Biomedical subjects

Pancy O S Tam

Publications and source records attributed to Pancy O S Tam.

8 recordsLinked to original sources

PubMed2006

Association of complement factor H polymorphisms with exudative age-related macular degeneration.

PURPOSE: Variants in the complement factor H (CFH) gene have been reported to be associated with age-related macular degeneration (AMD). We conducted a case-control association study to investigate the association of 6 single nucleotide polymorphisms (SNPs) in CFH with exudative AMD in the Chinese population. METHODS: We recruited 163 cases and 244 controls, all ethnic Chinese, with complete ophthalmic examination including fundus investigation. Cigarette smoking was recorded. Six SNPs (dbSNP ID: rs3753394, rs800292, rs1061147, rs1061170, rs380390, and rs1329428) in the CFH gene were genotyped by Taqman assays. RESULTS: Y402H (1277 T>C) has low frequencies in our study population, 5.8% in patients and 3.9% in controls. It was not associated with exudative AMD adjusted for age, gender and smoking. Significant associations were detected for AMD with rs3753394 (p=0.003, p(corr)=0.018), rs800292 (p=0.00053, p(corr)=0.0032), and rs1329428 (p=0.00092, p(corr)=0.0028), p(corr) values obtained after adjustment for multicomparison. A haplotype containing these four SNPs (TGTC) was found to confer a significantly increased likelihood of exudative AMD with an odds ratio of 1.68 (95% CI: 1.26-2.23) p=0.0003 (p(corr)=0.0026 after correction by permutation test). Logistic regression analysis detected no interactions between the SNPs and age, gender or smoking. CONCLUSIONS: We have found differences in the association between the CFH gene and exudative AMD in Chinese from Caucasians and Japanese. We detected SNP rs3753394 in the CFH promoter carrying a significantly increased risk for exudative AMD.

Aged↗

PubMed2006

HTRA1 promoter polymorphism in wet age-related macular degeneration.

Age-related macular degeneration (AMD), the most common cause of irreversible vision loss in individuals aged older than 50 years, is classified as either wet (neovascular) or dry (nonneovascular). Inherited variation in the complement factor H gene is a major risk factor for drusen in dry AMD. Here we report that a single-nucleotide polymorphism in the promoter region of HTRA1, a serine protease gene on chromosome 10q26, is a major genetic risk factor for wet AMD. A whole-genome association mapping strategy was applied to a Chinese population, yielding a P value of <10(-11). Individuals with the risk-associated genotype were estimated to have a likelihood of developing wet AMD 10 times that of individuals with the wild-type genotype.

Aged↗

PubMed2006

Novel myocilin mutation in a Chinese family with juvenile-onset open-angle glaucoma.

OBJECTIVE: To search for the genetic cause of juvenile-onset open-angle glaucoma (JOAG) in a Chinese family. METHODS: In a 3-generation glaucoma family affected with JOAG or ocular hypertension, we screened myocilin (MYOC) and optineurin (OPTN) for mutations and investigated apolipoprotein E (APOE) polymorphisms in 6 family members, 2 of them patients with JOAG, 2 patients with ocular hypertension, and 2 patients who were asymptomatic. Normal controls included 200 unrelated Chinese subjects. The COS-7 cell line was transfected with expression vectors encoding wild-type or mutated MYOC complementary DNA. Cellular and secreted MYOC proteins were characterized by Western blotting. RESULTS: One missense MYOC mutation, 734G>A: Cys245Tyr, was identified. It occurred in all 4 family members afflicted with JOAG or ocular hypertension but not in asymptomatic family members. No OPTN variations were observed. APOE polymorphism frequencies were similar to those for controls. The Cys245Tyr MYOC mutation cosegregated with the disorder within the family. It was absent in the 200 control subjects. The Cys245Tyr mutant MYOC protein formed homomultimeric complexes that migrated at molecular weights larger than their wild-type counterparts. These mutant complexes remained sequestered intracellularly in COS-7 cells. CONCLUSIONS: The Cys245Tyr MYOC mutation was the genetic cause of JOAG in this Chinese family. This mutation may alter covalent bonds that formed between MYOC cysteines. Clinical Relevance Genetic tests of MYOC mutations may be beneficial to predict new cases of the disease in families with JOAG.

