RGD Reference Report - Leu432Val polymorphism in CYP1B1 as a susceptible factor towards predisposition to primary open-angle glaucoma. - Rat Genome Database

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Leu432Val polymorphism in CYP1B1 as a susceptible factor towards predisposition to primary open-angle glaucoma.

Authors: Bhattacharjee, A  Banerjee, D  Mookherjee, S  Acharya, M  Banerjee, A  Ray, A  Sen, A  Ray, K  Ray, K 
Citation: Bhattacharjee A, etal., Mol Vis. 2008 May 8;14:841-50.
RGD ID: 7800658
Pubmed: PMID:18483560   (View Abstract at PubMed)
PMCID: PMC2375325   (View Article at PubMed Central)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
primary open angle glaucoma susceptibilityIAGP 7800658DNA:snp:cds:p.L432V (human)RGD 
primary open angle glaucoma susceptibilityISOCYP1B1 (Homo sapiens)7800658; 7800658DNA:snp:cds:p.L432V (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Increased cup-to-disc ratio susceptibilityIAGP 7800658DNA:snp:cds:p.L432VRGD 
Ocular hypertension susceptibilityIAGP 7800658DNA:snp:cds:p.L432VRGD 
Visual field defect susceptibilityIAGP 7800658DNA:snp:cds:p.L432VRGD 
Objects Annotated

Genes (Rattus norvegicus)
Cyp1b1  (cytochrome P450, family 1, subfamily b, polypeptide 1)

Genes (Mus musculus)
Cyp1b1  (cytochrome P450, family 1, subfamily b, polypeptide 1)

Genes (Homo sapiens)
CYP1B1  (cytochrome P450 family 1 subfamily B member 1)


Additional Information