Victor H.K. Yong

Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2)

Congenital hereditary endothelial dystrophy (CHED) is a heritable, bilateral corneal dystrophy characterized by corneal opacification and nystagmus. We describe seven different mutations in the SLC4A11 gene in ten families with autosomal recessive CHED. Mutations in SLC4A11, which encodes a membrane-bound sodium-borate cotransporter, cause loss of function of the protein either by blocking its membrane targeting or nonsense-mediated decay.

Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10−12), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10−10) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10−9). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.

Association Analysis of CFH, C2, BF, and HTRA1 Gene Polymorphisms in Chinese Patients with Polypoidal Choroidal Vasculopathy

PURPOSE Polypoidal choroidal vasculopathy (PCV) is a major cause of serosanguinous maculopathy in Chinese patients with age-related macular degeneration (AMD). Variants in the CFH and HTRA1/LOC387715 genes are strongly associated with AMD in Caucasians and Chinese. Variants in the C2 and BF genes have been found to confer a significantly reduced risk of AMD. This study was undertaken to determine whether these associations occur in Chinese patients with PCV. METHODS Patients of Chinese ethnicity with clinically and angiographically diagnosed PCV and normal control subjects were recruited from the Singapore National Eye Centre. Five single-nucleotide polymorphisms (SNPs) in the CFH gene, two each within the C2 and BF genes and two variants located in the LOC387715 and HTRA1 genes, were screened in all patients and control subjects. RESULTS Seventy-two patients with PCV and 93 normal control subjects were studied. A significant association was noted with CFH variants rs3753394 and rs800292 among the PCV cases (P = 0.0015 and P = 0.0045, respectively). Individuals homozygous for the TT genotype of rs3753394 had a significantly higher risk (P = 0.0076) of PCV (OR = 4.29; 95% CI: 1.47-12.50) than those carrying a single copy of the T allele (P = 0.3210; OR = 1.69; 95% CI: 0.60-4.78), after adjustment for such risk factors as age and sex. The genotype frequencies of rs11200638 and rs10490924 in HTRA1 and LOC387715, respectively, were also found to be significantly different between patients with PCV and normal control subjects (P = 0.00032 and P = 0.003, respectively). The AA genotype of rs11200638 and TT genotype of rs10490924 conferred a 4.9-fold (95% CI: 1.85-12.95) and 4.89-fold (95% CI: 1.85-12.90) increased risk of PCV, respectively, after adjustment for age and sex. The Y402H variant of CFH (rs1061170) and the BF and C2 variants were not significantly different in patients and normal control subjects. CONCLUSIONS The SNPs rs3753394 and rs800292 of CFH and rs11200638 of HTRA1 are significantly associated with the risk of PCV in Chinese patients.

Association of LOXL1 Gene Polymorphisms with Pseudoexfoliation in the Japanese

PURPOSE The single nucleotide polymorphisms (SNPs) rs1048661, rs3825942, and rs2165241 within the LOXL1 gene were recently found to confer risk of pseudoexfoliation glaucoma (XFG) through pseudoexfoliation syndrome (XFS) in Caucasians. The purpose of this study was to test this association in Japanese subjects with XFS/XFG. METHODS Japanese subjects with clinically diagnosed XFS/XFG and normal control subjects were recruited. Genomic DNA was extracted and the three SNPs of the LOXL1 gene were genotyped by bidirectional sequencing. The association of individual SNPs with XFG/XFS was evaluated by using chi(2) and the Fisher exact test. RESULTS Two hundred nine Japanese patients (106 XFG and 103 XFS) and 172 control subjects were studied. Strong associations were observed for all three SNPs of LOXL1 for XFS (odds ratio [OR] = 13.56, P = 3.39 x 10(-28) for allele T of rs1048661; OR = 10.71, P = 1.49 x 10(-7) for allele G of rs3825942; and OR = 4.55, P = 5.33 x 10(-4) for allele C of rs2165241) and XFG (OR = 25.21, P = 1.44 x 10(-34) for allele T of rs1048661; OR = 11.02, P = 1.40 x 10(-7) for allele G of rs3825942; and OR = 11.89, P = 4.76 x 10(-6) for allele C of rs2165241). The risk-associated alleles of rs1048661 and rs2165241 differed between the Japanese and Caucasians, whereas allele G of rs3825942 was associated with disease in both populations. Conditional analysis indicated that rs3825942 was not independent but correlated highly with rs1048661. The at-risk haplotype T-G-C was present at an approximately two times higher rate (94.7% vs. 50.6%, P = 4.22 x 10(-43)) in cases than in control subjects and conferred a 2.9-fold (95% confidence interval [CI], 2.357-3.464) increased likelihood of XFS. CONCLUSIONS Polymorphisms in the LOXL1 gene confer risk to XFS/XFG in the Japanese, but there are different risk-associated alleles and haplotypes in the Japanese.

