mtDNA nt13708A Variant Increases the Risk of Multiple Sclerosis

Abstract

BackgroundMitochondrial DNA (mtDNA) polymorphism is a possible factor contributing to the maternal parent-of-origin effect in multiple sclerosis (MS) susceptibility.Methods and FindingsIn order to investigate the role of mtDNA variations in MS, we investigated six European MS case-control cohorts comprising >5,000 individuals. Three well matched cohorts were genotyped with seven common, potentially functional mtDNA single nucleotide polymorphisms (SNPs). A SNP, nt13708 G/A, was significantly associated with MS susceptibility in all three cohorts. The nt13708A allele was associated with an increased risk of MS (OR = 1.71, 95% CI 1.28–2.26, P = 0.0002). Subsequent sequencing of the mtDNA of 50 individuals revealed that the nt13708 itself, rather than SNPs linked to it, was responsible for the association. However, the association of nt13708 G/A with MS was not significant in MS cohorts which were not well case-control matched, indicating that the significance of association was affected by the population structure of controls.ConclusionsTaken together, our finding identified the nt13708A variant as a susceptibility allele to MS, which could contribute to defining the role of the mitochondrial genome in MS pathogenesis.

Dissecting the effects of mtDNA variations on complex traits using mouse conplastic strains

“…We showed that the mtDNA variations could affect susceptibility to EAE. This observation is consistent with those in humans, in which mtDNA variations are associated with susceptibility to MS (Yu et al 2008). Our results provide confirmatory evidence for the role of mitochondria in MS.…”

“…The C57BL/6J strain is used widely for induction of EAE by immunization with MOG 53-55 peptides. In humans, it has been suggested that mtDNA variations affect susceptibility to MS (Yu et al 2008). Therefore, we investigated the effect of mtDNA variants on EAE.…”

“…In humans, mtDNA variations are associated with many neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), and bipolar disorder (Shoffner et al 1993;Kalman and Alder 1998;Kato et al 2001;van der Walt et al 2003). Recently, we reported that the mtDNA allele nt13708A increases susceptibility to MS (Yu et al 2008). To test the usefulness of this genetic resource, we investigated the conplastic strains with regard to nervous system phenotypes, in particular experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, and anxiety-like behavior as an aspect of bipolar disorder.…”

Polymorphisms in the mitochondrially encoded ATP synthase 8 gene are associated with susceptibility to bullous pemphigoid in the German population

“…Mitochondria contain their own 16-kb genome, the mitochondrial DNA (mtDNA), which encodes 37 genes, 13 proteincoding genes as well as 22 tRNA and 2 rRNA genes (2). Variations in mtDNA affecting OXPHOS functions may cause mitochondrial dysfunctions and have been reported to associate with complex diseases, including chronic inflammation and autoimmune diseases, for example systemic lupus erythematosus (5) and multiple sclerosis (6).…”

Association of UCP2 −866 G/A polymorphism with chronic inflammatory diseases

“…The less frequent A allele that is associated with an increased expression of the UCP2 gene transcript had a protective effect on the risk for developing MS in our earlier study. 4 We have also confirmed and extended the earlier reported associations between mtDNA variants and MS, 5 we identified the mtDNA nt13708A variant as a risk allele for MS. 6 In this study, we aimed to investigate the two aforementioned MS-associated mitochondrial variants in other chronic inflammatory diseases. That is, we tested UCP2 -866 G/A and mtDNA nt13708 G/A for an association with eight distinct chronic inflammatory diseases, which included rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Wegener' granulomatosis (WG), Churg-Strauss syndrome (CSS), Crohn's disease (CD), ulcerative colitis (UC), primary sclerosing cholangitis (PSC) and psoriasis.…”