A. Harroud

University of California San Francisco Neurology

Author Of 1 Presentation

Epidemiology Oral Presentation

FC04.05 - Understanding the relative contributions of obesity, vitamin D, leptin and adiponectin to MS risk: a Mendelian randomization mediation analysis

Speakers
Presentation Number
FC04.05
Presentation Topic
Epidemiology
Lecture Time
13:48 - 14:00

Abstract

Background

Obesity is increasingly recognized as a risk for multiple sclerosis (MS). While the underlying mechanisms remain undetermined, reduced vitamin D bioavailability and altered levels of the immunomodulatory cytokines adiponectin and leptin have been proposed.

Objectives

To determine the roles of vitamin D, adiponectin and leptin levels in explaining the effect of obesity on MS, using a Mendelian randomization (MR) mediation framework.

Methods

Independent genetic estimates for body mass index (BMI), 25-hydroxyvitamin D (25OHD), adiponectin and leptin levels were obtained from from large-scale genome-wide association studies and the UK Biobank, totalling over 800,000 participants. The effect on MS was measured using summary genetic data on 14,802 MS cases and 26,703 controls from the International MS Genetics Consortium (IMSGC). To avoid bias from population stratification, all participants were of European ancestry. We estimated the odds of MS for each of the exposures, and the proportion of the effect of BMI explained by potential mediators significantly associated with MS, using the product of coefficients method in a two-step MR framework.

Results

Each standard deviation (SD) increase in BMI was associated with a 40% increase in the odds of MS (95% CI 1.16 to 1.67, P=3.1x10-4). Similarly, a SD increase in standardized log transformed 25OHD levels reduced the odds of MS by 28% (95% CI 0.60-0.87, P=6.2x10-4). In contrast, we observed no notable effect of adiponectin (OR=1.05, 95% CI 0.74-1.49, P=0.78) or leptin (OR=1.18, 95% CI 0.59-2.36, P=0.64) on the odds of MS. In MR mediation analysis, we estimate that the reduction in 25OHD levels only explains 5.4% of the effect of increased BMI on the risk of MS (95% CI 0.4% to 30.5%). Sensitivity analyses showed that these estimates were robust to potential bias from pleiotropy.

Conclusions

This study found that only a minority of the increased risk of MS conferred by obesity is mediated by lowered vitamin D levels, while leptin and adiponectin had no measurable effect. This suggests that vitamin D supplementation would only modestly reverse the effect of obesity on MS, the majority of which remains unexplained.

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Presenter Of 1 Presentation

Epidemiology Oral Presentation

FC04.05 - Understanding the relative contributions of obesity, vitamin D, leptin and adiponectin to MS risk: a Mendelian randomization mediation analysis

Speakers
Presentation Number
FC04.05
Presentation Topic
Epidemiology
Lecture Time
13:48 - 14:00

Abstract

Background

Obesity is increasingly recognized as a risk for multiple sclerosis (MS). While the underlying mechanisms remain undetermined, reduced vitamin D bioavailability and altered levels of the immunomodulatory cytokines adiponectin and leptin have been proposed.

Objectives

To determine the roles of vitamin D, adiponectin and leptin levels in explaining the effect of obesity on MS, using a Mendelian randomization (MR) mediation framework.

Methods

Independent genetic estimates for body mass index (BMI), 25-hydroxyvitamin D (25OHD), adiponectin and leptin levels were obtained from from large-scale genome-wide association studies and the UK Biobank, totalling over 800,000 participants. The effect on MS was measured using summary genetic data on 14,802 MS cases and 26,703 controls from the International MS Genetics Consortium (IMSGC). To avoid bias from population stratification, all participants were of European ancestry. We estimated the odds of MS for each of the exposures, and the proportion of the effect of BMI explained by potential mediators significantly associated with MS, using the product of coefficients method in a two-step MR framework.

Results

Each standard deviation (SD) increase in BMI was associated with a 40% increase in the odds of MS (95% CI 1.16 to 1.67, P=3.1x10-4). Similarly, a SD increase in standardized log transformed 25OHD levels reduced the odds of MS by 28% (95% CI 0.60-0.87, P=6.2x10-4). In contrast, we observed no notable effect of adiponectin (OR=1.05, 95% CI 0.74-1.49, P=0.78) or leptin (OR=1.18, 95% CI 0.59-2.36, P=0.64) on the odds of MS. In MR mediation analysis, we estimate that the reduction in 25OHD levels only explains 5.4% of the effect of increased BMI on the risk of MS (95% CI 0.4% to 30.5%). Sensitivity analyses showed that these estimates were robust to potential bias from pleiotropy.

Conclusions

This study found that only a minority of the increased risk of MS conferred by obesity is mediated by lowered vitamin D levels, while leptin and adiponectin had no measurable effect. This suggests that vitamin D supplementation would only modestly reverse the effect of obesity on MS, the majority of which remains unexplained.

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