[Association study between candidate genes involved in cell-cell adhesion and non-syndromic cleft lip with or without cleft palate in Chinese population].

OBJECTIVE: To explore the association and gene-environment interaction between single nucleotide polymorphisms (SNPs) involved in cell-cell adhesion and non-syndromic cleft lip with or without cleft palate (NSCL/P) among Chinese population. METHODS: A total of 806 NSCL/P trios were drawn by an international consortium, which conducted a genome-wide association study (GWAS) using a case-parent trio design to investigate genes affecting risks to NSCL/P. The transmission disequilibrium test (TDT) was used to explore the association between cell-cell adhesion genes, including CDH1, CTNNB1, PVRL1, PVRL2, PVRL3, ACTN1, VCL, LEF1, and NSCL/P. Conditional Logistic regression models were used to estimate effects on risk of exposed and unexposed children. Four common maternal exposures including maternal smoking, environmental tobacco smoke, alcohol consumption and multivitamin supplementation during pregnancy were included in this study. RESULTS: A total of 226 SNP markers were tested after quality control in this study. Although 23 SNPs in three genes (CTNNB1, CDH1, ACTN1) showed nominal significant association with NSCL/P in the TDT (P<0.05).There were no significant evidence of linkage and association that remained in the transmission disequilibrium test after Bonferroni correction(P>0.000 2). Tests for gene-environment interaction yielded significant results between rs743127 in ACTN1 and environmental tobacco smoke (P=0.000 1) with an estimated OR (case|G and E)=2.00(95%CI: 1.23-3.26) and OR (case|G no E)=0.59 (95%CI: 0.38-0.90). Among the lower P value results in gene-environment tests, there were no significant results between rs1475034, rs370535, rs2273419 in ACTN1, rs106871 in CTNNB1 and environmental tobacco smoke interaction. There were also no significant results between rs7634000, rs2971366, rs2634553, rs1489032, rs7624812 in PVRL3 and multivitamin supplementation during pregnancy in gene-environment tests(P>0.000 2). CONCLUSION: There is no association between cell-cell adhesion genes, including CDH1, CTNNB1, PVRL1, PVRL2, PVRL3, ACTN1, VCL, LEF1, and NSCL/P when the genes are considered alone. But our results suggest that SNPs in ACTN1 may influence the risk to NSCL/P through gene-environment interaction.

Contribution of glucocerebrosidase mutation in a large cohort of sporadic Parkinson's disease in Taiwan.

BACKGROUND AND PURPOSE: The association between glucocerebrosidase (GBA) mutations and Parkinson's disease (PD) is attracting increased attention worldwide. In patients of Chinese ethnicity, other than the common L444P mutation, a few mutations have been reported. However, the contribution of GBA to PD can be answered only by a thorough investigation of its mutations in a unique large population. METHODS: We enrolled 1747 participants: 967 PD patients and 780 healthy individuals. We screened entire GBA coding regions and exon-intron boundaries in 30 randomly chosen PD patients, followed by testing five variants (L444P, D409H, R120W, L174P, and Q497R) in all participants. The G2385R and R1628P in LRRK2 had been previously studied in almost all participants. RESULTS: In total, 36 patients (3.72%) carried a heterozygous mutant GBA allele (27 L444P, 7 RecNciI, and 2 D409H). Only two controls (0.26%) carried heterozygous GBA mutation (1 L444P and 1 RecNciI). In PD group, the mean age at onset in carriers was younger than in non-carriers. The difference in percentage of mutation frequencies between patients and controls was highly significant for the L444P mutation (P < 0.0001). One L444P carrier was also associated with LRRK2 G2385R variant, but no atypical Parkinsonism was observed. CONCLUSIONS: The present study ascertains that L444P mutation in GBA gene may contribute to an earlier onset of development of PD in Han/Chinese population. Following LRRK2 variants, GBA is the second most frequent mutations indicated for sporadic PD development in the Han/Chinese population. These GBA carriers are associated with an earlier onset of Parkinsonism.

A longitudinal study of Taiwanese sialidosis type 1: an insight into the concept of cherry-red spot myoclonus syndrome.

BACKGROUND AND PURPOSE: Sialidosis type 1 (ST-1) is a neurodegenerative disorder with limited long-term follow-up report. This study is to document the chronological profile of ST-1. METHODS: We perform serial analysis of 17 Taiwanese patients with ST-1 focusing on evolution of clinical features, electrophysiological findings, genetic studies, and neuroimage examinations. RESULTS: All patients had a mutation at 554A-->G in exon 3 of the NEU1 gene causing Ser182Gly substitution. Fifteen patients were homozygous. Two patients were heterozygous with novel mutations, 956C-->T causing Ala319Val in one and 163C-->T causing Gln55stop codon in the other. The neuraminidase activity was markedly decreased in all 11 available patients. Only three patients (17.6%) manifested the macular cherry-red spot. The majority of patients (82.3%) developed full-blown manifestation of myoclonus, ataxia, and seizures within 5 years. Abnormal somatosensory evoked potentials with giant cortical waves were found in all patients. Prolonged P100 peak latency of the visual evoked potentials (VEPs) were found in 16 patients (94.1%) in the early stage even without visual symptoms. CONCLUSION: ST-1 in Taiwanese population illustrates distinct characteristics of phenotype with infrequent cherry-red spot. We suggest to screen the NEU1 mutations in patients presenting action myoclonus with abnormal VEPs, even without macular cherry-red spots.

p16INK4 gene mutation and allelic loss of chromosome 9p21-22 in Taiwanese hepatocellular carcinoma.

