Assessment of PINK1 (PARK6) polymorphisms in Finnish PD.

Recent data has demonstrated that mutations in PINK1, encoding PTEN-induced kinase 1, are a cause of early onset recessive parkinsonism (PARK6 locus). Common variability in genes implicated in hereditary forms of parkinsonism may be a predisposing factor in sporadic Parkinson's disease (PD). We analyzed whether six different genetic variants within and surrounding PINK1 contribute to the risk of sporadic PD in a Finnish case-control series. Our results indicate that this gene does not play a major role in the genetic predisposition to PD in this population.

The human prion gene M129V polymorphism is not associated with idiopathic Parkinson's disease in three distinct populations.

Coexistence of prion disease and idiopathic Parkinson's disease (IPD) has been previously described. It remains unclear whether this relationship may reflect the high incidence of IPD or whether both prion and IPD share common pathogenetic mechanisms. For this reason, we investigated the genotype distribution of the M129V polymorphism of the human prion gene for association with IPD (controls: n = 398, IPD cases: n = 400). No association between genotypes in codon 129 and IPD was detected in three distinct populations, suggesting that this PRNP polymorphism has no direct influence on the susceptibility to IPD.

Interaction of herpesviridae, APOE gene, and education in cognitive impairment.

While high age, low level of education and APOE epsilon4 allele are known to predict dementia, there is recent data suggesting that certain viruses and subtypes of APOE epsilon3 could be involved, too. We investigated these relationships in a home-dwelling cohort of 357 elderly people with various cardiovascular diseases (DEBATE study). MMSE score below 24 was used to define cognitive impairment (n = 58). When adjusted for age and the presence of diabetes, multivariate analysis demonstrated maximally increased risk of cognitive impairment in association with a combination of three factors: seropositivity for herpesviridae, presence of APOE epsilon4, and low education (risk ratio 6.1, 95% CI 2.4-15.2). In the subcohort of APOE3/3 individuals (n = 216) homozygosity for the -219G epsilon3 haplotype showed a similar association (risk ratio 8.8, 95% CI 2.6-29.8). These results demonstrate an interaction of specific genetic (APOE) and environmental (education and herpesviridae) risk factors in the development of cognitive impairment and indicate that not only the epsilon4 allele of APOE but also the epsilon3 haplotype is a risk factor for dementia.

A rare truncating mutation in ADH1C (G78Stop) shows significant association with Parkinson disease in a large international sample.

BACKGROUND: Alcohol dehydrogenases (ADHs) may be involved in the pathogenesis of neurodegenerative disorders because of their multiple roles in detoxification pathways and retinoic acid synthesis. In a previous study, significant association of an ADH class IV allele with Parkinson disease (PD) was found in a Swedish sample. PATIENTS: The previously associated single-nucleotide polymorphism plus 12 further polymorphisms in the ADH cluster on human chromosome 4q23 were screened for association in an extension of the original sample that now included 123 Swedish PD patients and 127 geographically matched control subjects. A rare nonsense single-nucleotide polymorphism in ADH1C (G78stop, rs283413) was identified in 3 of these patients but in no controls. To obtain sufficient power to detect a possible association of this rare variant with disease, we screened a large international sample of 1076 PD patients of European ancestry and 940 matched controls. RESULTS: The previously identified association with an ADH class IV allele remained significant (P<.02) in the extended Swedish study. Furthermore, in the international collaboration, the G78stop mutation in ADH1C was found in 22 (2.0%) of the PD patients but only in 6 controls (0.6%). This association was statistically significant (chi(2)(1) = 7.5; 2-sided P = .007; odds ratio, 3.25 [95% confidence interval, 1.31-8.05]). In addition, the G78stop mutation was identified in 4 (10.0%) of 40 Caucasian index cases with PD with mainly hereditary forms of the disorder. CONCLUSION: Findings presented herein provide further evidence for mutations in genes encoding ADHs as genetic risk factors for PD.

Lack of evidence for a genetic association between FGF20 and Parkinson's disease in Finnish and Greek patients.

BACKGROUND: Fibroblast growth factor 20 (FGF20) is a neurotrophic factor preferentially expressed in the substantia nigra of rat brain and could be involved in dopaminergic neurons survival. Recently, a strong genetic association has been found between FGF20 gene and the risk of suffering from Parkinson's disease (PD). Our aim was to replicate this association in two independent populations. METHODS: Allelic, genotypic, and haplotype frequencies of four biallelic polymorphisms were assessed in 151 sporadic PD cases and 186 controls from Greece, and 144 sporadic PD patients and 135 controls from Finland. RESULTS: No association was found in any of the populations studied. CONCLUSION: Taken together, these findings suggest that common genetic variants in FGF20 are not a risk factor for PD in, at least, some European populations.

Paraoxonase 1 (PON1) gene polymorphisms and Parkinson's disease in a Finnish population.

