Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India.
Gene. 2012 Nov 1;509(1):178-88. doi: 10.1016/j.gene.2012.07.077. Epub 2012 Aug 10.
Alcohol induced liver disease or alcoholic liver disease (ALD), a complex trait, encompasses a gamut of pathophysiological alterations in the liver due to continuous exposure to a toxic amount of alcohol (more than 80 g per day). Of all chronic heavy drinkers, only 15-20% develops hepatitis or cirrhosis concomitantly or in succession. Several studies revealed that inter-individual as well as inter-ethnic genetic variation is one of the major factors that predispose to ALD. The role of genetic factors in ALD has long been sought for in ethnically distinct population groups. ALD is fast emerging as an important cause of chronic liver disease in India; even in populations such as "Bengalis" who were "culturally immune" earlier. While the genetic involvement in the pathogenesis of ALD is being sought for in different races, the complex pathophysiology of ALD as well as the knowledge of population level diversity of the relevant alcohol metabolizing and inflammatory pathways mandates the need for well designed studies of genetic factors in ethnically distinct population groups. An array of cytokines plays a critical role as mediators of injury, inflammation, fibrosis and cirrhosis in ALD. We, therefore, studied the association of polymorphisms in five relevant cytokine genes with "clinically significant" ALD in an ethnic "Bengali" population in Eastern India. Compared with "alcoholic" controls without liver disease (n=110), TNFα -238AA genotype, IL1β -511CC genotype, TGFβ1 -509CC genotype and IL10 -592AA genotype were significantly overrepresented in ALD patients (n=181; OR=2.4 and 95% CI 1.2-5.5, P(genotype)=0.042, P(allelic)=0.008; OR=2.7 and 95% CI 1.2-5.9, P(genotype)=0.018, P(allelic)=0.023; OR=4.7 and 95% CI 1.7-13.1, P(genotype)=0.003, P(allelic)=0.014; and OR=2.2 and 95% CI 1.1-4.8, P(genotype)=0.04, P(allelic)=0.039 respectively). Moreover a cumulative genetic risk analysis revealed a significant trend for developing ALD with an increase in the number of risk alleles on IL10 and TGFβ1 loci among alcoholics. The risk genotype of IL1β and TGFβ1 also influences the total bilirubin, albumin and alanine aminotransferase levels among alcoholic "Bengalis". The present study is the first case-control study from Eastern India that comprehensively identified polymorphic markers in TNFα, IL10, IL1β and TGFβ1 genes to be associated with ALD in the Bengali population, accentuating the significance of genetic factors in clinical expressions of ALD.
酒精性肝病或酒精性肝病（ALD）是一种复杂的特征，它包括由于持续暴露于有毒量的酒精（每天超过 80 克）而导致的肝脏一系列病理生理改变。在所有慢性大量饮酒者中，只有 15-20%的人同时或相继发生肝炎或肝硬化。几项研究表明，个体间和种族间的遗传变异是导致 ALD 的主要因素之一。遗传因素在 ALD 中的作用在不同种族的人群中已经被长期研究。ALD 正在迅速成为印度慢性肝病的一个重要原因；即使在以前被认为是“文化免疫”的“孟加拉人”等人群中也是如此。虽然正在不同种族中寻找 ALD 发病机制中的遗传因素，但 ALD 的复杂病理生理学以及与相关酒精代谢和炎症途径相关的人群水平多样性的知识，需要在不同种族的人群中进行精心设计的遗传因素研究。一系列细胞因子作为介导 ALD 损伤、炎症、纤维化和肝硬化的关键介质发挥作用。因此，我们在印度东部的一个孟加拉族人群中研究了五个相关细胞因子基因的多态性与“临床显著”ALD 的关联。与没有肝病的“酒精性”对照（n=110）相比，TNFα-238AA 基因型、IL1β-511CC 基因型、TGFβ1-509CC 基因型和 IL10-592AA 基因型在 ALD 患者（n=181）中显著过度表达（OR=2.4，95%CI 1.2-5.5，P（基因型）=0.042，P（等位基因）=0.008；OR=2.7，95%CI 1.2-5.9，P（基因型）=0.018，P（等位基因）=0.023；OR=4.7，95%CI 1.7-13.1，P（基因型）=0.003，P（等位基因）=0.014；和 OR=2.2，95%CI 1.1-4.8，P（基因型）=0.04，P（等位基因）=0.039）。此外，累积遗传风险分析显示，在酒精中毒者中，IL10 和 TGFβ1 基因上的风险等位基因数量增加与 ALD 的发生呈显著趋势。IL1β 和 TGFβ1 的风险基因型也会影响孟加拉族酒精中毒者的总胆红素、白蛋白和丙氨酸氨基转移酶水平。本研究是印度东部首例从整体上确定 TNFα、IL10、IL1β 和 TGFβ1 基因中多态性标记物与孟加拉人群中 ALD 相关的病例对照研究，强调了遗传因素在 ALD 临床表达中的重要性。
