Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease.
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.
van der Walt
Joelle M
JM
Department of Medicine, and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC 27710, USA.
Nicodemus
Kristin K
KK
Martin
Eden R
ER
Scott
William K
WK
Nance
Martha A
MA
Watts
Ray L
RL
Hubble
Jean P
JP
Haines
Jonathan L
JL
Koller
William C
WC
Lyons
Kelly
K
Pahwa
Rajesh
R
Stern
Matthew B
MB
Colcher
Amy
A
Hiner
Bradley C
BC
Jankovic
Joseph
J
Ondo
William G
WG
Allen
Fred H
FH
Goetz
Christopher G
CG
Small
Gary W
GW
Mastaglia
Frank
F
Stajich
Jeffrey M
JM
McLaurin
Adam C
AC
Middleton
Lefkos T
LT
Scott
Burton L
BL
Schmechel
Donald E
DE
Pericak-Vance
Margaret A
MA
Vance
Jeffery M
JM
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
D004272:DNA, Mitochondrial