title: A polymorphism in the CYP1B1 promoter is functionally associated with primary congenital glaucoma.
abstract: Primary congenital glaucoma (PCG) is a childhood autosomal-recessive disorder caused by developmental defects in the trabecular meshwork and anterior chamber angle. These defects cause raised intraocular pressure (IOP) that damages the optic nerve and if left untreated, results in irreversible blindness. Mutations in CYP1B1 gene at the GLC3A locus (2p21) are associated with PCG. However, there has been very limited exploration of its promoter region. We resequenced the CYP1B1 promoter in a large cohort (n = 835) that included patients with PCG (n = 301), other primary glaucomas (primary open-angle glaucoma: n = 115 and primary angle closure glaucoma: n = 100) and unaffected controls (n = 319). We functionally characterized one associated variant by luciferase reporter assay using the trabecular meshwork (TM3) cell line. We found evidence of strong (P = 6.01 × 10(-4)) association of rs2567206 (T2805C) SNP in PCG and not in other primary glaucomas. Luciferase assay indicated a ∼90% reduction in CYP1B1 promoter activity in the risk-allele (C) compared to the other allele (T). The association of the risk allele was stronger in cases harboring homozygous CYP1B1 mutations (P = 3.42 × 10(-12)). The risk haplotype 'C-C-G' in the promoter had a strong non-random association to the previously characterized risk haplotype 'C-G-G-T-A' in the coding region. The independent effect of genotype at the promoter T2805C locus (P = 0.001), and the interaction effect of genotypes at the promoter and coding region mutations loci (P = 0.001) were significant for the presenting IOP of the worst affected eye. This is the first study that unequivocally shows the functional involvement of a CYP1B1 promoter variant in PCG.
authors.affiliation: Hyderabad Eye Research Foundation, Champalimaud Translational Centre, Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, India. subho@lvpei.org
authors.forename: Subhabrata
authors.initials: S
authors.lastname: Chakrabarti
authors.forename: Yashoda
authors.initials: Y
authors.lastname: Ghanekar
authors.forename: Kiranpreet
authors.initials: K
authors.lastname: Kaur
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Kaur
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mandal
authors.forename: Kollu N
authors.initials: KN
authors.lastname: Rao
authors.forename: Rajul S
authors.initials: RS
authors.lastname: Parikh
authors.forename: Ravi
authors.initials: R
authors.lastname: Thomas
authors.forename: Partha P
authors.initials: PP
authors.lastname: Majumder
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002478:Cells, Cultured; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D056726:Genetic Association Studies; D005819:Genetic Markers; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D006871:Hydrophthalmos / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D014129:Trabecular Meshwork / Q000166:cytology / Q000378:metabolism
chemical_list: D005136:Eye Proteins; D005819:Genetic Markers; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1