The relative contributions of obesity, vitamin D, leptin and adiponectin to multiple sclerosis risk: a Mendelian randomization mediation analysis

Adil  Harroud; Despoina Manousaki; Guillaume  Butler-Laporte; Ruth E Mitchell; George Davey Smith; J Brent Richards; Sergio E Baranzini

doi:10.1177/1352458521995484

The relative contributions of obesity, vitamin D, leptin and adiponectin to multiple sclerosis risk: a Mendelian randomization mediation analysis

Adil Harroud, Despoina Manousaki, Guillaume Butler-Laporte, Ruth E Mitchell, George Davey Smith, J Brent Richards, Sergio E Baranzini

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

Background:
Obesity is associated with increased risk of multiple sclerosis (MS); however, the underlying mechanisms remain unclear.

Objective:
To determine the extent to which decreased vitamin D bioavailability and altered levels of adiponectin and leptin mediate the association between obesity and MS.

Methods:
We performed Mendelian randomization (MR) analyses to estimate the effects on MS of body mass index (BMI), 25-hydroxyvitamin D (25OHD), adiponectin, and leptin levels in a cohort of 14,802 MS cases and 26,703 controls. We then estimated the proportion of the effect of obesity on MS explained by these potential mediators.

Results:
Genetic predisposition to higher BMI was associated with increased MS risk (odds ratio (OR) = 1.33 per standard deviation (SD), 95% confidence interval (CI) = 1.09–1.63), while higher 25OHD levels reduced odds of MS (OR = 0.72 per SD, 95% CI = 0.60–0.87). In contrast, we observed no effect of adiponectin or leptin. In MR mediation analysis, 5.2% of the association between BMI and MS was attributed to obesity lowering 25OHD levels (95% CI = 0.3%–31.0%).

Conclusions:
This study found that a minority of the increased risk of MS conferred by obesity is mediated by lowered vitamin D levels, while leptin and adiponectin had no effect. Consequently, vitamin D supplementation would only modestly reverse the effect of obesity on MS.

Original language	English
Pages (from-to)	1994-2000
Number of pages	7
Journal	Multiple Sclerosis Journal
Volume	27
Issue number	13
Early online date	19 Feb 2021
DOIs	https://doi.org/10.1177/1352458521995484
Publication status	Published - Nov 2021

Bibliographical note

Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the NMSS-ABF Clinician Scientist Development Award from the National Multiple Sclerosis Society and the Multiple Sclerosis Society of Canada (FAN-1808-32256 to A.H.), by the Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/1 to R.E.M.), and by the National Institutes of Health (NIH) (R01NS099240 to S.E.B). S.E.B. holds the Distinguished Professorship in Neurology I and is the Heidrich Family and Friends Endowed Chair in Neurology at University of California San Francisco (UCSF). The Richards research group is supported by the Canadian Institutes of Health Research (grants 365825; 409511), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation, the NIH Foundation, Cancer Research UK, Genome Québec, the Public Health Agency of Canada, and the Fonds de Recherche Québec Santé (FRQS). J.E.B. is supported by an FRQS Clinical Research Scholarship. Support from Calcul Québec and Compute Canada is acknowledged. TwinsUK is funded by the Welcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London.

Publisher Copyright:
© The Author(s), 2021.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

multiple sclerosis
Mendelian randomization
obesity
vitamin D
genetic epidemiology

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10.1177/1352458521995484

Full-text PDF (author’s accepted manuscript)
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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. (Principal Investigator) & Davey Smith, G. (Principal Investigator)
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Project: Research

Cite this

@article{cce12c15c54846d2b22513e8f2283ce2,

title = "The relative contributions of obesity, vitamin D, leptin and adiponectin to multiple sclerosis risk: a Mendelian randomization mediation analysis",

abstract = "Background: Obesity is associated with increased risk of multiple sclerosis (MS); however, the underlying mechanisms remain unclear. Objective: To determine the extent to which decreased vitamin D bioavailability and altered levels of adiponectin and leptin mediate the association between obesity and MS. Methods: We performed Mendelian randomization (MR) analyses to estimate the effects on MS of body mass index (BMI), 25-hydroxyvitamin D (25OHD), adiponectin, and leptin levels in a cohort of 14,802 MS cases and 26,703 controls. We then estimated the proportion of the effect of obesity on MS explained by these potential mediators. Results: Genetic predisposition to higher BMI was associated with increased MS risk (odds ratio (OR) = 1.33 per standard deviation (SD), 95\% confidence interval (CI) = 1.09–1.63), while higher 25OHD levels reduced odds of MS (OR = 0.72 per SD, 95\% CI = 0.60–0.87). In contrast, we observed no effect of adiponectin or leptin. In MR mediation analysis, 5.2\% of the association between BMI and MS was attributed to obesity lowering 25OHD levels (95\% CI = 0.3\%–31.0\%). Conclusions: This study found that a minority of the increased risk of MS conferred by obesity is mediated by lowered vitamin D levels, while leptin and adiponectin had no effect. Consequently, vitamin D supplementation would only modestly reverse the effect of obesity on MS.",

keywords = "multiple sclerosis, Mendelian randomization, obesity, vitamin D, genetic epidemiology",

author = "Adil Harroud and Despoina Manousaki and Guillaume Butler-Laporte and Mitchell, \{Ruth E\} and \{Davey Smith\}, George and Richards, \{J Brent\} and Baranzini, \{Sergio E\}",

note = "Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the NMSS-ABF Clinician Scientist Development Award from the National Multiple Sclerosis Society and the Multiple Sclerosis Society of Canada (FAN-1808-32256 to A.H.), by the Medical Research Council Integrative Epidemiology Unit (MC\_UU\_00011/1 to R.E.M.), and by the National Institutes of Health (NIH) (R01NS099240 to S.E.B). S.E.B. holds the Distinguished Professorship in Neurology I and is the Heidrich Family and Friends Endowed Chair in Neurology at University of California San Francisco (UCSF). The Richards research group is supported by the Canadian Institutes of Health Research (grants 365825; 409511), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation, the NIH Foundation, Cancer Research UK, Genome Qu{\'e}bec, the Public Health Agency of Canada, and the Fonds de Recherche Qu{\'e}bec Sant{\'e} (FRQS). J.E.B. is supported by an FRQS Clinical Research Scholarship. Support from Calcul Qu{\'e}bec and Compute Canada is acknowledged. TwinsUK is funded by the Welcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust in partnership with King{\textquoteright}s College London. Publisher Copyright: {\textcopyright} The Author(s), 2021.",

year = "2021",

month = nov,

doi = "10.1177/1352458521995484",

language = "English",

volume = "27",

pages = "1994--2000",

journal = "Multiple Sclerosis Journal",

issn = "1352-4585",

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}

The relative contributions of obesity, vitamin D, leptin and adiponectin to multiple sclerosis risk: a Mendelian randomization mediation analysis. / Harroud, Adil ; Manousaki, Despoina; Butler-Laporte, Guillaume et al.
In: Multiple Sclerosis Journal, Vol. 27, No. 13, 11.2021, p. 1994-2000.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - The relative contributions of obesity, vitamin D, leptin and adiponectin to multiple sclerosis risk

T2 - a Mendelian randomization mediation analysis

AU - Harroud, Adil

AU - Manousaki, Despoina

AU - Butler-Laporte, Guillaume

AU - Mitchell, Ruth E

AU - Davey Smith, George

AU - Richards, J Brent

AU - Baranzini, Sergio E

N1 - Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the NMSS-ABF Clinician Scientist Development Award from the National Multiple Sclerosis Society and the Multiple Sclerosis Society of Canada (FAN-1808-32256 to A.H.), by the Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/1 to R.E.M.), and by the National Institutes of Health (NIH) (R01NS099240 to S.E.B). S.E.B. holds the Distinguished Professorship in Neurology I and is the Heidrich Family and Friends Endowed Chair in Neurology at University of California San Francisco (UCSF). The Richards research group is supported by the Canadian Institutes of Health Research (grants 365825; 409511), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation, the NIH Foundation, Cancer Research UK, Genome Québec, the Public Health Agency of Canada, and the Fonds de Recherche Québec Santé (FRQS). J.E.B. is supported by an FRQS Clinical Research Scholarship. Support from Calcul Québec and Compute Canada is acknowledged. TwinsUK is funded by the Welcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. Publisher Copyright: © The Author(s), 2021.

