title: Mitochondrial DNA sequence variation in multiple sclerosis.
abstract: OBJECTIVE
  To assess the influence of common mitochondrial DNA (mtDNA) sequence variation on multiple sclerosis (MS) risk in cases and controls part of an international consortium.
  
  
  METHODS
  We analyzed 115 high-quality mtDNA variants and common haplogroups from a previously published genome-wide association study among 7,391 cases from the International Multiple Sclerosis Genetics Consortium and 14,568 controls from the Wellcome Trust Case Control Consortium 2 project from 7 countries. Significant single nucleotide polymorphism and haplogroup associations were replicated in 3,720 cases and 879 controls from the University of California, San Francisco.
  
  
  RESULTS
  An elevated risk of MS was detected among haplogroup JT carriers from 7 pooled clinic sites (odds ratio [OR] = 1.15, 95% confidence interval [CI] = 1.07-1.24, p = 0.0002) included in the discovery study. The increased risk of MS was observed for both haplogroup T (OR = 1.17, 95% CI = 1.06-1.29, p = 0.002) and haplogroup J carriers (OR = 1.11, 95% CI = 1.01-1.22, p = 0.03). These haplogroup associations with MS were not replicated in the independent sample set. An elevated risk of primary progressive (PP) MS was detected for haplogroup J participants from 3 European discovery populations (OR = 1.49, 95% CI = 1.10-2.01, p = 0.009). This elevated risk was borderline significant in the US replication population (OR = 1.43, 95% CI = 0.99-2.08, p = 0.058) and remained significant in pooled analysis of discovery and replication studies (OR = 1.43, 95% CI = 1.14-1.81, p = 0.002). No common individual mtDNA variants were associated with MS risk.
  
  
  CONCLUSIONS
  Identification and validation of mitochondrial genetic variants associated with MS and PPMS may lead to new targets for treatment and diagnostic tests for identifying potential responders to interventions that target mitochondria.
authors.affiliation: From the California Pacific Medical Center Research Institute (G.J.T.), San Francisco, CA; Department of Neurology (A.S., S.J.C., S.L.H., J.R.O.), University of California, San Francisco; Department of Health Sciences (S.D.), UPO and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Avogadro, Novara, Italy; and Department of Neuro-rehabilitation and INSPE (Institute of Experimental Neurology) (F.M.B.), Scientific Institute San Raffaele, Milan, Italy. gtranah@sfcc-cpmc.edu.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tranah
authors.affiliation: From the California Pacific Medical Center Research Institute (G.J.T.), San Francisco, CA; Department of Neurology (A.S., S.J.C., S.L.H., J.R.O.), University of California, San Francisco; Department of Health Sciences (S.D.), UPO and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Avogadro, Novara, Italy; and Department of Neuro-rehabilitation and INSPE (Institute of Experimental Neurology) (F.M.B.), Scientific Institute San Raffaele, Milan, Italy.
authors.forename: Adam
authors.initials: A
authors.lastname: Santaniello
authors.affiliation: From the California Pacific Medical Center Research Institute (G.J.T.), San Francisco, CA; Department of Neurology (A.S., S.J.C., S.L.H., J.R.O.), University of California, San Francisco; Department of Health Sciences (S.D.), UPO and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Avogadro, Novara, Italy; and Department of Neuro-rehabilitation and INSPE (Institute of Experimental Neurology) (F.M.B.), Scientific Institute San Raffaele, Milan, Italy.
authors.forename: Stacy J
authors.initials: SJ
authors.lastname: Caillier
authors.affiliation: From the California Pacific Medical Center Research Institute (G.J.T.), San Francisco, CA; Department of Neurology (A.S., S.J.C., S.L.H., J.R.O.), University of California, San Francisco; Department of Health Sciences (S.D.), UPO and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Avogadro, Novara, Italy; and Department of Neuro-rehabilitation and INSPE (Institute of Experimental Neurology) (F.M.B.), Scientific Institute San Raffaele, Milan, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: D'Alfonso
authors.affiliation: From the California Pacific Medical Center Research Institute (G.J.T.), San Francisco, CA; Department of Neurology (A.S., S.J.C., S.L.H., J.R.O.), University of California, San Francisco; Department of Health Sciences (S.D.), UPO and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Avogadro, Novara, Italy; and Department of Neuro-rehabilitation and INSPE (Institute of Experimental Neurology) (F.M.B.), Scientific Institute San Raffaele, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Martinelli Boneschi
authors.affiliation: From the California Pacific Medical Center Research Institute (G.J.T.), San Francisco, CA; Department of Neurology (A.S., S.J.C., S.L.H., J.R.O.), University of California, San Francisco; Department of Health Sciences (S.D.), UPO and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Avogadro, Novara, Italy; and Department of Neuro-rehabilitation and INSPE (Institute of Experimental Neurology) (F.M.B.), Scientific Institute San Raffaele, Milan, Italy.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.affiliation: From the California Pacific Medical Center Research Institute (G.J.T.), San Francisco, CA; Department of Neurology (A.S., S.J.C., S.L.H., J.R.O.), University of California, San Francisco; Department of Health Sciences (S.D.), UPO and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Avogadro, Novara, Italy; and Department of Neuro-rehabilitation and INSPE (Institute of Experimental Neurology) (F.M.B.), Scientific Institute San Raffaele, Milan, Italy.
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
mesh_terms: D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial