The fat mass and obesity-associated FTO rs9939609 polymorphism is associated with elevated homocysteine levels in patients with multiple sclerosis screened for vascular risk factors

Abstract

To investigate the mechanism underlying homocysteine accumulation in MS patients. A total of 114 patients and 195 population-matched controls were analysed for the FTO rs9939609 polymorphism. Homocysteine levels were measured in a subgroup of 60 patients and 87 controls screened for multiple vascular risk factors. After adjustment for potential confounders, the risk-associated FTO rs9939609 A-allele was associated with raised homocysteine levels (p = 0.003) in patients diagnosed with MS, but not in controls. Homocysteine levels correlated positively with body mass index (BMI) (p = 0.045) and total cholesterol levels (p = 0.048). Both homocysteine (p = 0.011) and BMI (p = 0.017) were significantly reduced with higher intake of folate in the diet. Higher BMI also correlated with increased intake of saturated/trans fat (p < 0.01) and low physical activity (p < 0.006). Daily intake of at least five fruits and vegetables had a favourable lowering effect on the Expanded Disability Status Scale (EDSS) (p = 0.035), while smoking increased MS disability (p < 0.001). This study has shown for the first time that having a diagnosis of MS moderates the effect of the FTO rs9939609 polymorphism on homocysteine levels. This is consistent with the role of FTO in demethylation and epigenetic changes. Identification of FTO rs9939609 reinforces the importance of adequate fruit, vegetable and folate and restriction of saturated/trans fat intake in the diet.

Serum levels of Homocysteine, Vitamin B12 and Folate in Patients with Multiple Sclerosis: an Updated Meta-Analysis

“…Twenty-nine articles were excluded because they did not include related information or were not written in English. Finally, a total of 17 studies were selected according to the predefined inclusion and exclusion criteria [6,11,12,16,[27][28][29][30][31][32][33][34][35][36][37][38][39]. The association between Vitamin B12 and MS has been investigated by 50 different studies.…”

“…As for the subgroup analysis, Hcy levels were divided into three groups according to different subtypes of MS, including 9 studies for relapsing-remitting MS (RRMS) [6,11,12,29,30,32,33,36,39], 5 studies for secondary progressive MS (SPMS) [6,11,29,32,36], and 3 studies for primary progressive MS (PPMS) [29,32,36]. Furthermore, we analyzed Hcy levels in different gender subgroups [30,32,36,38]. The flow diagrams summarizing the selection process were presented in Figs.…”

Complex Relationship between Obesity and the Fat Mass and Obesity Locus

“…In a mouse model in which FTO was knocked out only in DA neurons, FTO demethylates an mRNA subset that is involved in neuronal function, which provides more evidence for the critical role of FTO in RNA metabolism 135, 136. This research applied diazirine photo-cross-linking to m6A recognition mediated by the FTO demethylase.…”

“…As a nucleic acid demethylase, FTO removes methyl groups from both DNA and RNA 134, 135, 139, 140. There is a prevalent belief that the most significant function of FTO is demethylating N6-methyladenosine (m6A), which could adjust the alternative splicing of mRNAs 141-143.…”

Folate Metabolism Regulates Oligodendrocyte Survival and Differentiation by Modulating AMPKα Activity

“…In addition, recent studies indicate that high homocysteine levels may contribute to the pathogenesis of MS 17 . Though folate acts to accelerate the degradation of homocysteine, its role in MS pathology (oligodendrocyte loss and demyelination) remains controversial 18, 19 . Thus, understanding the effect of folate supplement and folate metabolic pathway activation on oligodendrocyte development is important for devising remyelination strategies in the CNS.…”