Roy Neelanjana, Dasgupta Debanjali, Mukhopadhyay Indranil, Chatterjee Ankita, Das Kausik, Bhowmik Pradip, Das Soumyajit, Basu Priyadarshi, Santra Amal K, Datta Simanti, Dhali Gopal Krishna, Chowdhury Abhijit, Banerjee Soma
Center for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.
Indian Statistical Institute, Kolkata, India.
PLoS One. 2016 Mar 3;11(3):e0149843. doi: 10.1371/journal.pone.0149843. eCollection 2016.
Genetic susceptibility is an important modifier of clinical outcome and natural history of progression in Alcoholic liver disease (ALD). While the significance of ethnicity in this evolution is very clear, subtle inter-individual genetic variant(s) might be important and thus we investigated those in an Indian population. Fourteen markers were genotyped within two alcohol metabolism genes [Alcohol dehydrogenase (ADH) gene clusters (ADH1B and ADH1C) and Aldehyde dehydrogenase (ALDH2)], one microsomal ethanol oxidizing enzyme cytochrome p450 (CYP2E1) and three oxidative stress response (OSR) genes (MnSOD, GSTT1 and GSTM1) among 490 Bengali individuals (322 ALD and 168 control) from Eastern and North-Eastern India and validation was performed in a new cohort of 150 Bengali patients including 100 ALD and 50 advanced non-alcoholic steatohepatitis (NASH). Out of 14 genetic variants, carriage of 5 genotypes (rs2066701CC in ADH1B, rs1693425TT in ADH1C, rs4880TT in MnSOD and GSTT1/GSTM1 null, p-value <0.05) were noted significantly higher among ALD patients while inter or intra group gene-gene interaction analysis revealed that addition of risk genotype of any OSR gene enhanced the possibility of ALD synergistically. Multiple logistic regression analysis showed independent association of rs2066701CC, rs4880TT and GSTM1 null genotype with ALD while lower frequencies of those genotypes in advanced NASH patients further confirmed their causal relation to ALD. Thus these findings suggest that the three variants of ADH1C, MnSOD and GSTM1 can be used to identify individuals who are at high risk to develop ALD and may be helpful in proper management of Indian alcoholics.
遗传易感性是酒精性肝病（ALD）临床结局和疾病进展自然史的重要调节因素。虽然种族在这一演变过程中的重要性非常明确，但个体间细微的基因变异可能也很重要，因此我们在印度人群中对其进行了研究。在来自印度东部和东北部的490名孟加拉人（322例ALD患者和168例对照）中，对两个酒精代谢基因[乙醇脱氢酶（ADH）基因簇（ADH1B和ADH1C）和乙醛脱氢酶（ALDH2）]、一种微粒体乙醇氧化酶细胞色素p450（CYP2E1）以及三个氧化应激反应（OSR）基因（MnSOD、GSTT1和GSTM1）中的14个标记进行了基因分型，并在一个由150名孟加拉患者组成的新队列中进行了验证，该队列包括100例ALD患者和50例晚期非酒精性脂肪性肝炎（NASH）患者。在14种基因变异中，ALD患者中5种基因型（ADH1B中的rs2066701CC、ADH1C中的rs1693425TT、MnSOD中的rs4880TT以及GSTT1/GSTM1缺失，p值<0.05）的携带率显著更高，而组间或组内基因-基因相互作用分析显示，任何OSR基因的风险基因型的增加都会协同增强患ALD的可能性。多因素logistic回归分析显示，rs2066701CC、rs4880TT和GSTM1缺失基因型与ALD独立相关，而这些基因型在晚期NASH患者中的频率较低，进一步证实了它们与ALD的因果关系。因此，这些发现表明，ADH1C、MnSOD和GSTM1的三种变异可用于识别发生ALD风险较高的个体，可能有助于对印度酗酒者进行合理管理。
