RESUMEN
PURPOSE: Single nucleotide polymorphisms (SNPs) in the LOC387715 (rs10490924), HTRA1 (rs11200638), and CFH (rs1061170) genes have been implicated in age-related macular degeneration (AMD). The present study was undertaken to determine the involvement of the LOC387715 and HTRA1 in an AMD cohort from India. METHODS: The coding region of LOC387715 (exon 1) and the promoter of HTRA1 were screened by resequencing in AMD cases and normal controls. Odds ratios were calculated to assess the risk of individual genotypes. Linkage disequilibrium (LD) and haplotype frequencies were estimated with Haploview software. Population attributable risk (PAR %) for the associated SNPs and their combined effects were calculated. RESULTS: Resequencing revealed seven different SNPs in these genes, of which significant associations were noted with the risk alleles of rs10490924 (T allele; P = 5.34 x 10(-12)) in LOC387715, and rs11200638 (A allele; P = 4.32 x 10(-12)) and rs2672598 (C allele; P = 3.39 x 10(-11)) in HTRA1 among the cases. Correspondingly, the homozygous risk genotypes TT, AA, and CC in these SNPs exhibited higher disease odds and PAR %. rs10490924 and rs11200638 were in tight LD (D', 0.90; 95% CI, 0.84-0.93). G-C-T-A-C was the risk haplotype (P = 8.04 x 10(-15)), whereas the G-C-G-G-T haplotype was protective (P = 2.01 x 10(-4)). The combined effect of the CFH (CC) and LOC387715 (TT) risk genotypes exhibited a PAR of 93.7% (OR, 73.89; 95% CI, 8.69-628.13). CONCLUSIONS: The present data provided an independent validation of the association of LOC387715 and HTRA1 SNPs, along with their risk estimates among Indian patients with AMD. These associations underscore their significant involvement in AMD susceptibility, which may be useful for predictive testing.
Asunto(s)
Cromosomas Humanos Par 10/genética , Degeneración Macular/genética , Polimorfismo de Nucleótido Simple , Proteínas/genética , Serina Endopeptidasas/genética , Anciano , Factor H de Complemento/genética , Exones/genética , Haplotipos , Serina Peptidasa A1 que Requiere Temperaturas Altas , Humanos , India , Desequilibrio de Ligamiento , Metaanálisis como Asunto , Persona de Mediana Edad , Familia de Multigenes , Oportunidad Relativa , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas/genética , Factores de RiesgoRESUMEN
PURPOSE: To screen polymorphisms in complement factor-H (CFH), toll-like receptor 4 (TLR4), and APOE genes as potential risk factors for age-related macular degeneration (AMD) in Indian patients. METHODS: One hundred patients with AMD and 120 normal control subjects were screened for the polymorphisms by restriction digestion and resequencing. Five intragenic SNPs in CFH were screened to generate haplotype data in cases and controls. The data were analyzed in conjunction with data from other populations based on genotype and haplotype frequencies, and odds ratios were computed to estimate the risk of AMD in the different genotypes. RESULTS: Significant association was noted with the CFH variant (Tyr402His) among AMD cases (P = 1.19 x 10(-7)). Individuals homozygous for the mutant genotype CC had a significantly higher risk (P < 0.0001) of AMD (OR = 11.52; 95% CI 5.05-26.28) than those carrying a single copy of the C allele (OR = 1.51; 95% CI 0.82-2.80), after adjusting for age, gender, and diabetes. Linkage disequilibrium and haplotype analysis at the CFH locus indicated the C-G-T-C-A-G to be a risk haplotype (P = 0.0003). No significant differences were observed in the genotype frequencies of APOE polymorphisms among patients and control subjects (P = 0.76). The carriers of epsilon4 allele had a reduced risk (P = 0.03) of AMD (OR = 0.42, 95% CI 0.19-0.91). TLR4 did not exhibit any association with AMD. CONCLUSIONS: The CFH polymorphism Tyr402His appears indicative of AMD pathogenesis. Diabetes, age, and gender in the presence of the homozygous "CC" genotype in CFH carry an increased risk of AMD. Hence this polymorphism could be used as a potential marker for predictive testing across continents.
Asunto(s)
Apolipoproteínas E/genética , Marcadores Genéticos , Degeneración Macular/genética , Polimorfismo de Nucleótido Simple , Receptor Toll-Like 4/genética , Anciano , Factor H de Complemento/genética , Electroforesis en Gel de Poliacrilamida , Femenino , Genotipo , Haplotipos , Humanos , India , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Reacción en Cadena de la Polimerasa , Factores de RiesgoRESUMEN
AIM: The fork-head transcription factor gene (FOXL2) gene has been implicated in Blepharophimosis Ptosis Epicanthus Inversus Syndrome (BPES) type I and type II. The authors aimed to evaluate the involvement of FOXL2 in familial and sporadic cases of BPES in an Indian cohort. METHODS: The present cohort comprised clinically well-characterised BPES cases that included six affected families, two sporadic cases and 60 unaffected normal controls. The 5' untranslated and coding region of FOXL2 was screened by resequencing and confirmed by restriction digestion. Further, genotype-phenotype correlations were done to understand the implications of the observed mutation. RESULTS: Six mutations were observed in eight cases (87.5%). These included a novel deletion (c.860delC), three previously reported duplications (c.663-692dup 30, c.672-701dup30 and c.843-859dup17), a frame shift (c.804dupC) and a homozygous missense mutation (p.E69K). The p.E69k mutation was seen in both heterozygous and homozygous form in a large four-generational family, and disease severity was found to be directly linked to the allelic dosage. Two SNPs (c.501CâT, c.536CâG) were also noted. An unusual coexistence of polycystic ovarian disease (PCOD) with BPES was also seen in one of the families. DISCUSSION: Mutations in the region downstream of the fork-head domain were predominantly responsible for BPES among Indian patients.