Non-synonymous GIGYF2 variants in Parkinson's disease from two Asian populations.

Mutations in the GIGYF2 gene at the PARK11 locus have recently been reported in Parkinson's disease (PD). However, the pathogenicity of some of these mutations has been debated. We conducted a comprehensive genetic analysis of the entire GIGYF2 gene in a cohort of young onset and familial PD patients, followed up with screening of specific variants in a separate group of PD and healthy controls. A total of 850 study subjects [450 Parkinson's disease (PD) patients and 400 controls] from two Asian countries were included. Our analysis revealed 17 variants distributed across the entire GIGYF2 gene. Ten of these were novel variants out of which eight were non-synonymous (all heterozygous). Out of these eight, half were novel polymorphic variants (0.2-2%) whereas four were novel non-synonymous variants which were not detected in healthy controls. The seven PD patients with non-synonymous variants had a mean age and age at onset of 55.3 and 50.9 years. All had typical features of PD and only one had a positive family history. The collective frequency of these non-synonymous variants was higher in PD compared to controls (1.6 vs. 0%, P = 0.016, relative risk 1.9, 95% CI 1.2, 1.9). None of the previously reported pathogenic mutations in Italian and French patients were present in our cohort. Our data suggest that GIGYF2 is unlikely to play a major role in our Asian populations. Rare non-synonymous variants appeared to be enriched in our PD patients compared to healthy controls. However, in vivo functional studies and segregation analysis in large pedigrees will be needed to determine if these single heterozygous variants represent rare mutations, risk alleles or benign polymorphisms.

Essential tremor and the common LRRK2 G2385R variant.

Co-existence of Parkinson's disease (PD) and essential tremor (ET) suggests a possible overlapping pathophysiology between these two conditions. PD patients with leucine-rich repeat kinase-2 (LRRK2) mutations have been reported to present initially with ET. A common LRRK2 Gly2385Arg variant has been widely shown to be associated with a two fold increased risk of PD in various Asian populations. We analyzed the Gly2385Arg variant in a cohort of ET and controls. A total of 419 subjects comprising of 172 ET and 247 controls were included. The mean age, age at onset of ET, and age of controls were 52.1+/-19.6, 41.8+/-21.6, and 62.2+/-11.6 years, comprising of 53.0% and 54.3% men, respectively. The Gly2385Arg variant was demonstrated in 5/172 (2.9%) ET patients compared to 10/247 (4.0%) of controls (odds ratio=0.72, 95% CI 0.24, 2.1, p=0.6). All the Gly2385Arg carriers were heterozygotes. The LRRK2 Gly2385Arg variant is not a significant risk factor for ET in our population.

Pathogenicity of LRRK2 P755L variant in Parkinson's disease.

A heterozygous 2264C-->T variant (P755L) in LRRK2 gene has been reported to be a likely pathogenic variant among ethnic Chinese patients with Parkinson's disease (PD). In a case control study, we performed genetic analysis of the P755L variant in an independent cohort of Chinese patients with PD and controls. The P755L variant was present in 4/204 (2.0%) of PD compared with 6/235 (2.6%) of controls (odds ratio = 0.76, 95% CI 0.23, 2.6, P = 0.76). All subjects carried the heterozygous genotype. Subset analysis in the group > or = 65 years of age revealed a prevalence of 2.8% in PD compared with 3.1% in controls (odds ratio = 0.92, 95% CI 022, 3.7, P = 0.9), and in the group < 65 years of age showed a 0% in PD versus 2.1% in controls (P = 0.2). The phenotype of patients with PD with the P755L variant was generally similar to other patients with PD and none of the carriers reported a positive family history. The lack of functional data, absence of segregation of the variant with disease, and the presence of the variant in apparently healthy individuals suggest that P755L is possibly a rare polymorphism in the Chinese population. Further validation of our findings in other populations would be important.

Association between caffeine intake and risk of Parkinson's disease among fast and slow metabolizers.

INTRODUCTION: Cytochrome P450 1A2 (CYP 1A2) is responsible for more than 90% of caffeine clearance. A polymorphic variant of CYP1A2 (-163C>A) (rs762551) is associated with high CYP1A2 inducibility. Both caffeine and its main metabolite, paraxanthine, may be neuroprotective. The association between caffeine intake and risk of Parkinson's disease (PD) in fast and slow caffeine metabolizers has not been compared. OBJECTIVE: In a case-control study, we analyzed the relationship between caffeine intake and risk of PD in both fast and slow caffeine metabolizers. METHODS: All the study participants were recruited prospectively, and interviewed for information on the amount and duration of caffeine intake. Genotyping of the CYP1A2 variant was carried out using the allelic discrimination method. RESULTS: Out of 1000 participants who were initially screened, 886 consisting of 418 PD and 468 race, sex and age matched controls were included. No evidence existed to suggest any association between CYP1A2 and the onset of PD (P=0.08). A significant association was seen between caffeine intake and the onset of PD (P=2.01x10(-5)), with the odds ratio for moderate and high drinkers at 0.71 [95% confidence interval (CI): 0.50-1.00] and 0.47 (95% CI: 0.34-0.65), respectively against the low drinkers. Multivariate analysis revealed no evidence of any interaction effects of caffeine with CYP1A2 (P=0.956). CONCLUSION: The association between caffeine intake and risk of PD was similarly observed in both fast and slow caffeine metabolizers, supporting experimental evidence in animal models that both caffeine and its major metabolite, paraxanthine, are neuroprotective.

