Abstract
A recent genome-wide copy number (CNV) scan identified a 13q12.11 duplication in the exportin-4 (XPO4) gene to be associated with non-alcoholic steatohepatitis (NASH). We sought to confirm the finding in a larger cohort and to assess the serum XPO4 pattern in a broad spectrum of non-alcoholic fatty liver disease (NAFLD) cases. We analysed 249 NAFLD patients and 232 matched controls using TaqMan assay and serum XPO4 was measured. Copy number distribution was as follows: copy number neutral (NAFLD: 53.8%, controls: 68.6%), copy number losses (NAFLD: 13.3%, controls: 12.9%), copy number gains (NAFLD: 32.9%, controls: 18.5%). CNV gain was significantly associated with a greater risk of NAFLD (adjusted OR 2.22, 95% CI 1.42–3.46, P = 0.0004) and NASH (adjusted OR 2.33, 95% CI 1.47–3.68, P = 0.0003). Interestingly, subjects carrying extra copy number showed significantly higher serum ALT and triglyceride (P < 0.05). Serum XPO4 levels progressively declined (P = 0.043) from controls (24.6 ng/mL) to simple steatosis (20.8 ng/mL) to NASH (13.8 ng/mL). In conclusion, XPO4 CNV duplication was associated with histological severity of NAFLD, and accompanied by changes in serum XPO4 levels providing insights into NAFLD pathogenesis, and has the potential for biomarker development.
Highlights
high-density lipoprotein cholesterol (HDL) high-density lipoprotein, low-density lipoprotein cholesterol (LDL) low-density lipoprotein, NAFLD non-alcoholic fatty liver disease, XPO4 exportin-4. aNumber of subjects (n) was not equal to overall subjects. *P-values obtained using MannWhitney U test except for gender and ethnicity used χ 2 test. **P-values obtained using Analysis of Covariance (ANCOVA) with age, gender and ethnicity as covariates
We have further assessed CNVR 13q12.11 because (i) CNV gain at locus 13q is one of the highest differentially expressed CNVs in the hepatocellular carcinoma (HCC) genome[10]; (ii) it contains exportin-4 (XPO4), a tumor suppressor gene involved in the pathogenesis of HCC11; and (iii) a previous report has shown that XPO4 is known to be expressed in both the liver and peripheral blood[12]
Previous studies have suggested that XPO4 plays a role in the initiation of HCC as its expression level decreases with the development of cancer[14,15]
Summary
HDL high-density lipoprotein, LDL low-density lipoprotein, NAFLD non-alcoholic fatty liver disease, XPO4 exportin-4. aNumber of subjects (n) was not equal to overall subjects. *P-values obtained using MannWhitney U test except for gender and ethnicity used χ 2 test. **P-values obtained using ANCOVA with age, gender and ethnicity as covariates. Two genome-wide association scans have pioneered the study of CNV in NAFLD8,9 These have suggested that both the risk of non-alcoholic fatty liver disease (NAFLD) and its progression can be linked to DNA copy number variation (CNVs), which has added a whole new level of complexity to the study of molecular determinants of NAFLD. We have further assessed CNVR 13q12.11 because (i) CNV gain at locus 13q is one of the highest differentially expressed CNVs in the hepatocellular carcinoma (HCC) genome[10]; (ii) it contains exportin-4 (XPO4), a tumor suppressor gene involved in the pathogenesis of HCC11; and (iii) a previous report has shown that XPO4 is known to be expressed in both the liver and peripheral blood[12]. The expression of XPO4 seems to be significantly decreased in cirrhotic livers and after chronic hepatitis B infection when compared with normal healthy controls[12]
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