Analysis of rare variants in the C3 gene in patients with age-related macular degeneration

Age-related macular degeneration (AMD) is a progressive retinal disorder affecting over 33 million people worldwide. Genome-wide association studies (GWASs) for AMD identified common variants at 19 loci accounting for 15-65% of the heritability and it has been hypothesized that the missing heritability may be attributed to rare variants with large effect sizes. Common variants in the complement component 3 (C3) gene have been associated with AMD and recently a rare C3 variant (Lys155Gln) was identified which exerts a large effect on AMD susceptibility independent of the common variants. To explore whether additional rare variants in the C3 gene are associated with AMD, we sequenced all coding exons in 84 unrelated AMD cases. Subsequently, we genotyped all identified variants in 1474 AMD cases and 2258 controls. Additionally, because of the known genetic overlap between AMD and atypical hemolytic uremic syndrome (aHUS), we genotyped two recurrent aHUS-associated C3 mutations in the entire cohort. Overall, we identified three rare variants (Lys65Gln (P = 0.04), Arg735Trp (OR = 17.4, 95% CI = 2.2-136; P = 0.0003), and Ser1619Arg (OR = 5.2, 95% CI = 1.0-25; P = 0.05) at the C3 locus that are associated with AMD in our EUGENDA cohort. However, the Arg735Trp and Ser1619Arg variants were not found to be associated with AMD in the Rotterdam Study. The Lys65Gln variant was only identified in patients from Nijmegen, the Netherlands, and thus may represent a region-specific AMD risk variant

Analyses of Sequence Variants in the MYOC Gene and of Single Nucleotide Polymorphisms in the NR3C1 and FKBP5 Genes in Corticosteroid-Induced Ocular Hypertension

Item does not contain fulltextBACKGROUND: To perform an independent replication study to determine whether genetic variants in MYOC, NR3C1 and FKBP5 are involved in steroid-induced ocular hypertension. MATERIALS AND METHODS: A retrospective case-control study was peformed on native Dutch patients who were treated with 4.0 mg intravitreal triamcinolone acetonide (IVTA). The patients were divided into an intraocular hypertension group (intraocular pressure >21 mmHg within a year after IVTA) and a non-intraocular hypertension group. The cohort was genotyped for 31 single-nucleotide polymorphisms (SNPs): 21 in NR3C1 and 10 in FKBP5. In addition, the open reading frame of MYOC was sequenced. RESULTS: A total of 102 patients were included in this study: 58 steroid responders and 44 non-responders. No significant associations were found for the studied SNPs in NR3C1 and FKBP5. Heterozygous amino acid variants were detected in the MYOC gene in two patients of the non-intraocular hypertension group. CONCLUSIONS: This study does not confirm a role for genetic variants in the MYOC, NR3C1 and FKBP5 genes in the pathogenesis of corticosteroid-induced ocular hypertension

Association of known common genetic variants with primary open angle, primary angle closure, and pseudoexfoliation glaucoma in Pakistani cohorts

Contains fulltext : 138859.pdf (publisher's version ) (Open Access)PURPOSE: Despite the different etiology of primary open angle glaucoma (POAG), primary angle closure glaucoma (PACG), and pseudoexfoliative glaucoma (PEXG), several studies have suggested that these forms of glaucoma have overlapping genetic risk factors. Therefore, the aim of this study was to evaluate the role of genetic variants recently associated with POAG in different types of glaucoma in Pakistani POAG, PACG, and PEXG patient cohorts. METHODS: Six variants in CDKN2B-AS1 (rs4977756), CDKN2B (rs1063192), ATOH7 (rs1900004), CAV1 (rs4236601), TMCO1 (rs4656461), and SIX1 (rs10483727) were genotyped using TaqMan assays. A total of 513 unrelated patients with glaucoma (268 with POAG, 125 with PACG, and 120 with PEXG) and 233 healthy controls were included in the study. Genotypic and allelic associations were analyzed with a chi-square test. RESULTS: The frequency of the G allele of TMCO1 rs4656461 was significantly lower in the patients with POAG (p=0.003; OR [odds ratio]=0.57), PACG (p=0.009; OR=0.52), and PEXG (p=0.01; OR=0.54) compared to the control individuals. The T allele of ATOH7 rs1900004 was observed less frequently in the patients with PACG (p=0.03; OR=0.69) compared to the control individuals. The A allele of CAV1 rs4236601 was found more frequently in the patients with POAG (p=0.008; OR=1.49) compared to the control individuals. This study demonstrates that the TMCO1 rs4656461 variant is associated with POAG, PACG and PEXG in the Pakistani population. Our study was unable to confirm previous associations reported for variants in CDKN2B-AS1, CDKN2B, and SIX1 with any type of glaucoma. CONCLUSIONS: In conclusion, we found consistent evidence of the significant association of three common variants in TMCO1, ATOH7, and CAV1

Association of a polymorphism in the BIRC6 gene with pseudoexfoliative glaucoma.

Contains fulltext : 136715.pdf (publisher's version ) (Open Access

Analysis of rare variants in the C3 gene in patients with age-related macular degeneration

Contains fulltext : 136382.pdf (publisher's version ) (Open Access)Age-related macular degeneration (AMD) is a progressive retinal disorder affecting over 33 million people worldwide. Genome-wide association studies (GWASs) for AMD identified common variants at 19 loci accounting for 15-65% of the heritability and it has been hypothesized that the missing heritability may be attributed to rare variants with large effect sizes. Common variants in the complement component 3 (C3) gene have been associated with AMD and recently a rare C3 variant (Lys155Gln) was identified which exerts a large effect on AMD susceptibility independent of the common variants. To explore whether additional rare variants in the C3 gene are associated with AMD, we sequenced all coding exons in 84 unrelated AMD cases. Subsequently, we genotyped all identified variants in 1474 AMD cases and 2258 controls. Additionally, because of the known genetic overlap between AMD and atypical hemolytic uremic syndrome (aHUS), we genotyped two recurrent aHUS-associated C3 mutations in the entire cohort. Overall, we identified three rare variants (Lys65Gln (P=0.04), Arg735Trp (OR=17.4, 95% CI=2.2-136; P=0.0003), and Ser1619Arg (OR=5.2, 95% CI=1.0-25; P=0.05) at the C3 locus that are associated with AMD in our EUGENDA cohort. However, the Arg735Trp and Ser1619Arg variants were not found to be associated with AMD in the Rotterdam Study. The Lys65Gln variant was only identified in patients from Nijmegen, the Netherlands, and thus may represent a region-specific AMD risk variant

Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity

Butterfly-shaped pigment dystrophy is an eye disease characterized by lesions in the macula that can resemble the wings of a butterfly. Here we report the identification of heterozygous missense mutations in the CTNNA1 gene (encoding α-catenin 1) in three families with butterfly-shaped pigment dystrophy. In addition, we identified a Ctnna1 missense mutation in a chemically induced mouse mutant, tvrm5. Parallel clinical phenotypes were observed in the retinal pigment epithelium (RPE) of individuals with butterfly-shaped pigment dystrophy and in tvrm5 mice, including pigmentary abnormalities, focal thickening and elevated lesions, and decreased light-activated responses. Morphological studies in tvrm5 mice demonstrated increased cell shedding and the presence of large multinucleated RPE cells, suggesting defects in intercellular adhesion and cytokinesis. This study identifies CTNNA1 gene variants as a cause of macular dystrophy, indicates that CTNNA1 is involved in maintaining RPE integrity and suggests that other components that participate in intercellular adhesion may be implicated in macular disease