title: Genetic variants of homocysteine metabolism and multiple sclerosis: a case-control study.
abstract: Methylenetetrahydrofolate reductase (MTHFR) is necessary for the synthesis of methionine and S-adenosylmethionine, which is necessary for CNS (re-)myelination. The MTHFR variant c.1298A>C was associated with the development of relapsing remitting multiple sclerosis (RRMS) in a German population. This study aimed at analyzing whether further genetic variants of methionine metabolism are associated with the development or the clinical course of RRMS. Therefore, genomic DNA of 147 serial German RRMS patients and 147 matched healthy controls was genotyped for five polymorphic variants of methionine metabolism. Statistical analyses were performed using multivariate binary and linear regression analyses. We show that the insertion allele of cystathionine beta-synthase (CBS) c.844_855ins68bp and the G-allele of reduced folate carrier 1 (RFC1) c.80G>A were associated with an earlier age of onset of MS, suggesting gene-dose effects (median age of onset in years: 25-26-32; standardized regression coefficient beta: 0.216; p=0.030, and 29-31-35 years; beta: 0.282; p=0.005, respectively). Conclusively, mutant variants of CBS and RFC1 may be associated with the age of RRMS onset. Since methionine metabolism can be manipulated by supplementation of vitamins and amino acids, our data provide a rationale for novel ideas of preventive and therapeutic strategies in RRMS.
authors.affiliation: Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Benjamin V
authors.initials: BV
authors.lastname: Ineichen
authors.affiliation: Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Salla
authors.initials: S
authors.lastname: Keskitalo
authors.affiliation: Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Melinda
authors.initials: M
authors.lastname: Farkas
authors.affiliation: Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Nadja
authors.initials: N
authors.lastname: Bain
authors.affiliation: Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Ulf
authors.initials: U
authors.lastname: Kallweit
authors.affiliation: Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.affiliation: Department of Inflammatory Disorders of the Nervous System, and Neurooncology, University Hospital Münster, Münster, Germany.
authors.forename: Luisa
authors.initials: L
authors.lastname: Klotz
authors.affiliation: Department of Neurology, University Hospital Zurich, Zurich, Switzerland. Electronic address: michael.linnebank@usz.ch.
authors.forename: Michael
authors.initials: M
authors.lastname: Linnebank
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D000328:Adult; D016022:Case-Control Studies; D003541:Cystathionine beta-Synthase / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D008297:Male; D008715:Methionine / Q000235:genetics / Q000378:metabolism*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D012436:S-Adenosylmethionine / Q000235:genetics
chemical_list: D006710:Homocysteine; D012436:S-Adenosylmethionine; D008715:Methionine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D003541:Cystathionine beta-Synthase
keywords: Cystathionine beta-synthase; Folate; Homocysteine; Multiple sclerosis; Reduced folate carrier 1; S-adenosylmethionine