Genetic variants of Complex I in multiple sclerosis.
OBJECTIVE
A mitochondrial mechanism contributes to neurodegeneration in multiple sclerosis (MS). Genetic variants of Complex I genes may influence the nature of tissue response to inflammation in the central nervous system (CNS).


BACKGROUND
Complex I is encoded by seven mitochondrial and 38 nuclear genes. Many of the nuclear genes colocalize with regions where full genome scans detected linkage in MS. Previous studies revealed an association between variants of mitochondrial (mt)DNA encoded subunits of Complex I and MS. Biochemical studies suggested a functional involvement of Complex I in the degenerative processes downstream to inflammatory injury in the CNS.


METHODS
Patients with all MS phenotypes were included. DNA specimens of affected sib pair, trio and multiplex families were studied. Single nucleotide polymorphisms (SNP) were determined by using the Taqman assay. The association of MS with nuclear DNA encoded alleles and haplotypes of Complex I was tested by the pedigree disequilibrium test (PDT) and by the transmit program in the families. Haplotypes were further investigated by using ldmax (GOLD). The association of mtDNA encoded variants with MS was tested by the Fisher's Exact Test.


RESULTS
The previously identified MS-associated mtDNA variants and haplotypes were not increased in mothers as compared to fathers in these families. However, an association of all clinical phenotypes with haplotypes within NDUFS5 (1p34.2-p33), NDUFS7 (19p13) and NDUFA7 (19p13) was detected. The inclusion of families with primary progressive (PP)-MS phenotype did not modify the outcome and, as a subgroup alone, did not have a sufficient size to draw conclusion regarding phenotype specific associations.


CONCLUSIONS
SNP haplotypes within Complex I genes are associated with MS. Further studies are needed to refine the identification of disease relevant variants nearby or within these haplotypes. Molecular and functional properties of Complex I subunits may offer novel explanations to better understand the relationship between inflammation and neurodegeneration.
Vyshkina
Tamara
T
Department of Neurology, SLRHC, Columbia University, 432W 58th Street, New York, NY 10019, USA.
Banisor
Ileana
I
Shugart
Yin Yao
YY
Leist
Thomas P
TP
Kalman
Bernadette
B
D000483:Alleles; D002874:Chromosome Mapping; D004272:DNA, Mitochondrial; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D005805:Genes, MHC Class I / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
D004272:DNA, Mitochondrial