Copy number variation in exportin-4 (XPO4) gene and its association with histological severity of non-alcoholic fatty liver disease

• Main Authors: Zain, Shamsul Mohd, Mohamed, Zahurin, Pirmohamed, M., Tan, H.L., Alshawsh, Mohammed Abdullah, Mahadeva, Sanjiv, Chan, Wah Kheong, Mustapha, N.R.N., Mohamed, Rosmawati
• Format: Article
• Published: Nature Publishing Group 2015
• Subjects: R Medicine; RM Therapeutics. Pharmacology
• Online Access: http://eprints.um.edu.my/19296/; http://dx.doi.org/10.1038/srep13306

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 (24.6ng/mL) to simple steatosis (20.8ng/mL) to NASH (13.8ng/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.