Adolescent↗

PubMed2006

A genome-wide scan maps a novel juvenile-onset primary open-angle glaucoma locus to 15q.

PURPOSE: To map the disease-associated locus of a family with autosomal dominant juvenile-onset primary open-angle glaucoma (JOAG). METHODS: A complete ophthalmic examination was conducted, and genomic DNA was obtained from 25 members of a Chinese family, of which eight were confirmed as having JOAG. Myocilin (MYOC), optineurin (OPTN), and WD repeat-domain 36 (WDR36) were screened for sequence alterations, by PCR and direct sequencing. Subsequently, a genome-wide scan was performed (Prism Linkage Mapping Set MD-10; Applied Biosystems, Inc., Foster City, CA). Two-point and multipoint linkage analyses were performed with the MLINK, ILINK, and LINKMAP programs. For fine mapping, additional markers flanking the most promising region on 15q were analyzed. The significance of the lod score was tested with simulation analyses by using FASTLINK. Haplotypes were constructed with Simwalk2. Three candidate genes, NR2E3, SMAD6, and CLN6, located within the critical region, were screened for mutations. RESULTS: MYOC, OPTN, and WDR36 mutations were excluded in all family members. A maximum two-point lod score of 3.31 at theta = 0.0 was obtained for the marker D15S125. Four adjacent markers, rs2030040, rs169169963, D15S153, and D15S131, gave two-point lod scores of 2.41, 2.90, 3.02, and 2.68, respectively, at theta = 0.0. Haplotype analysis and recombination mapping further confined this region to 15q22-q24 within a genetic distance of 16.6 Mb flanked by D15S1036 and rs922693. No mutations were found in the coding exons and splicing junctions of NR2E3, SMAD6, and CLN6. CONCLUSIONS: The results provide evidence for the mapping of a novel locus for JOAG at 15q22-q24. A further search for the disease-causing gene in this new JOAG locus is in progress.

Adolescent↗

PubMed2004

Absence of myocilin and optineurin mutations in a large Philippine family with juvenile onset primary open angle glaucoma.

PURPOSE: To analyze the role of the two primary open angle glaucoma (POAG) genes, myocilin (MYOC) and optineurin (OPTN), in a large Philippine family segregating autosomal dominant juvenile onset open angle glaucoma (JOAG). METHODS: The coding sequences of the MYOC and OPTN genes were screened in 27 family members by polymerase chain reaction and direct sequencing. The specific MYOC promoter polymorphism (MYOC.mtl) was identified by restriction endonuclease assay. All of the ABI MD-10 microsatellite markers on chromosomes 1, 2, 3, 7, 8, and 10, which harbor the six known POAG loci, were analyzed for linkage with POAG. RESULTS: No mutation was identified in this large kindred. Instead, three polymorphisms (-80G->A, -1000G->C, R76K) in MYOC and four polymorphisms (T34T, M98K, R545Q, IVS7+24G->A) in OPTN were found. All markers flanking the six known POAG loci gave LOD scores not more than 1.1. Non-parametric linkage analysis for all these markers resulted in p values more than 0.05. CONCLUSIONS: Both mutation testing and linkage analysis provide strong evidence against MYOC and OPTN being the causative gene in this large family. It indicates that unidentified genes will underlie the occurrence of glaucoma in this family.

Adult↗

PubMed2004

Polymorphisms in the myocilin promoter unrelated to the risk and severity of primary open-angle glaucoma.