Paraoxonase 1 (PON1) is involved in the metabolism and detoxification of insecticides and pesticides. Two polymorphisms within the gene affect the enzyme activity. One is a methionine to leucine change at position 54 (M54L) and the other is a glutamine to arginine variant at position 192 (Q192R). There are contrasting reports assessing the role of these variants in Parkinson's disease (PD). We performed a case--control association study in order to elucidate the possible contribution of variability within PON1 to the risk of sporadic PD in a Finnish population. There was no statistically significant association of the allele, genotype or haplotype distribution with PD (all P values > 0.75). Our results suggest that the M54L and Q192R polymorphisms are not major risk factors for PD in the Finnish population.

The tau H2 haplotype is almost exclusively Caucasian in origin.

We have assessed the distribution of the tau H1/H2 haplotype in the publicly available reference series of samples with representatives of most racial groups. This analysis shows that the H2 haplotype is probably exclusively Caucasian in origin and its marginal occurrence in other racial groups is likely to reflect admixture. We discuss this observation in terms of the origin of the H2 haplotype and the epidemiology of the tauopathies.

POLG1 polyglutamine tract variants associated with Parkinson's disease.

A possible role of allelic variation of the mitochondrial DNA polymerase gamma (POLG1) gene in Parkinson's disease (PD) has been suggested. First, POLG1 missense mutations have been found in patients with familial parkinsonism and mitochondrial myopathy. Second, increased frequency of rare alleles of the POLG1 CAG-repeat (poly-Q) has been found in Finnish idiopathic apparently sporadic PD patients, but conflicting reports exist. The POLG1 poly-Q exhibits one major allele with 10 repeats (10Q, frequency >/=80%) and several less common alleles such as 11Q (frequency 6-9%), 6Q-9Q and 12Q-14Q (frequencies <4%). It is not known, whether the poly-Q variation modulates POLG1 function. Here we sequenced the poly-Q in 641 North American Caucasian PD patients and 292 controls. Caucasian literature controls were also used. Normal allele was defined either as 10/11Q or as 10Q according to the previous literature. The frequency of the non-10/11Q alleles in cases was not significantly different from the controls. Variant alleles defined as non-10Q were significantly increased in the PD patients compared to the North American controls (17.6% vs. 12.3%, p=0.004) as well as compared to the larger set of 897 controls (17.6% vs. 13.2%, p=0.0007). These results suggest that POLG1 poly-Q alleles other than the conserved 10Q allele may increase susceptibility to PD. This finding may be attributable to a beneficial function of the 10Q repeat protein or linkage disequilibrium between the 10Q allele and another variation within or close to POLG1. Other large case-control studies and analyses on functional differences of POLG1 poly-Q variants are warranted.

No evidence for shorter leukocyte telomere length in Parkinson's disease patients.

Telomeres constitute the protective ends of chromosomes. They become shorter after each cell division, and therefore, telomere length is considered as an indicator of cellular aging. Interestingly, both inflammation and oxidative stress, which play a role in the etiology of Parkinson's disease (PD), may accelerate telomere shortening. Furthermore, it has been suggested that leukocyte telomere shortening may be accelerated in PD. To replicate the earlier findings, we analyzed telomere length of peripheral blood leukocytes in a sample of 131 PD patients (aged 66.8 ± 9.7 years) and 115 controls (aged 65.4 ± 9.8 years) from Finland. As expected, age associated significantly with telomere length (p = .01). However, telomere length did not differ significantly between PD patients and controls (p = .54). Furthermore, extremely short telomeres were not more frequent in PD patients than in controls, as suggested in an earlier study. Our results do not support the concept of accelerated leukocyte telomere shortening in PD.

Tyrosinase exacerbates dopamine toxicity but is not genetically associated with Parkinson's disease.

Tyrosinase is a key enzyme in the synthesis of melanin in skin and hair and has also been proposed to contribute to the formation of neuromelanin (NM). The presence of NM, which is biochemically similar to melanin in peripheral tissues, identifies groups of neurons susceptible in Parkinson's disease (PD). Whether tyrosinase is beneficial or detrimental to neurons is unclear; whilst the enzyme activity of tyrosinase generates dopamine-quinones and other oxidizing compounds, NM may form a sink for such radical species. In the present study, we demonstrated that tyrosinase is expressed at low levels in the human brain. We found that mRNA, protein and enzyme activity are all present but at barely detectable levels. In cell culture systems, expression of tyrosinase increases neuronal susceptibility to oxidizing conditions, including dopamine itself. We related these in vitro observations to the human disease by assessing whether there was any genetic association between the gene encoding tyrosinase and idiopathic PD. We found neither genotypic or haplotypic association with three polymorphic markers of the gene. This argues against a strong genetic association between tyrosinase and PD, although the observed contribution to cellular toxicity suggests that a biochemical association is likely.