title: Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease.
abstract: Mitochondrial (mt) impairment, particularly within complex I of the electron transport system, has been implicated in the pathogenesis of Parkinson disease (PD). More than half of mitochondrially encoded polypeptides form part of the reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme. To test the hypothesis that mtDNA variation contributes to PD expression, we genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34-0.91; P=.02) or K (OR 0.52; 95% CI 0.30-0.90; P=.02) demonstrated a significant decrease in risk of PD versus individuals carrying the most common haplogroup, H. Furthermore, a specific SNP that defines these two haplogroups, 10398G, is strongly associated with this protective effect (OR 0.53; 95% CI 0.39-0.73; P=.0001). SNP 10398G causes a nonconservative amino acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men (OR 0.43; 95% CI 0.27-0.71; P=.0009). In addition, SNP 9055A of ATP6 demonstrated a protective effect for women (OR 0.45; 95% CI 0.22-0.93; P=.03). Our results suggest that ND3 is an important factor in PD susceptibility among white individuals and could help explain the role of complex I in PD expression.
authors.affiliation: Department of Medicine, and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Joelle M
authors.initials: JM
authors.lastname: van der Walt
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Nicodemus
authors.forename: Eden R
authors.initials: ER
authors.lastname: Martin
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.forename: Martha A
authors.initials: MA
authors.lastname: Nance
authors.forename: Ray L
authors.initials: RL
authors.lastname: Watts
authors.forename: Jean P
authors.initials: JP
authors.lastname: Hubble
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: William C
authors.initials: WC
authors.lastname: Koller
authors.forename: Kelly
authors.initials: K
authors.lastname: Lyons
authors.forename: Rajesh
authors.initials: R
authors.lastname: Pahwa
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Stern
authors.forename: Amy
authors.initials: A
authors.lastname: Colcher
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Hiner
authors.forename: Joseph
authors.initials: J
authors.lastname: Jankovic
authors.forename: William G
authors.initials: WG
authors.lastname: Ondo
authors.forename: Fred H
authors.initials: FH
authors.lastname: Allen
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Goetz
authors.forename: Gary W
authors.initials: GW
authors.lastname: Small
authors.forename: Frank
authors.initials: F
authors.lastname: Mastaglia
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Stajich
authors.forename: Adam C
authors.initials: AC
authors.lastname: McLaurin
authors.forename: Lefkos T
authors.initials: LT
authors.lastname: Middleton
authors.forename: Burton L
authors.initials: BL
authors.lastname: Scott
authors.forename: Donald E
authors.initials: DE
authors.lastname: Schmechel
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Vance
mesh_terms: D004272:DNA, Mitochondrial / Q000235:genetics*; D005060:Europe / Q000208:ethnology; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values; D012307:Risk Factors; D006113:United Kingdom; D014481:United States; D044465:White People / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial