title: Copy number variation in exportin-4 (XPO4) gene and its association with histological severity of non-alcoholic fatty liver disease.
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.
authors: The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.|Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Shamsul Mohd
authors: SM
authors: Zain
authors: The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.|Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Zahurin
authors: Z
authors: Mohamed
authors: The Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, United Kingdom.
authors: Munir
authors: M
authors: Pirmohamed
authors: The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.|Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Hwa Li
authors: HL
authors: Tan
authors: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Mohammed Abdullah
authors: MA
authors: Alshawsh
authors: Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Sanjiv
authors: S
authors: Mahadeva
authors: Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Wah-Kheong
authors: WK
authors: Chan
authors: Department of Pathology, Hospital Sultanah Bahiyah, Alor Setar, Malaysia.
authors: Nik Raihan Nik
authors: NR
authors: Mustapha
authors: Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Rosmawati
authors: R
authors: Mohamed
mesh_terms: D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D003710:Demography; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D028884:Karyopherins / Q000097:blood / Q000235:genetics*; D008099:Liver / Q000473:pathology; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D012720:Severity of Illness Index
chemical_list: D028884:Karyopherins; C414440:Xpo4 protein, human