PY - 2021/11

Y1 - 2021/11

N2 - Background: Obesity is associated with increased risk of multiple sclerosis (MS); however, the underlying mechanisms remain unclear. Objective: To determine the extent to which decreased vitamin D bioavailability and altered levels of adiponectin and leptin mediate the association between obesity and MS. Methods: We performed Mendelian randomization (MR) analyses to estimate the effects on MS of body mass index (BMI), 25-hydroxyvitamin D (25OHD), adiponectin, and leptin levels in a cohort of 14,802 MS cases and 26,703 controls. We then estimated the proportion of the effect of obesity on MS explained by these potential mediators. Results: Genetic predisposition to higher BMI was associated with increased MS risk (odds ratio (OR) = 1.33 per standard deviation (SD), 95% confidence interval (CI) = 1.09–1.63), while higher 25OHD levels reduced odds of MS (OR = 0.72 per SD, 95% CI = 0.60–0.87). In contrast, we observed no effect of adiponectin or leptin. In MR mediation analysis, 5.2% of the association between BMI and MS was attributed to obesity lowering 25OHD levels (95% CI = 0.3%–31.0%). Conclusions: This study found that a minority of the increased risk of MS conferred by obesity is mediated by lowered vitamin D levels, while leptin and adiponectin had no effect. Consequently, vitamin D supplementation would only modestly reverse the effect of obesity on MS.

AB - Background: Obesity is associated with increased risk of multiple sclerosis (MS); however, the underlying mechanisms remain unclear. Objective: To determine the extent to which decreased vitamin D bioavailability and altered levels of adiponectin and leptin mediate the association between obesity and MS. Methods: We performed Mendelian randomization (MR) analyses to estimate the effects on MS of body mass index (BMI), 25-hydroxyvitamin D (25OHD), adiponectin, and leptin levels in a cohort of 14,802 MS cases and 26,703 controls. We then estimated the proportion of the effect of obesity on MS explained by these potential mediators. Results: Genetic predisposition to higher BMI was associated with increased MS risk (odds ratio (OR) = 1.33 per standard deviation (SD), 95% confidence interval (CI) = 1.09–1.63), while higher 25OHD levels reduced odds of MS (OR = 0.72 per SD, 95% CI = 0.60–0.87). In contrast, we observed no effect of adiponectin or leptin. In MR mediation analysis, 5.2% of the association between BMI and MS was attributed to obesity lowering 25OHD levels (95% CI = 0.3%–31.0%). Conclusions: This study found that a minority of the increased risk of MS conferred by obesity is mediated by lowered vitamin D levels, while leptin and adiponectin had no effect. Consequently, vitamin D supplementation would only modestly reverse the effect of obesity on MS.

KW - multiple sclerosis

KW - Mendelian randomization

KW - obesity

KW - vitamin D

KW - genetic epidemiology

U2 - 10.1177/1352458521995484

DO - 10.1177/1352458521995484

M3 - Article (Academic Journal)

C2 - 33605807

SN - 1352-4585

VL - 27

SP - 1994

EP - 2000

JO - Multiple Sclerosis Journal

JF - Multiple Sclerosis Journal

IS - 13

ER -

The relative contributions of obesity, vitamin D, leptin and adiponectin to multiple sclerosis risk: a Mendelian randomization mediation analysis

Abstract

Bibliographical note

UN SDGs

Keywords

Access to Document

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Projects

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Cite this