PURPOSE: To investigate the proximal 2.5 kb promoter in the myocilin (MYOC) gene for mutations in Chinese patients with primary open-angle glaucoma (POAG). PATIENTS AND METHODS: We screened for sequence alterations in the MYOC promoter in 88 unrelated Chinese patients with POAG and 94 unrelated individuals without glaucoma, aged 50 years or above, as control subjects. In addition, the specific MYOC.mt1 polymorphism was determined in a total of 212 POAG patients and 221 control subjects. The relationships between POAG phenotype and the identified polymorphisms were studied by univariate analysis, multivariable logistic regression analysis, and haplotype analysis. RESULTS: All polymorphisms identified in this study followed Hardy-Weinberg equilibrium (P > 0.12) both in POAG patients and controls. Both univariate and multivariable logistic regression analyses showed no polymorphism that was significantly associated with the risk of POAG, P > 0.08 and P > 0.044 respectively. Haplotype analysis further indicated no association of MYOC promoter polymorphisms with the susceptibility for POAG (P > 0.1). On the other hand, there was no difference of POAG phenotypes among different genotypes of MYOC.mt1 (P > 0.31). CONCLUSIONS: In this study on the Chinese population, polymorphisms in the MYOC promoter are not related to the risk of POAG. There is no association between the MYOC.mt1 promoter polymorphism with the severity of POAG.

Adolescent↗

PubMed2003

Different optineurin mutation pattern in primary open-angle glaucoma.

PURPOSE: The optineurin gene (OPTN) is the second gene besides MYOC in which mutations have been identified to be associated with primary open-angle glaucoma (POAG). In this study, sequence alterations in the OPTN gene associated with POAG in Chinese subjects were investigated. METHODS: All the coding exons of OPTN were screened, including the intron-exon boundaries, for sequence alterations in a Chinese sample of 119 sporadic patients with POAG and 126 unrelated control subjects by polymerase chain reaction-conformation-sensitive gel electrophoresis and DNA sequencing. RESULTS: Sixteen sequence changes were identified: 3 had been reported (T34T, M98K, and R545Q) and 13 were novel (T49T, E103D, V148V, P199P, T202T, H486R, IVS6-5T-->C, IVS6-10G-->A, IVS7+24G-->A, IVS8+20G-->A, IVS13+21C-->G, IVS15+10G-->A, and IVS15-48C-->A). Among them, only E103D, H486R, V148V, and IVS13+21C-->G were found exclusively in patients with POAG, whereas P199P, T202T, and IVS8+20G-->A were present only in control subjects. The genotype of IVS7+24G-->A showed a significant association with POAG (P = 0.02, Fisher two-tailed exact test) and with and increased cup-to-disc ratio in these patients (P = 0.005, Mann-Whitney test). CONCLUSIONS: The findings in the current study enrich the evidence on the OPTN gene as a causative gene for POAG and suggest a different mutation pattern of OPTN in Chinese than in whites. The wide spectrum of putative mutations detected in this study suggests that both structural and functional disruptions in OPTN may contribute to the pathogenesis of glaucoma.

Adolescent↗

PubMedDate not supplied

Familial high myopia linkage to chromosome 18p.

A locus for autosomal dominant high myopia was reported on chromosome 18p. We sought to confirm this finding and narrow the reported interval by analyzing high myopia among families of Hong Kong Chinese, in whom myopia is common. In 15 families with a possibly autosomal dominant inheritance of high myopia (>or=-6 dpt) in at least 2 generations, 10 chromosome 18p markers were analyzed for linkage with high myopia. Two-point linkage analysis showed trends toward linkage of markers D18S476 and D18S62 with high myopia, with maximum logarithm of odds (LOD) scores of at least 1.1 and 1.7, respectively. Multipoint analysis of those 2 markers gave a maximum LOD score of at least 2.1. To attempt to account for likely genetic heterogeneity, 5 families showing evidence of linkage of the 2 markers with high myopia were selected for further multipoint linkage analysis, resulting in a maximum LOD score of 2.4 at D18S476. While multiple genetic and environmental factors likely contribute to myopia, these data are consistent with the possibility of a locus on chromosome 18p.

Asian People↗