Genome-wide analysis of copy number variation identifies candidate gene loci associated with the progression of non-alcoholic fatty liver disease.

Shamsul Mohd Zain,Rosmawati Mohamed,Nurul Shielawati Mohamed Rosli,Anis Shafina Mahfudz,Rozaimi Razali,Arif Anwar,Sanjay Rampal,Zahurin Mohamed,David N Cooper,Wah-Kheong Chan,Sanjiv Mahadeva,Phaik-Leng Cheah,Roma Choudhury Basu,Yanqiao Zhang

doi:10.1371/journal.pone.0095604

Abstract

Between 10 and 25% of individuals with non-alcoholic fatty liver disease (NAFLD) develop hepatic fibrosis leading to cirrhosis and hepatocellular carcinoma (HCC). To investigate the molecular basis of disease progression, we performed a genome-wide analysis of copy number variation (CNV) in a total of 49 patients with NAFLD [10 simple steatosis and 39 non-alcoholic steatohepatitis (NASH)] and 49 matched controls using high-density comparative genomic hybridization (CGH) microarrays. A total of 11 CNVs were found to be unique to individuals with simple steatosis, whilst 22 were common between simple steatosis and NASH, and 224 were unique to NASH. We postulated that these CNVs could be involved in the pathogenesis of NAFLD progression. After stringent filtering, we identified four rare and/or novel CNVs that may influence the pathogenesis of NASH. Two of these CNVs, located at 13q12.11 and 12q13.2 respectively, harbour the exportin 4 (XPO4) and phosphodiesterase 1B (PDE1B) genes which are already known to be involved in the etiology of liver cirrhosis and HCC. Cross-comparison of the genes located at these four CNV loci with genes already known to be associated with NAFLD yielded a set of genes associated with shared biological processes including cell death, the key process involved in ‘second hit’ hepatic injury. To our knowledge, this pilot study is the first to provide CNV information of potential relevance to the NAFLD spectrum. These data could prove invaluable in predicting patients at risk of developing NAFLD and more importantly, those who will subsequently progress to NASH.

Highlights

Non-alcoholic fatty liver disease (NAFLD) has emerged as a silent epidemic, with its worldwide prevalence continuing to increase with the growing incidence of obesity [1]
Seven percent of copy number variation (CNV) calls were attributable to the sex chromosomes, but we opted to exclude these chromosomes from further analysis owing to the evolutionary biases due to small imbalances of the sex chromosomes [28]
Studies on CNVs are becoming increasingly important in studies of inherited disease, with growing evidence attesting to the substantial impact that they can have on human phenotypic variability and genetic susceptibility

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) has emerged as a silent epidemic, with its worldwide prevalence continuing to increase with the growing incidence of obesity [1]. NAFLD comprises a spectrum of diseases ranging from simple steatosis, which is essentially benign fatty infiltration of the liver, to its inflammatory counterpart non-alcoholic steatohepatitis (NASH) [2]. The ‘‘first hit’’ is the development of steatosis and involves the accumulation of triglycerides in the liver due to insulin resistance. A significant proportion of individuals with NAFLD develop hepatic fibrosis, a key feature of the condition which is associated with progression of the disease to cirrhosis and its related complications, including hepatic failure and hepatocellular carcinoma [4]. A high prevalence of NASH is found among those with insulin resistance-related comorbidities such as obesity and type 2 diabetes [5]. The mortality rate among NASH patients has been found to be much higher than for patients with simple fatty liver (simple steatosis) [6]

Methods

Results

Conclusion