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1.
Exp Eye Res ; 228: 109403, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36736852

RESUMEN

Fuchs endothelial corneal dystrophy (FECD) is an age-related, bilateral corneal condition, characterized by apoptosis of the terminally differentiated endothelial cells. A genome-wide association study (GWAS) conducted in the European population in 2017, identified a new single nucleotide polymorphism (SNP), rs1200114 in the intergenic region between long intergenic non-protein coding RNA 970 (LINC00970) and ATPase Na+/K+ transporting subunit beta 1 (ATP1B1). The major focus of the current study is to understand the genetic association of this intergenic variant, rs1200114 with FECD in the Indian population. Sanger sequencing followed by statistical analysis indicated a significant difference in the allelic frequency between controls and cases (P = 0.01) with the minor allele 'G' of rs1200114 imparting a 1.64 fold increased risk for the disease. Luciferase reporter assay revealed no significant difference in the luciferase activity between allele 'A' and 'G' of rs1200114. However, quantitative RT-PCR assay revealed lower expression of ATP1B1 in FECD subjects compared with controls (P = 0.007). Therefore, to find whether another nearby SNP imparts regulatory effect, tag SNP association analysis was carried out; which revealed a significant association of another SNP, rs1200108, present in the intergenic region between LINC00970 and ATP1B1 with FECD (P = 0.009). The protective allele 'A' of rs1200108 displayed reduced reporter activity as opposed to the risk allele 'G' (P = 0.014). Furthermore, haplotype 'A-A' of rs1200108 - rs1200114 was present at a higher frequency in control subjects, suggesting it as a protective haplotype. Altogether, this study inferred the genetic association of rs1200114 and rs1200108 along with the decreased expression of ATP1B1 related to FECD pathogenesis in the Indian population.


Asunto(s)
Distrofia Endotelial de Fuchs , Humanos , Distrofia Endotelial de Fuchs/genética , Genotipo , Estudio de Asociación del Genoma Completo , Células Endoteliales/patología , ADN Intergénico , Endotelio Corneal/patología , ATPasa Intercambiadora de Sodio-Potasio/genética
2.
Gene ; 817: 146179, 2022 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-35031421

RESUMEN

AIMS: To investigate the genetic and functional association of an intronic variant of LAMC1, rs3768617 with Fuchs endothelial corneal dystrophy (FECD) in the Indian population. METHODS: Blood samples were collected from age and sex matched 356 controls and 120 FECD patients after a detailed assessment via specular microscopy. Genomic DNA was extracted and genotyping was done by fluorescence based capillary electrophoresis. The genetic association of rs3768617 polymorphisms was computed by the chi-square (χ2) test. Bioinformatics studies were performed to find the allele specific binding of different transcription factors in the region of rs3768617 and functional evaluation assessed by luciferase assay followed by Electrophoretic Mobility Shift Assay (EMSA) and Chromatin Immunoprecipitation assay (ChIP). Immunofluorescence assay was carried out to check for any differential expression of GFI1B between control and FECD endothelium samples. RESULTS: SNP rs3768617 {chr1:183123365 (GRCh38.p13)} was found to be genetically associated with FECD in Indian population (p = 2.646 × 10-8). Luciferase assay suggested that the rs3768617 locus has a regulatory role. In silico analysis showed that the transcription factor, GFI1B binds to the risk allele 'G' of rs3768617, but not to the protective allele 'A' which was also experimentally validated by EMSA. High enrichment of DNA flanking the surrounding region of rs3768617 was also found in presence of GFI1B specific antibody in ChIP assay. There was a 0.63 fold decrease in GFI1B expression in FECD affected corneal endothelium compared to control endothelium. CONCLUSIONS: The genetic association of rs3768617 in LAMC1 with FECD pathogenesis is mediated by GFI1B, thus finding the functional role of LAMC1 in FECD pathogenesis.


Asunto(s)
Distrofia Endotelial de Fuchs/genética , Laminina/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Anciano , Alelos , Femenino , Distrofia Endotelial de Fuchs/metabolismo , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Células HEK293 , Humanos , India , Intrones , Laminina/metabolismo , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Unión Proteica , Secuencias Reguladoras de Ácidos Nucleicos , Factores de Riesgo
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