Association of TNF-α gene alterations (c.-238G>A, c.-308G>A, c.-857C>T, c.-863C>A) with primary glaucoma in north Indian cohort.

ABSTRACT

BACKGROUND: Tumor Necrosis Factor-alpha (TNF-α) a pleuripotent pro-inflammatory cytokine, is involved in retinal ganglion cells apoptosis in glaucoma. Thus present study aimed to analyze the association of TNF-α promoter region alterations (c.-238G>A (rs361525), c.-308G>A (rs1800629), c.-857C>T (rs1799724) and c.-863C>A (rs1800630)) with glaucoma in north Indian cohort. METHODS: Present hospital based case control study involved 286 glaucoma patients (Primary Open Angle Glaucoma [POAG], Primary Angle Closure Glaucoma [PACG], Primary Congenital Glaucoma [PCG]) and 300 controls. TNF-α gene alteration (c.-238G>A (also referred as c.-418G>A; NM_000594.3)), c.-308G>A (c.-488G>A; NM_000594.3), c.-857C>T (c.-1037C>T; NM_000594.3) and c.-863C>A (c.-1043C>A; NM_000594.3) harboring regions were PCR amplified and sequenced by Sanger sequencing. Allele frequency and genotype distribution in glaucoma cases and controls were compared using chi-square test and genetic association tested using different genetic models. RESULTS: Statistically significant genotype and allelic association was observed between glaucoma cases and controls for c.-308G>A and c.-863C>A alterations (p = 0.001, p = 0.001; p = 0.001, p = 0.001 respectively). AA genotype of c.-308G>A conferred ~7 fold increased risk towards glaucoma (OR = 6.82, 95% CI = 2.82-16.53, p = 0.001). c.-863C>A alteration under dominant, recessive and co-dominant genetic models conferred ~2 fold increased risk for glaucoma. However, no association for c.-238G>A and c.-857C>T variants with glaucoma was observed. Further, three haplotypes (GGCA, GACC and GACA) (OR = 0.48, 95% CI = 0.35-0.67, p = 0.001; OR = 0.58, 95% CI = 0.36-0.91, p = 0.019 and OR = 0.16, 95% CI = 0.05-0.51, p = 0.002, respectively) conferred protective role towards glaucoma. CONCLUSIONS: Present study is the first to indicate significant association of c.-308G>A and c.-863C>A alterations with glaucoma in cases from north Indian cohort. Also it is the first study from India to analyze the association and interaction of four promoter region alterations (c.-238G>A, c.-308G>A, c.-857C>T and c.-863C>A) in TNF-α resulting in three protective haplotypes.