Genetic analysis of DJ-1 in a cohort Parkinson's disease patients of different ethnicity.

Mutations in the DJ-1 gene have been described in autosomal recessive Parkinson's disease patients (ARPD) of European ancestry and young onset (YOPD) Ashkenazi Jewish and Afro-Caribbean patients. There is little information on the prevalence of DJ-1 mutations amongst Asian PD populations. In this study, we examined for DJ-1 mutations in consecutive YOPD and ARPD in a multi-ethnic cohort (Chinese, Malays, and Indians) of PD patients in a tertiary referral center. Sequence analysis of all the exons and the exon and intron boundaries of the DJ-1 gene were carried out. We did not find any DJ-1 mutations in these patients. A number of intronic variants with genotype frequency ranging from 15 to 90% were detected. Unlike Parkin, pathogenic DJ-1 mutations appear to be restricted to certain populations and are unlikely to be of clinical importance in our Asian cohort.

Genetic analysis of Nurr1 haplotypes in Parkinson's disease.

Nurr1 gene plays an important role in the development of the mesencephalic dopaminergic system. Genetic variability of Nurr1 gene may be associated with risk of Parkinson's disease (PD). We found three polymorphic loci (c.-2922(C)2-3, IVS6+18insG and EX8+657 (9-10CA)) of the Nurr1 gene in our PD patients and a novel intron 7+33 C-->T variant in one PD patient. We proceeded to perform a haplotype analysis in a case control study. A total of 202 PD patients (mean age 65.04+/-9.44 years, 55.4% men) and 202 age, gender and race matched controls (mean age 64.33+/-10.12 years, 54.0% men) were studied. The intron 7+33 C-->T variant was present in only one of the PD patients (0.5%) but in none of the controls. The Nurr1 mRNA levels in the lymphocytes did not significantly differ between the affected patient and controls. We found complete linkage disequilibrium between c.-2922(C)2-3 and IVS6+18insG polymorphic loci (D=0.25). Analysis of the three loci haplotype frequencies did not demonstrate any significant difference between PD and controls. There were also no significant differences in the haplotype frequencies between young and late onset PD patients. In conclusion, we demonstrated a large common haplotype block spanning the Nurr1 gene in our population. The intron 7+33 C-->T variant most likely represents either a non-functional mutation or a rare polymorphism in our study population. Our study suggests that Nurr1 variability is unlikely to play a major role in the majority of our PD patients.

Alpha synuclein promoter and risk of Parkinson's disease: microsatellite and allelic size variability.

Polymorphism of the alpha synuclein promoter region (non-amyloid component of plaques (NACP)-Rep1) is associated with an increased risk of Parkinson's disease (PD) in three separate studies. We studied NACP-Rep1 polymorphism in two independent case control studies in our population. In study one, 104 PD and 104 age, gender and race matched controls; and in study two, 102 PD and 102 age, gender and race matched controls were examined separately. The results of both studies were analyzed independent of one another. We found three polymorphic alleles (designated 0, 1, 2). In study one, the frequency of allele 2 was significantly higher in PD patients as compared to healthy controls (0.37 versus 0.23, P=0.01, X(2)=9.98). In study two, the frequency of allele 2 was similar between PD and controls (0.31 versus 0.33, P=1.00, X(2)=0.30). There was a non-significant higher allele 2 frequency in PD when both studies were analyzed together (0.34 versus 0.28, P=0.20, X(2)=3.4). No significant differences of the various genotypes between PD and controls were found. However there were differences of the mixed dinucleotide repeats sequences for similar homozygous genotypes. Variability of the microsatellite region and potential interacting factors that could affect alpha synuclein gene transcription should be further examined.

Association of Caucasian-identified variants with colorectal cancer risk in Singapore Chinese.

BACKGROUND: Genome-wide association studies (GWAS) in Caucasians have identified fourteen index single nucleotide polymorphisms (iSNPs) that influence colorectal cancer (CRC) risk. METHODS: We investigated the role of eleven iSNPs or surrogate SNPs (sSNPs), in high linkage disequilibrium (LD, r(2)≥ 0.8) and within 100 kb vicinity of iSNPs, in 2,000 age- and gender-matched Singapore Chinese (SCH) cases and controls. RESULTS: Only iSNP rs6983267 at 8q24.21 and sSNPs rs6695584, rs11986063, rs3087967, rs2059254, and rs7226855 at 1q41, 8q23.3, 11q23.1, 16q22.1 and 18q21.1 respectively showed evidence of association with CRC risk, with odds ratios (OR) ranging from 1.13 to 1.40. sSNP rs827401 at 10p14 was associated with rectal cancer risk (OR = 0.74, 95% CI 0.63-0.88) but not disease prognosis (OR = 0.91, 95% CI 0.69-1.20). Interestingly, sSNP rs3087967 at 11q23.1 was associated with CRC risk in men (OR = 1.34, 95% CI 1.14-1.58) but not women (OR = 1.07, 95% CI: 0.88-1.29), suggesting a gender-specific role. Half of the Caucasian-identified variants, including the recently fine-mapped BMP pathway loci, BMP4, GREM1, BMP2 and LAMA 5, did not show any evidence for association with CRC in SCH (OR ~1; p-value >0.1). Comparing the results of this study with that of the Northern and Hong Kong Chinese, only variants at chromosomes 8q24.21, 10p14, 11q23.1 and 18q21.1 were replicated in at least two out of the three Chinese studies. CONCLUSIONS: The contrasting results between Caucasians and Chinese could be due to different LD patterns and allelic frequencies or genetic heterogeneity. The results suggest that additional common variants contributing to CRC predisposition remained to be identified.

Colorectal cancer screening: yield of faecal occult blood testing.

The incidence of colorectal cancer is rising and increasing public awareness of this condition has stimulated interest in screening tests. Colorectal cancer is treatable and curable in its early stages and clear benefits are present if the cancer can be detected in its early stages. Sensitivity of the faecal occult blood test (FOBT) by immunochemical techniques for colorectal (CRC) cancer screening has been reported as 67% to 89% in certain population screening programs. Although much work has been done to address screening of colorectal cancer in the community, not much has been done to establish what the expected outcomes of screening are in a cohort of voluntary asymptomatic individuals. This paper retrospectively reviews the findings in such a cohort who sought health assessment (including a FOBT) at a Health Screening Centre in a tertiary hospital in Singapore over the period of 2002 to 2007. The outcomes are discussed together with references to other relevant studies on faecal occult blood test screening of CRC.

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.

Nurr1 mutational screen in Parkinson's disease.

We performed sequence analysis of all the exons and exon-intron boundaries in familial and young-onset Parkinson's disease (PD) in an Asian cohort. None of the patients carried any pathogenic mutations in the Nurr1 gene. We demonstrated a 5 to 10% prevalence of the intron 7 +33 C-->T variant among Malay and Indian PD and healthy controls, suggesting that this variant, which was previously described only in 1 Chinese patient, was not a silent mutation but a common polymorphic variant in some ethnic races.