Analysis of the Posterior Polymorphous Corneal Dystrophy 3 Gene, TCF8, in Late-Onset Fuchs Endothelial Corneal Dystrophy

PURPOSE Because the endothelial (posterior) corneal dystrophies share common pathologic features and result from primary endothelial dysfunction, it is possible that a proportion of them could be clinical manifestations of different mutations of the same gene. The aim of our study was to determine whether mutations of the TCF8 gene, recently implicated in posterior polymorphous dystrophy, may also play a role in the development of the more common Fuchs endothelial corneal dystrophy (FECD). METHODS Genomic DNA was extracted from leukocytes of peripheral blood, and the nine exons of the TCF8 gene were PCR amplified and subjected to bidirectional sequencing and analysis. Samples from 74 unrelated Chinese patients (55 women, 19 men) with a diagnosis of late-onset FECD and 93 age- and race-matched controls were studied. RESULTS The affected probands ranged in age from 52 to 91 years (mean age, 65.1 years); 8 had familial FECD and 66 had sporadic FECD. The authors found two mutations in the coding region of the TCF8 gene: a novel missense mutation in one patient c.2087A>G in exon 7 (Asn696Ser) and a silent mutation in exon 2 c.192T>C (D64D). CONCLUSIONS The identification of a novel missense mutation in only one of the patients implied that TCF8 does not play a significant role in the pathogenesis of FECD in this Chinese population.

ABCC5, a Gene That Influences the Anterior Chamber Depth, Is Associated with Primary Angle Closure Glaucoma

Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size = −0.045 mm, P = 8.17×10−9). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06–1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45×10−9; 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions.

Lack of association between the rs2664538 polymorphism in the MMP-9 gene and primary angle closure glaucoma in Singaporean subjects.

PurposeA recent study identified the single nucleotide polymorphism (SNP) rs2664538 within the MMP-9 gene with risk for acute primary angle closure glaucoma (PACG). The aim of this study was to confirm this association in Singaporean Chinese subjects with both acute and chronic PACG. MethodsThis was an observational cross-sectional study. Genomic DNA was extracted from leukocytes of peripheral blood and genotypes were determined by polymerase chain reaction and direct sequencing. The association of the SNP with PACG was evaluated using χ2 tests. ResultsA total of 217 subjects with PACG (consisting of 85 acute and 132 chronic PACG), and 83 normal control Chinese subjects were studied. There was no significant difference in the rs2664538 SNP allele frequencies for acute or chronic PACG subjects compared with controls. ConclusionsThis study did not find an association between the rs2664538 polymorphism within the MMP-9 gene and PACG in this sample of Chinese subjects.

Surgical management and genetic analysis of a Chinese family with the S171P mutation in the UBIAD1 gene, the gene for Schnyder corneal dystrophy

Background: To describe the underlying molecular genetic basis, surgical management and phenotypic variation of Schnyder corneal dystrophy (SCD) identified in a four-generation Chinese family. Methods: This is an interventional case series of 13 members from a non-consanguineous Chinese family. All patients underwent complete ophthalmological examination and slit-lamp photography. Subsequent corneal transplantations were performed (n = 3). Blood samples were taken for DNA extraction and subsequent genetic analysis. Results: Genotyping indicated linkage to the locus at chromosome 1p36. Screening of the UBIAD1 gene identified a highly conserved mutation, Ser171Pro. Phenotypic variation in this large pedigree is similar to that seen in Caucasian patients. Surgical management of patients with anterior lamellar keratoplasty and deep anterior lamellar keratoplasty showed good visual outcomes. Conclusions: The S171P mutation is described for the first time in a Chinese family. This is the largest non-Caucasian pedigree described with SCD. Visual rehabilitation may be performed successfully with lamellar surgical procedures as opposed to full-thickness corneal grafts.

CYP1B1 and MYOC Mutations in Vietnamese Primary Congenital Glaucoma Patients.

Purpose:Primary congenital glaucoma (PCG, OMIM 231300), the most common glaucoma in infancy, is caused by developmental defects in the anterior chamber angle. The 3 implicated genes are cytochrome P450 family I subfamily B polypeptide 1 (CYP1B1), latent transforming growth factor &bgr;-binding protein 2 (LTBP2), and myocilin (MYOC). In this study, we sought to determine CYP1B1 and MYOC sequence variations in a Vietnamese cohort of index cases with PCG and their families. Methods:Thirty Vietnamese subjects with PCG and 120 normal Vietnamese subjects were recruited. PCG was defined by the presence of at least 2 of the following clinical manifestations: increased corneal diameter (>10 mm at birth), corneal edema, Haab’s striae, optic disc changes, and absence of other ocular or systemic diseases associated with childhood glaucoma. The coding exons, intron and exon boundaries, and untranslated regions of CYP1B1 and MYOC genes were PCR amplified and subjected to bidirectional sequencing in all subjects. Results:We identified 2 homozygous and 3 heterozygous CYP1B1 sequence alterations in our study subjects. Among the 5 mutations identified, 2 (p.H279L and p.L283F) were novel mutations, whereas 3 (p.A121_S122insDRPAFA, p.L107V, and p.V320L) had been previously reported in PCG cases. None of these mutations was observed in any of the 120 controls. Haplotypes generated with 6 non–disease-causing intragenic single nucleotide polymorphisms detected in CYP1B1 indicated that the most common haplotype in Vietnamese population is similar to that found in Chinese and Japanese. The genotype-phenotype correlation showed no significant difference between mutation and no-mutation groups for quantitative clinical features (presenting intraocular pressure, corneal diameter, number of surgeries performed, the cup-to-disc ratio) as well as for qualitative factors (bilateral cases, phenotype severity, and the prognosis) (P>0.05). Conclusions:Five out of 30 families with PCG (16.7%) had disease attributable to CYP1B1 alterations suggesting that CYP1B1 is not the major gene causing PCG in Vietnamese unlike in the case of Arab or Romany patients. This percentage is similar to that detected in studies of Japanese and Chinese patients with sporadic PCG. PCG has proven to be an ocular disease of genetic heterogeneity, calling for further studies to identify novel genes causing this disease.