mtDNA nt13708A variant increases the risk of multiple sclerosis.
BACKGROUND
Mitochondrial DNA (mtDNA) polymorphism is a possible factor contributing to the maternal parent-of-origin effect in multiple sclerosis (MS) susceptibility.


RESULTS
In 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.


CONCLUSIONS
Taken 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.
Yu
Xinhua
X
Section of Immunogenetics, University of Rostock, Rostock, Germany.
Koczan
Dirk
D
Sulonen
Anna-Maija
AM
Akkad
Denis A
DA
Kroner
Antje
A
Comabella
Manuel
M
Costa
Gianna
G
Corongiu
Daniela
D
Goertsches
Robert
R
Camina-Tato
Montserrat
M
Thiesen
Hans-Juergen
HJ
Nyland
Harald I
HI
Mørk
Sverre J
SJ
Montalban
Xavier
X
Rieckmann
Peter
P
Marrosu
Maria G
MG
Myhr
Kjell-Morten
KM
Epplen
Joerg T
JT
Saarela
Janna
J
Ibrahim
Saleh M
SM
D000483:Alleles; D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000235:genetics*; D005060:Europe / Q000453:epidemiology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics*; D017720:Molecular Epidemiology; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D017422:Sequence Analysis, DNA
D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; C481838:MT-ND5 protein, human; D042967:Electron Transport Complex I