Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India.
Multidisciplinary Research Unit, Government Medical College, Amritsar, Punjab, India.
Gene. 2019 Aug 15;709:25-35. doi: 10.1016/j.gene.2019.05.035. Epub 2019 May 25.
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.
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.
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.
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.
肿瘤坏死因子-α（TNF-α）是一种多能促炎细胞因子，参与青光眼的视网膜神经节细胞凋亡。因此，本研究旨在分析 TNF-α启动子区域改变（c.-238G>A（rs361525）、c.-308G>A（rs1800629）、c.-857C>T（rs1799724）和 c.-863C>A（rs1800630））与印度北部队列中青光眼的关联。
本基于医院的病例对照研究纳入了 286 名青光眼患者（原发性开角型青光眼[POAG]、原发性闭角型青光眼[PACG]、原发性先天性青光眼[PCG]）和 300 名对照。TNF-α基因改变（c.-238G>A（也称为 c.-418G>A；NM_000594.3））、c.-308G>A（c.-488G>A；NM_000594.3）、c.-857C>T（c.-1037C>T；NM_000594.3）和 c.-863C>A（c.-1043C>A；NM_000594.3）携带区域通过聚合酶链反应（PCR）扩增，然后用 Sanger 测序进行测序。使用卡方检验比较青光眼病例和对照组的等位基因频率和基因型分布，使用不同的遗传模型检验遗传关联。
c.-308G>A 和 c.-863C>A 改变在青光眼病例和对照组之间存在统计学显著的基因型和等位基因关联（p=0.001，p=0.001；p=0.001，p=0.001）。c.-308G>A 的 AA 基因型使青光眼的风险增加约 7 倍（OR=6.82，95%CI=2.82-16.53，p=0.001）。c.-863C>A 改变在显性、隐性和共显性遗传模型下使青光眼的风险增加约 2 倍。然而，c.-238G>A 和 c.-857C>T 变体与青光眼之间没有关联。此外，三个单倍型（GGCA、GACC 和 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 和 OR=0.16，95%CI=0.05-0.51，p=0.002）对青光眼具有保护作用。
本研究首次表明 c.-308G>A 和 c.-863C>A 改变与印度北部队列中青光眼的显著关联。此外，这也是印度首次分析 TNF-α 四个启动子区域改变（c.-238G>A、c.-308G>A、c.-857C>T 和 c.-863C>A）与三个保护性单倍型相关的关联和相互作用。