BACKGROUND: The p16INK4 (MTS1/CDNK2A) gene, located on chromosome 9p21, is an inhibitor of cyclin-dependent kinase 4. Various data have shown that it is frequently inactivated in several types of cell lines and primary human cancers. MATERIALS AND METHODS: Thirty cases with hepatocellular carcinoma were studied for possible p16INK4 gene mutation in Taiwan. Homozygous deletion was determined using polymerase chain reaction (PCR). The p16INK4 gene mutation was first screened by single strand conformation polymorphism, then direct DNA sequencing was performed on the cases with mobility shifts. Deletion mapping of chromosome 9p21-22 was also carried out with two polymorphic microsatellite markers (D9S925 and D9S168) using PCR. RESULTS: One of the 30 cases had homozygous deletion at exon 3 of the p16INK4 gene. Another tumor had altered electrophoresed mobility in exon 2 with G to T transversion in the first nucleotide of codon 61 by direct sequencing causing a stop codon (GAG-->TAG). At the D9S925 and D9S168 loci, six out of 24 (25%) and three out of 19 (16%) informative cases showed loss of heterozygosity, respectively. CONCLUSION: Point mutation and homozygous deletion of the p16INK4 gene are present in a subset of hepatocellular carcinomas in Taiwan. The patterns of the p16INK4 gene alteration are, however, different from those from other regions. In addition, allelic loss on chromosome 9p21-22 is not an uncommon event in hepatocellular carcinomas. Therefore, the significance of chromosome 9p loss deserves to be extensively investigated.

Analysis of the UCHL1 genetic variant in Parkinson's disease among Chinese.

The inverse association of the functional ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y variant with Parkinson's disease (PD) among Caucasian populations has been debated. We conducted a large-scale analysis to investigate the age-of-onset effect of the UCHL1 variant in PD among ethnic Chinese. Individual data sets from 5 centers comprising a total of 4088 study subjects were analyzed. In the univariate analysis, only data from 1 center showed a trend towards a protective effect among young subjects. However, in the combined analysis, no significant association between the UCHL1 variant and PD was detected (A allele frequency 0.531 vs. 0.528, p=0.87, OR 1.01, 95% CI 0.92-1.1). Among subjects less than 60 years old, the OR is 0.99 (95% CI 0.84-1.16, p=0.88). A multivariate logistic regression analysis showed that family history, UCHL1 variant and the interaction of UCHL1 variant and age at onset (p=0.816) were not significantly associated with PD.

Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations.

Isolated oral clefts, including cleft lip with/without cleft palate (CL/P) and cleft palate (CP), have a complex and heterogeneous etiology. Case-parent trios from three populations were used to study genes spanning chromosome 2, where single nucleotide polymorphic (SNP) markers were analyzed individually and as haplotypes. Case-parent trios from three populations (74 from Maryland, 64 from Singapore and 95 from Taiwan) were genotyped for 962 SNPs in 104 genes on chromosome 2, including two well-recognized candidate genes: TGFA and SATB2. Individual SNPs and haplotypes (in sliding windows of 2-5 SNPs) were used to test for linkage and disequilibrium separately in CL/P and CP trios. A novel candidate gene (ZNF533) showed consistent evidence of linkage and disequilibrium in all three populations for both CL/P and CP. SNPs in key regions of ZNF533 showed considerable variability in estimated genotypic odds ratios and their significance, suggesting allelic heterogeneity. Haplotype frequencies for regions of ZNF533 were estimated and used to partition genetic variance into among-and within-population components. Wright's fixation index, a measure of genetic diversity, showed little difference between Singapore and Taiwan compared with Maryland. The tensin-1 gene (TNS1) also showed evidence of linkage and disequilibrium among both CL/P and CP trios in all three populations, albeit at a lower level of significance. Additional genes (VAX2, GLI2, ZHFX1B on 2p; WNT6-WNT10A and COL4A3-COL4A4 on 2q) showed consistent evidence of linkage and disequilibrium only among CL/P trios in all three populations, and TGFA showed significant evidence in two of three populations.

PARK6-linked autosomal recessive early-onset parkinsonism in Asian populations.

The authors performed linkage analysis in 39 families with autosomal recessive early-onset PD (AR-EOPD) negative for parkin and DJ-1 mutations. Eight families including three Japanese, two Taiwanese, one Turkish, one Israeli, and one Philippine showed evidence of linkage with PARK6 with multipoint log of the odds (lod) score of 9.88 at D1S2732. The results indicate worldwide distribution of PARK6-linked parkinsonism.