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Leu432Val polymorphism in CYP1B1 as a susceptible factor towards predisposition to primary open-angle glaucoma
PURPOSE: Defects in cytochrome P450 1B1 (CYP1B1) cause primary congenital glaucoma. However, defects in the gene have also been reported in primary open-angle glaucoma (POAG). Since POAG is primarily a complex disease, we examined the potential of coding single nucleotide polymorphisms (cSNPs) in th...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Molecular Vision
2008
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2375325/ https://www.ncbi.nlm.nih.gov/pubmed/18483560 |
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author | Bhattacharjee, Ashima Banerjee, Deblina Mookherjee, Suddhasil Acharya, Moulinath Banerjee, Antara Ray, Ananya Sen, Abhijit Variation Consortium, the Indian Genome Ray, Kunal |
author_facet | Bhattacharjee, Ashima Banerjee, Deblina Mookherjee, Suddhasil Acharya, Moulinath Banerjee, Antara Ray, Ananya Sen, Abhijit Variation Consortium, the Indian Genome Ray, Kunal |
author_sort | Bhattacharjee, Ashima |
collection | PubMed |
description | PURPOSE: Defects in cytochrome P450 1B1 (CYP1B1) cause primary congenital glaucoma. However, defects in the gene have also been reported in primary open-angle glaucoma (POAG). Since POAG is primarily a complex disease, we examined the potential of coding single nucleotide polymorphisms (cSNPs) in the gene for association with the disease. METHODS: Five coding SNPs – c.514 C>G (Arg48Gly), c.727 G>T (Ala119Ser), c.1666 C>G (Leu432Val), c.1719 C>T (Asp449Asp), and c.1730 A>G (Asn453Ser) – were genotyped in 264 unrelated POAG patients and 95 controls. In addition, 542 normal individuals selected from various ethnic groups representing the Indian population were also genotyped for these cSNPs. The patterns of linkage disequilibrium between the SNPs and haplotype variations for comparison between POAG patients and controls as well as different ethnic groups of the Indian population were determined using Haploview. Allelic variants of Leu432Val were cloned by site-directed mutagenesis of normal CYP1B1 cDNA, which were used for transfection of retinal pigment epithelium (RPE) cells. The generation of reactive oxygen species (ROS) was quantified by measuring fluorescence emission by degradation of CM-H2DCFDA using a fluoremeter. RESULTS: The c.1666G allele of the Leu432Val in CYP1B1 showed a statistically significant higher representation among POAG patients compared to controls (p=0.0001; Odds ratio=6.027; 95% CI: 3.863–9.401) suggesting it to be a potential risk allele toward disease predisposition. Analysis of genotype frequencies of the polymorphism between the two groups demonstrated GG as a potential risk genotype (p=0.0001; Odds ratio=15.505; 95% CI: 5.529–43.474) for the disease. CYP1B1 Val432 was estimated to generate higher ROS in RPE cells compared to its allelic variant (Leu432; p=0.0245 for 15 min and p=0.0197 for 30 min). Comparison of haplotype diversities revealed CGGTA as the risk haplotype for the disease (p=0.0001, by Fisher’s exact test). CONCLUSIONS: We report CYP1B1 c.1666G (Val432) as a susceptible allele for POAG and CGGTA as the risk haplotype for the disease. Higher ROS generation by Val432 in CYP1B1 might lead to apoptotic change that leads to glaucoma. Remarkable variation of the cSNPs observed among ethnic groups of India could provide insight for future epidemiological studies on POAG in these population groups. |
format | Text |
id | pubmed-2375325 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Molecular Vision |
record_format | MEDLINE/PubMed |
