Background

Non-alcoholic fatty liver disease (NAFLD) is a global epidemic that often progresses to liver cirrhosis and hepatocellular carcinoma. In contrast to most world populations where NAFLD is mostly prevalent among obese, NAFLD among Indians and generally among South and South-East Asians is unique and highly prevalent among individuals who are lean. Genetics of NAFLD in Indian populations is understudied. In this study, we have used an exome-wide approach to identify genetic determinants of hepatic fat content (HFC) in India.

Methods

HFC was measured in 244 participants using Proton magnetic resonance spectroscopy (H1-MRS). Quantitative trait loci (QTL) mapping was done exome-wide, to identify SNPs associated with HFC. The effects of the interaction between adiposity and QTLs on HFC were studied using a regression model. Association of the significant loci with disease severity was studied in 146 NAFLD patients among 244 participants, who underwent liver biopsy.

Results

Our study identified 4 significantly associated SNPs (rs738409 and rs2281135 (PNPLA3), rs3761472 (SAMM50), rs17513722 (FAM161A) and rs4788084), with HFC after adjusting for the effects of covariates (p-value < 0.0005). rs738409, rs2281135 (PNPLA3), and rs3761472 (SAMM50) were associated with hepatocyte ballooning, lobular and portal inflammation and non-alcoholic steatohepatitis (NASH) (p-value < 0.05). rs4788048 is an eQTL for IL27 and SULT1A2 genes, both of which are highly expressed in healthy livers and are likely to be involved in NAFLD pathogenesis.

Conclusions

Our study identified the novel association of rs4788084 with HFC, which regulates the expression of IL-27, an immune regulatory gene. We further showed that adiposity affected the HFC, irrespective of the genetic predisposition.

中文翻译：

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全基因组扫描确定IL27启动子中的rs4788084与印第安人肝脂肪含量增加之间的显着相关性

背景

非酒精性脂肪肝疾病（NAFLD）是一种全球流行病，通常会发展为肝硬化和肝细胞癌。与世界上大多数肥胖人群中NAFLD普遍存在的人群相反，NAFLD在印第安人中以及在南亚和东南亚人中普遍存在，在肥胖人群中是独特且高度流行的。印度人口中NAFLD的遗传学尚未得到研究。在这项研究中，我们使用了一种全外显子组方法来确定印度肝脂肪含量（HFC）的遗传决定因素。

方法

使用质子磁共振波谱（H1-MRS）在244名参与者中测量了HFC。在整个外显子组范围内进行了定量性状基因座（QTL）定位，以鉴定与HFC相关的SNP。使用回归模型研究了肥胖与QTL之间相互作用对HFC的影响。在244位接受肝活检的参与者中，有146位NAFLD患者研究了显着基因座与疾病严重性的关系。

结果

我们的研究确定了4个与HFC显着相关的SNP（rs738409和rs2281135（PNPLA3），rs3761472（SAMM50），rs17513722（FAM161A）和rs4788084），并在调整了协变量的影响后（p值<0.0005）。rs738409，rs2281135（PNPLA3）和rs3761472（SAMM50）与肝细胞膨胀，小叶和门静脉炎症以及非酒精性脂肪性肝炎（NASH）相关（p值<0.05）。rs4788048是IL27和SULT1A2基因的eQTL ，这两个基因均在健康的肝脏中高表达，并可能参与了NAFLD的发病机理。

结论

我们的研究确定了rs4788084与HFC的新型关联，后者可以调节免疫调节基因IL-27的表达。我们进一步表明，肥胖与HFC无关，而与遗传易感性无关。