The role of body fat in multiple sclerosis susceptibility and severity: A Mendelian randomisation study

Almramhi, Mona Mohammad; Storm, Catherine S.; Kia, Demis A.; Coneys, Rachel; Chhatwal, Burleen K; Wood, Nicholas W.

doi:10.1177/13524585221092644

Cited by 7 publications

(7 citation statements)

References 38 publications

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“…The remaining SNPs were used to calculate the mean F-statistic and the proportion of variance explained ( R 2 ) to evaluate the strength of the selected variants. 19 The value of the mean F-statistics more than 10 indicates that bias due to weak instruments is negligible. 19…”

Section: Methodsmentioning

confidence: 99%

“…19 The value of the mean F-statistics more than 10 indicates that bias due to weak instruments is negligible. 19…”

Section: Methodsmentioning

confidence: 99%

“…evaluate the strength of the selected variants. 19 The value of the mean F-statistics more than 10 indicates that bias due to weak instruments is negligible. 19 To investigate the potential role of and mechanisms used by statins in MS risk and severity, expression quantitative trait loci (eQTL) data with p-values <5 × 10 −8 were obtained from the eQTLGen to genetically mimic statin effects.…”

Section: Genetic Instrument Selection For Exposuresmentioning

confidence: 99%

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Exploring the Role of Plasma Lipids and Statin Interventions on Multiple Sclerosis Risk and Severity

Almramhi,

Finan,

Storm

et al. 2023

Neurology

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BackgroundThere has been considerable interest in statins due to their pleiotropic effects beyond their lipid-lowering properties. Many of these pleiotropic effects are predominantly ascribed to Rho small guanosine triphosphatases (Rho GTPases) proteins. We aimed to genetically investigate the role of lipids and statin interventions on multiple sclerosis (MS) risk and severity.MethodWe employed two-sample Mendelian randomization (MR) to investigate: (1) the causal role of genetically mimic both cholesterol-dependent (via low-density lipoprotein cholesterol (LDL-C) and cholesterol biosynthesis pathway) and cholesterol-independent (via Rho GTPases) effects of statins on MS risk and MS severity, (2) the causal link between lipids (high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG)) levels and MS risk and severity; and (3) the reverse causation between lipid fractions and MS risk. We used summary statistics from the Global Lipids Genetics Consortium (GLGC), eQTLGen Consortium and the International MS Genetics Consortium (IMSGC) for lipids, expression quantitative trait loci and MS, respectively (GLGC: n = 188,577; eQTLGen: n = 31,684; IMSGC (MS risk): n = 41,505; IMSGC (MS severity): n =7,069).ResultsThe results of MR using the inverse variance weighted method show that genetically predictedRAC2, a member of cholesterol-independent pathway, (OR 0.86 (95% CI 0.78 to 0.95), p-value 3.80E-03) is implicated causally in reducing MS risk. We found no evidence for the causal role of LDL-C and the member of cholesterol biosynthesis pathway on MS risk. MR results also show that lifelong higher HDL-C (OR 1.14 (95% CI 1.04 to1.26), p-value 7.94E-03) increase MS risk but TG was not. Furthermore, we found no evidence for the causal role of lipids and genetically mimicked statins on MS severity. There is no evidence of reverse causation between MS risk and lipids.ConclusionEvidence from this study suggests thatRAC2is a genetic modifier of MS risk. SinceRAC2has been reported to mediate some of the pleiotropic effects of statins, we suggest that statins may reduce MS risk via a cholesterol-independent pathway (i.e., RAC2-related mechanism(s)). MR analyses also support a causal effect of HDL-C on MS risk.

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Section: Methodsmentioning

confidence: 99%

“…19 The value of the mean F-statistics more than 10 indicates that bias due to weak instruments is negligible. 19…”

Section: Methodsmentioning

confidence: 99%

Section: Genetic Instrument Selection For Exposuresmentioning

confidence: 99%

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Exploring the Role of Plasma Lipids and Statin Interventions on Multiple Sclerosis Risk and Severity

Almramhi,

Finan,

Storm

et al. 2023

Neurology

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“…The remaining SNPs were used to calculated the mean F-statistic and the proportion of variance explained (R 2 ) to evaluate the strength of the selected variants 18 . The value of the mean F-statistics more than 10, indicates that bias due to weak instruments is negligible 18 .…”