Analysis of LRRK2 Gly2385Arg genetic variant in non-Chinese Asians.

A common LRRK2 missense variant, Gly2385Arg, has been found to be a genetic risk factor for Parkinson's disease (PD) in ethnic Chinese and Japanese. However, the presence of the variant in other non-Chinese Asian patients has not been fully clarified. We performed genetic analysis of the Gly2385Arg variant in 472 non-Chinese Asian subjects in Singapore (comprising of 166 PD and 306 controls of Malay/Indian ethnicity). The frequency of the heterozygous Gly2385Arg genotype was not significantly different in PD compared with controls (1.2% vs. 0.8%, odds ratio = 2.83, 95% CI 0.40, 20.2, P = 0.3). No subjects carried the homozygous genotype. Stratification by Malay and Indian ethnicity revealed that there were two carriers each among 98 (2.0%) Malay PD and 173 (1.2%) Malay controls (odds ratio = 1.78, 95% CI 0.25, 12.8, P = 0.6), but there were no carriers among 66 Indian PD and 133 Indian controls. We demonstrated that the Gly2385Arg variant could be detected in our Malay subjects. However, its frequency was much lower than the 8 to 10% prevalence previously reported in our Singaporean and Taiwanese Chinese PD population. The relevance of Gly2385Arg as a genetic risk factor may be restricted to selected Asian races, and more studies will be needed to confirm our observations.

Case-control study of UCHL1 S18Y variant in Parkinson's disease.

A recent meta-analysis observed a greater significant inverse association of the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y variant with Parkinson's disease (PD) for Asian (predominantly Japanese) populations compared with Caucasian populations. We performed an independent case-control study in 335 PD and 341 control subjects with data from a Chinese population to investigate the age-of-onset effect of the UCHL1 variant in PD. The Y/Y and Y/S genotypes were less frequent in the PD young-onset group than in controls and the frequency of the Y alleles was higher in young controls compared to young-onset PD (age at examination

PINK1 mutations in sporadic early-onset Parkinson's disease.

Pathogenic PINK1 mutations have been described in PARK6-linked Parkinson's disease (PD) patients of Asian origin. However, data on the frequency of PINK1 mutations in sporadic early-onset Parkinson's disease (EOPD) Asian patients are lacking. The objectives of this study were to report the frequency of PINK1 mutations of sporadic EOPD in an Asian cohort comprising of ethnic Chinese, Malays, and Indians, and to highlight a PINK1-positive patient who presented with restless legs symptoms. Eighty consecutive sporadic EOPD patients from the movement disorder clinics of two major tertiary institutions in the country were included. We performed sequence analysis of all the coding and exon-intron junctions of the PINK1 using specific primer sets. In addition, we genotyped polymorphisms detected from the analysis in a group of sporadic PD patients and controls. Three different mutations (two homozygous nonsense and one heterozygous missense) in the putative kinase domain were found in three patients, giving a 3.7% frequency of PINK1 mutations in our EOPD cohort. All the mutations were absent in 200 healthy controls. One patient with a novel homozygous nonsense PINK1 mutation presented unusually with restless legs symptoms. Separately, analysis of the frequency of four PINK1 polymorphisms in a group of sporadic PD and controls did not reveal any significant differences. We highlight a 3.7% frequency of PINK1 mutations in an Asian cohort (ethnic Chinese, Malay, and Indian) of EOPD. The phenotypic spectrum associated with PINK1-positive patients may be wider than previously reported. Polymorphisms of PINK1 do not appear to modulate risk of PD in our population.

Alpha-synuclein mRNA expression in sporadic Parkinson's disease.

The expression of alpha-synuclein gene can be influenced by the genomic load and/or epigenetic factors. By using quantitative real-time polymerase chain reaction techniques, we demonstrated that the alpha-synuclein gene mRNA expression in sporadic PD did not differ from healthy controls (median [range] 0.110 ]0.012-0.628] vs. 0.120 [0.028-0.447]; P = 0.15). There was no difference in the alpha-synuclein gene dosage between PD patients with high and low mRNA expression. Multivariate analysis did not reveal age, gender, or cigarette smoking as confounding variables. Our study suggests that there was no significant alteration of alpha-synuclein mRNA expression in our sporadic PD patients compared to controls. However, the role of alpha-synuclein mRNA expression in select groups of sporadic PD patients and its interaction with environmental agents need to be further determined.