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Genetic variants of Complex I in multiple sclerosis.

Abstract

HYPOTHESIS

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.

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  • Authors+Show Affiliations

    ,

    Department of Neurology, SLRHC, Columbia University, 432W 58th Street, New York, NY 10019, USA.

    , , ,

    Source

    Journal of the neurological sciences 228:1 2005 Jan 15 pg 55-64

    MeSH

    Alleles
    Chromosome Mapping
    DNA, Mitochondrial
    Family Health
    Female
    Gene Frequency
    Genes, MHC Class I
    Genetic Predisposition to Disease
    Genetic Variation
    Genotype
    Humans
    Male
    Multiple Sclerosis
    Polymorphism, Single Nucleotide

    Pub Type(s)

    Comparative Study
    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    15607211

    Citation

    Vyshkina, Tamara, et al. "Genetic Variants of Complex I in Multiple Sclerosis." Journal of the Neurological Sciences, vol. 228, no. 1, 2005, pp. 55-64.
    Vyshkina T, Banisor I, Shugart YY, et al. Genetic variants of Complex I in multiple sclerosis. J Neurol Sci. 2005;228(1):55-64.
    Vyshkina, T., Banisor, I., Shugart, Y. Y., Leist, T. P., & Kalman, B. (2005). Genetic variants of Complex I in multiple sclerosis. Journal of the Neurological Sciences, 228(1), pp. 55-64.
    Vyshkina T, et al. Genetic Variants of Complex I in Multiple Sclerosis. J Neurol Sci. 2005 Jan 15;228(1):55-64. PubMed PMID: 15607211.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Genetic variants of Complex I in multiple sclerosis. AU - Vyshkina,Tamara, AU - Banisor,Ileana, AU - Shugart,Yin Yao, AU - Leist,Thomas P, AU - Kalman,Bernadette, PY - 2004/02/16/received PY - 2004/09/15/revised PY - 2004/09/15/accepted PY - 2004/12/21/pubmed PY - 2005/4/12/medline PY - 2004/12/21/entrez SP - 55 EP - 64 JF - Journal of the neurological sciences JO - J. Neurol. Sci. VL - 228 IS - 1 N2 - HYPOTHESIS: 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. SN - 0022-510X UR - https://www.unboundmedicine.com/medline/citation/15607211/Genetic_variants_of_Complex_I_in_multiple_sclerosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-510X(04)00345-4 DB - PRIME DP - Unbound Medicine ER -