Section: Methods Genetic Instruments Selection For Exposuresmentioning

confidence: 99%

Exploring the Role of Plasma Lipids and Statins Interventions on Multiple Sclerosis Risk and Severity: A Mendelian Randomization Study

ALMRAMHI

Finan

Storm

et al. 2022

Preprint

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Background There has been considerable interest in statins due to their pleiotropic effects beyond their lipid-lowering properties. Many of these pleiotropic effects are predominantly ascribed to their capacity to inhibit the isoprenylation of Rho small guanosine triphosphatases (Rho GTPases). We aimed to genetically investigate the role of lipids and statin interventions on multiple sclerosis (MS) risk and severity. Method We employed two-sample Mendelian randomization (MR) to: (1) investigate the causal role of lipids (high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG)) levels in MS risk and severity, (2) genetically mimic both cholesterol-dependent (via low-density lipoprotein cholesterol (LDL-C) and cholesterol biosynthesis pathway) and cholesterol-independent (via Rho GTPases) effects of statins on MS risk and MS severity. Results The results of MR using the inverse variance weighted method show that lifelong higher HDL-C (OR 1.14 (95% CI 1.04 to1.26), p-value 7.94E-03) increase MS risk, but LDL-C and TG were not. MR results also show that genetically predicted RAC2 (OR 0.86 (95% CI 0.78 to 0.95), p-value 3.80E-03) is implicated causally in reducing MS risk. Furthermore, we found no evidence for the causal role of lipids and genetically mimicked statins on MS severity. There is no evidence of reverse causation between MS risk and lipids. Conclusions Evidence from this study suggests that HDL-C is a risk factor for MS development. The MR findings suggest that RAC2 (a member of Rho GTPases) is a potent genetic modifier of MS risk. Since RAC2 has been reported to mediate some of the pleiotropic effects of statins, we suggest that statins reduce MS risk via a RAC2-related mechanism(s) (i.e., cholesterol-independent pathway).

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“…Таким чином, ряд ознак, пов'язаних з ожирінням були факторами ризику розвитку РС та погіршували тяжкість перебігу захворювання. Також виявлено, що зріст і м'язова частка не мають зв'язку з ризиком розвитку або тяжкістю перебігу РС [1].…”

Section: результати обговоренняunclassified

The role of constitutional features of body structure in the occurrence and course of multiple sclerosis (literature review)

Gunas¹

2022

Rep. of Vinnytsia Nation. Med. Univ.

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Annotation. The widespread prevalence of multiple sclerosis in different parts of the world among representatives of different races, nationalities, age groups, gender groups, chronic course of disease, the high cost of treatment and a significant percentage of disability of the working population makes this disease more relevant for scientific research than ever. One of the understudied aspects of domestic scientists is the anthropometric indicators іn group of patients suffering from multiple sclerosis. The aim of the study is to conduct a review a literary sources for the period 2012-2022, related to the topic of the human constitution and multiple sclerosis. A study of 29 sources that met the inclusion criteria was carried out. For the most part, the following anthropometric indicators were found in the publications, which had one or another reliable connection with the risk of occurrence or the course of multiple sclerosis: body mass index, ratio of muscles and fat in the body, waist circumference. Also important factors that were pay attention to account by the researchers and as a result in addition influenced the results of the research were: nationality, race, age and sex. According to the data of the analyzed studies, body mass index has the greatest contribution to the rate of disease progression between the studied groups with different course of multiple sclerosis, while sex had a greater influence on the occurrence of a certain specific type of course of multiple sclerosis. Accordingly to the analysis of literary sources revealed that there is a need to conduct an anthropometric study of Ukrainians suffering from multiple sclerosis in order to further form groups of key indicators that can be used to predict the risk of occurrence and course of this disease. This will become possible due to conducting a clinical and anthropological study that will be carried out in the future.

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The role of body fat in multiple sclerosis susceptibility and severity: A Mendelian randomisation study

Cited by 7 publications

References 38 publications

Exploring the Role of Plasma Lipids and Statin Interventions on Multiple Sclerosis Risk and Severity

Exploring the Role of Plasma Lipids and Statin Interventions on Multiple Sclerosis Risk and Severity

Exploring the Role of Plasma Lipids and Statins Interventions on Multiple Sclerosis Risk and Severity: A Mendelian Randomization Study

The role of constitutional features of body structure in the occurrence and course of multiple sclerosis (literature review)

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