MtDNA nt13708A Variant Increases the Risk of Multiple Sclerosis

Xinhua Yu,Denis A Akkad,Daniela Corongiu,Manuel Comabella,Saleh M Ibrahim,Antje Kroner,Gianna Costa,Robert Goertsches,Dirk Koczan,Peter Rieckmann,Anna-Maija Sulonen,Janna Saarela,M Camiña-Tato ,Hans‐Juergen Thiesen ,Jörg T Epplen ,Harald Nyland ,Kjell‐Morten Myhr ,Xavier Montalbán ,Maria Giovanna Marrosu ,Sverre Mørk

doi:10.1371/journal.pone.0001530

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.

Highlights

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease that affects the central nervous system in genetically susceptible individuals
Taken together, our finding identified the nt13708A variant as a susceptibility allele to multiple sclerosis (MS), which could contribute to defining the role of the mitochondrial genome in MS pathogenesis
MtDNA variations play an important role in neurodegenerative diseases, with deleterious Mitochondrial DNA (mtDNA) mutations causing early onset neurodegenerative disorders, and common mtDNA polymorphisms are associated with late-onset neurodegenerative disorders [1,2,3,4,5]

Summary

Introduction

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease that affects the central nervous system in genetically susceptible individuals. MtDNA variations play an important role in neurodegenerative diseases, with deleterious mtDNA mutations causing early onset neurodegenerative disorders, and common mtDNA polymorphisms are associated with late-onset neurodegenerative disorders [1,2,3,4,5]. Lebers hereditary optic neuropathy (LHON), a disease caused by mtDNA mutations, includes symptoms of inflammatory demyelination similar to MS [6]. Those observations suggest that mtDNA could play a role in pathogenesis of MS. Mitochondrial DNA (mtDNA) polymorphism is a possible factor contributing to the maternal parent-of-origin effect in multiple sclerosis (MS) susceptibility

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