PubMed Central - PubMed

Affiliation: Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.

ABSTRACT

Background: Observational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS.

Methods and findings: We identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D. Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10-10 to 2 × 10-109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD. We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level. We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10-12). Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple Sclerosis Genetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls). Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions. MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7-2.5; p = 7.7 × 10-12; I2 = 63%, 95% CI: 0%-88%). This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio [OR] = 1.7, 95% CI: 1.3-2.2; p = 2.3 × 10-5; I2 = 47%, 95% CI: 0%-85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6-2.6, p = 1 × 10-9; ORmetabolism = 1.9, 95% CI: 1.3-2.7, p = 0.002). While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely.

Conclusions: A genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.

No MeSH data available.


Related in: MedlinePlus

Mendelian randomization estimate of the association of 25OHD level with risk of multiple sclerosis excluding the DHCR7 locus.Estimates obtained using a fixed-effects model.
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pmed.1001866.g005: Mendelian randomization estimate of the association of 25OHD level with risk of multiple sclerosis excluding the DHCR7 locus.Estimates obtained using a fixed-effects model.

Mentions: In order to estimate the association of genetically lowered 25OHD with MS, we used a fixed-effects model in which all four 25OHD-decreasing alleles of the MR set were included. We observed that each 1-SD decrease in natural-log-transformed 25OHD level was associated with an increased risk of MS (OR = 2.02, 95% CI: 1.65–2.46, p = 7.72 × 10−12) (Table 2; Fig 4). Given that the I2 estimate of heterogeneity was somewhat increased (I2 = 63%, 95% CI: 0%–88%), we also undertook random-effects meta-analysis, which generated similar findings (OR = 2.07, 95% CI: 1.45–2.96, p = 5.74 × 10−5) (Table 2; S1 Fig). We note that since our model included only four SNPs, the 95% CIs of the I2 statistic are wide, and consequently heterogeneity cannot be accurately measured using this parameter. In addition, to address the potential effects of population stratification and pleiotropy, we undertook a sensitivity analysis excluding the rs12785878 SNP (DHCR7). Despite removal of this variant, we observed a clear association of genetically lowered 25OHD level with the risk of MS (OR = 1.72, 95% CI: 1.34–2.21, p = 2.28 × 10−5; I2 = 47%, 95% CI: 0%–85%) (Table 3; Fig 5), which remained significant using a random-effects meta-analysis (OR = 1.82, 95% CI: 1.24–2.67, p = 2.13 × 10−3; I2 = 47%, 95% CI: 0%–85%) (Table 3; S2 Fig). Removal of the rs2282679 SNP (GC), which may possibly be influenced by pleiotropy, did not influence the MR results using a fixed-effects or random-effects model (OR = 2.17, 95% CI: 1.73–2.72, p = 1.7 × 10−11; I2 = 67%, 95% CI: 0%–91%; and OR = 2.32, 95% CI: 1.49–3.61, p = 1.8 × 10−4; I2 = 67%, 95% CI: 0%–90%, respectively) (S3 and S4 Figs). To further assess the effect of the independent vitamin D pathways on the risk of MS, we analyzed SNPs near genes implicated in 25OHD synthesis (DHCR7 and CYP2R1) and metabolism (GC and CYP24A1) separately and found that both strongly associated with increased risk of MS (Table 4; S5 and S6 Figs).


Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study.

Mokry LE, Ross S, Ahmad OS, Forgetta V, Smith GD, Leong A, Greenwood CM, Thanassoulis G, Richards JB - PLoS Med. (2015)

Mendelian randomization estimate of the association of 25OHD level with risk of multiple sclerosis excluding the DHCR7 locus.Estimates obtained using a fixed-effects model.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4549308&req=5

pmed.1001866.g005: Mendelian randomization estimate of the association of 25OHD level with risk of multiple sclerosis excluding the DHCR7 locus.Estimates obtained using a fixed-effects model.
Mentions: In order to estimate the association of genetically lowered 25OHD with MS, we used a fixed-effects model in which all four 25OHD-decreasing alleles of the MR set were included. We observed that each 1-SD decrease in natural-log-transformed 25OHD level was associated with an increased risk of MS (OR = 2.02, 95% CI: 1.65–2.46, p = 7.72 × 10−12) (Table 2; Fig 4). Given that the I2 estimate of heterogeneity was somewhat increased (I2 = 63%, 95% CI: 0%–88%), we also undertook random-effects meta-analysis, which generated similar findings (OR = 2.07, 95% CI: 1.45–2.96, p = 5.74 × 10−5) (Table 2; S1 Fig). We note that since our model included only four SNPs, the 95% CIs of the I2 statistic are wide, and consequently heterogeneity cannot be accurately measured using this parameter. In addition, to address the potential effects of population stratification and pleiotropy, we undertook a sensitivity analysis excluding the rs12785878 SNP (DHCR7). Despite removal of this variant, we observed a clear association of genetically lowered 25OHD level with the risk of MS (OR = 1.72, 95% CI: 1.34–2.21, p = 2.28 × 10−5; I2 = 47%, 95% CI: 0%–85%) (Table 3; Fig 5), which remained significant using a random-effects meta-analysis (OR = 1.82, 95% CI: 1.24–2.67, p = 2.13 × 10−3; I2 = 47%, 95% CI: 0%–85%) (Table 3; S2 Fig). Removal of the rs2282679 SNP (GC), which may possibly be influenced by pleiotropy, did not influence the MR results using a fixed-effects or random-effects model (OR = 2.17, 95% CI: 1.73–2.72, p = 1.7 × 10−11; I2 = 67%, 95% CI: 0%–91%; and OR = 2.32, 95% CI: 1.49–3.61, p = 1.8 × 10−4; I2 = 67%, 95% CI: 0%–90%, respectively) (S3 and S4 Figs). To further assess the effect of the independent vitamin D pathways on the risk of MS, we analyzed SNPs near genes implicated in 25OHD synthesis (DHCR7 and CYP2R1) and metabolism (GC and CYP24A1) separately and found that both strongly associated with increased risk of MS (Table 4; S5 and S6 Figs).

Bottom Line: We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10-12).MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7-2.5; p = 7.7 × 10-12; I2 = 63%, 95% CI: 0%-88%).While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely.

View Article: PubMed Central - PubMed

Affiliation: Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.

ABSTRACT

Background: Observational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS.

Methods and findings: We identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D. Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10-10 to 2 × 10-109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD. We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level. We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10-12). Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple Sclerosis Genetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls). Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions. MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7-2.5; p = 7.7 × 10-12; I2 = 63%, 95% CI: 0%-88%). This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio [OR] = 1.7, 95% CI: 1.3-2.2; p = 2.3 × 10-5; I2 = 47%, 95% CI: 0%-85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6-2.6, p = 1 × 10-9; ORmetabolism = 1.9, 95% CI: 1.3-2.7, p = 0.002). While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely.

Conclusions: A genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.

No MeSH data available.


Related in: MedlinePlus