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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.

SUBMITTER: van der Walt JM

PROVIDER: S-EPMC1180345 | biostudies-literature | 2003 Apr

REPOSITORIES: biostudies-literature

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Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease.

van der Walt Joelle M JM 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

American journal of human genetics 20030228 4

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 ...[more]

PMID: 12618962

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Project description:ImportanceLoneliness is associated with morbidity and mortality, including higher risk of neurodegenerative diseases. To our knowledge, no study has examined whether the association between loneliness and detrimental outcomes extends to Parkinson disease (PD).ObjectiveTo assess whether loneliness is associated with risk of incident PD and whether the association is independent of other risk factors or modified by age, sex, and genetic vulnerability.Design, setting, and participantsThis prospective cohort study included a population-based sample of UK Biobank participants aged 38 to 73 years with loneliness data and without a diagnosis of PD at baseline who were first assessed from March 13, 2006, to October 1, 2010, and followed up to October 9, 2021.ExposureFeeling lonely and covariates that are known risk factors for or prodromal features of PD.Main outcome and measureIncident PD was ascertained through UK National Health Service health records.ResultsOf 491 603 participants (mean [SD] age, 56.54 [8.09] years; 54.4% female), 2822 developed PD during the 15-year follow-up. Individuals who reported being lonely had a higher risk of PD (hazard ratio [HR], 1.37; 95% CI, 1.25-1.51), an association that remained after accounting for demographic factors, socioeconomic status, social isolation, PD polygenetic risk score, smoking, physical activity, body mass index, diabetes, hypertension, stroke, myocardial infarction, depression, and ever seeing a psychiatrist (fully adjusted model: HR 1.25; 95% CI, 1.12-1.39). The association between loneliness and incident PD was not moderated by sex (HR for interaction, 0.98; 95% CI, 95% CI, 0.81-1.18), age (HR for interaction, 0.99; 95% CI, 0.98-1.01), or polygenic risk score (HR for interaction, 0.93; 95% CI, 0.85-1.02). Contrary to expectations for a prodromal syndrome, when stratified by time, loneliness was not associated with risk for incident PD during the first 5 years (HR, 1.15; 95% CI, 0.91-1.45) but was associated with PD risk during the subsequent 10 years (HR, 1.32; 95% CI, 1.19-1.46).Conclusions and relevanceThis large cohort study found that loneliness was associated with risk of incident PD across demographic groups and independent of depression and other prominent risk factors and genetic risk. The findings add to the evidence that loneliness is a substantial psychosocial determinant of health.

Project description:Few epidemiologic studies have evaluated the effects of air pollution on the risk of Parkinson disease (PD).We investigated the associations of long-term residential concentrations of ambient particulate matter (PM) < 10 ?m in diameter (PM10) and < 2.5 ?m in diameter (PM2.5) and nitrogen dioxide (NO2) in relation to PD risk.Our nested case-control analysis included 1,556 self-reported physician-diagnosed PD cases identified between 1995 and 2006 and 3,313 controls frequency-matched on age, sex, and race. We geocoded home addresses reported in 1995-1996 and estimated the average ambient concentrations of PM10, PM2.5, and NO2 using a national fine-scale geostatistical model incorporating roadway information and other geographic covariates. Air pollutant exposures were analyzed as both quintiles and continuous variables, adjusting for matching variables and potential confounders.We observed no statistically significant overall association between PM or NO2 exposures and PD risk. However, in preplanned subgroup analyses, a higher risk of PD was associated with higher exposure to PM10 (ORQ5 vs. Q1 = 1.65; 95% CI: 1.11, 2.45; p-trend = 0.02) among women, and with higher exposure to PM2.5 (ORQ5 vs. Q1 = 1.29; 95% CI: 0.94, 1.76; p-trend = 0.04) among never smokers. In post hoc analyses among female never smokers, both PM2.5 (ORQ5 vs. Q1 = 1.79; 95% CI: 1.01, 3.17; p-trend = 0.05) and PM10 (ORQ5 vs. Q1 = 2.34; 95% CI: 1.29, 4.26; p-trend = 0.01) showed positive associations with PD risk. Analyses based on continuous exposure variables generally showed similar but nonsignificant associations.Overall, we found limited evidence for an association between exposures to ambient PM10, PM2.5, or NO2 and PD risk. The suggestive evidence that exposures to PM2.5 and PM10 may increase PD risk among female never smokers warrants further investigation. Citation: Liu R, Young MT, Chen JC, Kaufman JD, Chen H. 2016. Ambient air pollution exposures and risk of Parkinson disease. Environ Health Perspect 124:1759-1765;?http://dx.doi.org/10.1289/EHP135.

Project description:BackgroundIt has been reported that polymorphisms of transferrin (TF) G258A and transferrin receptor (TFR) A82G might be associated with susceptibility to Parkinson disease (PD).ObjectiveOwing to limitation of sample size and inconclusive results, we conducted a meta-analysis to clarify the association.MethodsBy searching PubMed, Embase, Chinese National Knowledge Infrastructure, China Biological Medicine Database, and Wanfang Databases, the published articles about studies of the association of the TF G258A, TFR A82G gene polymorphisms with the risk of PD were collected. Q-statistics and I statistics were calculated to examine heterogeneity and summary odds ratios (ORs) and 95% confidence intervals (95%CI) were evaluated the association.ResultsFive studies assessed the relationship between TF G258A and risk of PD. A significant increased protective of A allele and AA genotype was observed in allele model and recessive model (the allele model A vs G: OR = 0.54, 95%CI 0.40-0.72, P < .001; the recessive model AA vs GA + GG: OR = 0.32, 95%CI 0.20-0.52, P < .001). The remaining models of the TF G258A genotype showed no significant association with PD risk, while the protective tendency were increased (the heterozygote model GA vs GG: OR = 0.93, 95%CI 0.61-1.43, P = .75; the homozygous model AA vs GG: OR = 0.47, 95%CI 0.21-1.04, P = .06; the dominant model GA + AA vs GG: OR = 0.75, 95%CI 0.50-1.11, P = .15). There was also a lack of association between TFR A82G polymorphism and PD (the allele model G vs A: OR = 0.92, 95%CI 0.75-1.13, P = .43; the heterozygote model AG vs AA: OR = 1.17, 95%CI 0.79-1.71, P = .43; the homozygous model GG vs AA: OR = 0.91, 95%CI 0.60-139, P = .66; the dominant model AG + GG vs AA: OR = 1.05, 95%CI 0.73-1.49, P = .81; the recessive model GG vs AG +AA: OR = 0.80, 95%CI 0.59-1.09, P = .16).ConclusionOur study suggests that TF G258A polymorphism may be associated with PD, while TFR A82G polymorphism may not contribute to PD based on the current evidence.

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Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease.

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Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease.

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