spelling | pubmed-23753252008-05-15 Leu432Val polymorphism in CYP1B1 as a susceptible factor towards predisposition to primary open-angle glaucoma Bhattacharjee, Ashima Banerjee, Deblina Mookherjee, Suddhasil Acharya, Moulinath Banerjee, Antara Ray, Ananya Sen, Abhijit Variation Consortium, the Indian Genome Ray, Kunal Mol Vis Research Article PURPOSE: Defects in cytochrome P450 1B1 (CYP1B1) cause primary congenital glaucoma. However, defects in the gene have also been reported in primary open-angle glaucoma (POAG). Since POAG is primarily a complex disease, we examined the potential of coding single nucleotide polymorphisms (cSNPs) in the gene for association with the disease. METHODS: Five coding SNPs – c.514 C>G (Arg48Gly), c.727 G>T (Ala119Ser), c.1666 C>G (Leu432Val), c.1719 C>T (Asp449Asp), and c.1730 A>G (Asn453Ser) – were genotyped in 264 unrelated POAG patients and 95 controls. In addition, 542 normal individuals selected from various ethnic groups representing the Indian population were also genotyped for these cSNPs. The patterns of linkage disequilibrium between the SNPs and haplotype variations for comparison between POAG patients and controls as well as different ethnic groups of the Indian population were determined using Haploview. Allelic variants of Leu432Val were cloned by site-directed mutagenesis of normal CYP1B1 cDNA, which were used for transfection of retinal pigment epithelium (RPE) cells. The generation of reactive oxygen species (ROS) was quantified by measuring fluorescence emission by degradation of CM-H2DCFDA using a fluoremeter. RESULTS: The c.1666G allele of the Leu432Val in CYP1B1 showed a statistically significant higher representation among POAG patients compared to controls (p=0.0001; Odds ratio=6.027; 95% CI: 3.863–9.401) suggesting it to be a potential risk allele toward disease predisposition. Analysis of genotype frequencies of the polymorphism between the two groups demonstrated GG as a potential risk genotype (p=0.0001; Odds ratio=15.505; 95% CI: 5.529–43.474) for the disease. CYP1B1 Val432 was estimated to generate higher ROS in RPE cells compared to its allelic variant (Leu432; p=0.0245 for 15 min and p=0.0197 for 30 min). Comparison of haplotype diversities revealed CGGTA as the risk haplotype for the disease (p=0.0001, by Fisher’s exact test). CONCLUSIONS: We report CYP1B1 c.1666G (Val432) as a susceptible allele for POAG and CGGTA as the risk haplotype for the disease. Higher ROS generation by Val432 in CYP1B1 might lead to apoptotic change that leads to glaucoma. Remarkable variation of the cSNPs observed among ethnic groups of India could provide insight for future epidemiological studies on POAG in these population groups. Molecular Vision 2008-05-08 /pmc/articles/PMC2375325/ /pubmed/18483560 Text en http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Bhattacharjee, Ashima Banerjee, Deblina Mookherjee, Suddhasil Acharya, Moulinath Banerjee, Antara Ray, Ananya Sen, Abhijit Variation Consortium, the Indian Genome Ray, Kunal Leu432Val polymorphism in CYP1B1 as a susceptible factor towards predisposition to primary open-angle glaucoma |
title | Leu432Val polymorphism in CYP1B1 as a susceptible factor towards predisposition to primary open-angle glaucoma |
title_full | Leu432Val polymorphism in CYP1B1 as a susceptible factor towards predisposition to primary open-angle glaucoma |
title_fullStr | Leu432Val polymorphism in CYP1B1 as a susceptible factor towards predisposition to primary open-angle glaucoma |
title_full_unstemmed | Leu432Val polymorphism in CYP1B1 as a susceptible factor towards predisposition to primary open-angle glaucoma |
title_short | Leu432Val polymorphism in CYP1B1 as a susceptible factor towards predisposition to primary open-angle glaucoma |
title_sort | leu432val polymorphism in cyp1b1 as a susceptible factor towards predisposition to primary open-angle glaucoma |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2375325/ https://www.ncbi.nlm.nih.gov/pubmed/18483560 |
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