title: Genome-wide analysis of copy number variation identifies candidate gene loci associated with the progression of non-alcoholic fatty liver disease.
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.
authors.affiliation: The Pharmacogenomics Laboratory, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Shamsul Mohd
authors.initials: SM
authors.lastname: Zain
authors.affiliation: Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Rosmawati
authors.initials: R
authors.lastname: Mohamed
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.affiliation: Sengenics Sdn Bhd, High Impact Reseach Building, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Rozaimi
authors.initials: R
authors.lastname: Razali
authors.affiliation: Julius Centre University of Malaya, Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Rampal
authors.affiliation: Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Mahadeva
authors.affiliation: Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Wah-Kheong
authors.initials: WK
authors.lastname: Chan
authors.affiliation: Sengenics Sdn Bhd, High Impact Reseach Building, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Arif
authors.initials: A
authors.lastname: Anwar
authors.affiliation: Sengenics Sdn Bhd, High Impact Reseach Building, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Nurul Shielawati Mohamed
authors.initials: NS
authors.lastname: Rosli
authors.affiliation: Medical Imaging Unit, Faculty of Medicine, University of Technology MARA, Sungai Buloh Campus, Selangor, Malaysia.
authors.forename: Anis Shafina
authors.initials: AS
authors.lastname: Mahfudz
authors.affiliation: Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Phaik-Leng
authors.initials: PL
authors.lastname: Cheah
authors.affiliation: Clinical Investigation Centre, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
authors.forename: Roma Choudhury
authors.initials: RC
authors.lastname: Basu
authors.affiliation: The Pharmacogenomics Laboratory, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Zahurin
authors.initials: Z
authors.lastname: Mohamed
mesh_terms: D055028:Comparative Genomic Hybridization / Q000379:methods; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D028884:Karyopherins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics*
chemical_list: D028884:Karyopherins; C414440:Xpo4 protein, human; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1
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