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Common variant in the glucokinase regulatory gene rs780094 and risk of nonalcoholic fatty liver disease: a meta-analysis

Zain SM, Mohamed Z, Mohamed R

J Gastroenterol Hepatol, 2015 Jan;30(1):21-7.
PMID: 25167786 DOI: 10.1111/jgh.12714

BACKGROUND AND AIM: Although studies have suggested that rs780094, a common variant in the glucokinase regulatory (GCKR) gene to be associated with type 2 diabetes, obesity, and their related traits, the genetic basis of the association between GCKR rs780094 and nonalcoholic fatty liver disease (NAFLD) is still being examined. This meta-analysis was performed to evaluate the effect strength caused by GCKR rs780094 on NAFLD.
METHODS: We searched Medline, PubMed, Scopus, and Embase for relevant articles published up to April 2014. Data were extracted, and summary estimates of the association between GCKR rs780094 and NAFLD were examined. Heterogeneity and publication bias were also examined.
RESULTS: This meta-analysis incorporated a total of 2091 NAFLD cases and 3003 controls from five studies. Overall, the pooled result indicated that the GCKR rs780094 was significantly associated with increased risk of NAFLD (additive: odds ratio (OR) 1.25, 95% confidence interval (CI) 1.14-1.36, P non-Asians (OR 1.27, 95%CI 1.12-1.45, P = 0.0003 and OR 1.22, 95%CI 1.10-1.37, P = 0.0003, respectively).
CONCLUSIONS: Our meta-analysis provides evidence of significant association between GCKR rs780094 and risk of NAFLD. Similar effect size was demonstrated in both Asian and non-Asian populations.

Matched MeSH terms: Non-alcoholic Fatty Liver Disease/genetics*
Fulltext Genome-wide analysis of copy number variation identifies candidate gene loci associated with the progression of non-alcoholic fatty liver disease

Zain SM, Mohamed R, Cooper DN, Razali R, Rampal S, Mahadeva S, et al.

PLoS One, 2014;9(4):e95604.
PMID: 24743702 DOI: 10.1371/journal.pone.0095604

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.

Matched MeSH terms: Non-alcoholic Fatty Liver Disease/genetics*
Association of glucokinase regulatory gene polymorphisms with risk and severity of non-alcoholic fatty liver disease: an interaction study with adiponutrin gene

Tan HL, Zain SM, Mohamed R, Rampal S, Chin KF, Basu RC, et al.

J Gastroenterol, 2014 Jun;49(6):1056-64.
PMID: 23800943 DOI: 10.1007/s00535-013-0850-x

BACKGROUND: Recent genome-wide association studies demonstrated an association between single nucleotide polymorphisms (SNPs) on the glucokinase regulatory gene (GCKR) with hepatic steatosis. This study attempted to investigate the association of GCKR rs780094 and rs1260326 with susceptibility to non-alcoholic fatty liver disease (NAFLD) and its severity.
METHODS: The genotypes were assessed on 144 histologically confirmed NAFLD patients and 198 controls using a Sequenom MassARRAY platform.
RESULTS: The GCKR rs1260326 and rs780094 allele T were associated with susceptibility to NAFLD (OR 1.49, 95 % CI 1.09-2.05, p = 0.012; and OR 1.51, 95 % CI 1.09-2.09, p = 0.013, respectively), non-alcoholic steatohepatitis (NASH) (OR 1.55, 95 % CI 1.10-2.17, p = 0.013; and OR 1.56, 95 % CI 1.10-2.20, p = 0.012, respectively) and NASH with significant fibrosis (OR 1.50, 95 % CI 1.01-2.21, p = 0.044; and OR 1.52, 95 % CI 1.03-2.26, p = 0.038, respectively). Following stratification by ethnicity, significant association was seen in Indian patients between the two SNPs and susceptibility to NAFLD (OR 2.64, 95 % CI 1.28-5.43, p = 0.009; and OR 4.35, 95 % CI 1.93-9.81, p < 0.0001, respectively). The joint effect of GCKR with adiponutrin rs738409 indicated greatly increased the risk of NAFLD (OR 4.14, 95 % CI 1.41-12.18, p = 0.010). Histological data showed significant association of GCKR rs1260326 with high steatosis grade (OR 1.76, 95 % CI 1.08-2.85, p = 0.04).
CONCLUSION: This study suggests that risk allele T of the GCKR rs780094 and rs1260326 is associated with predisposition to NAFLD and NASH with significant fibrosis. The GCKR and PNPLA3 genes interact to result in increased susceptibility to NAFLD.

Matched MeSH terms: Non-alcoholic Fatty Liver Disease/genetics*
Fulltext Copy number variation in exportin-4 (XPO4) gene and its association with histological severity of non-alcoholic fatty liver disease

Zain SM, Mohamed Z, Pirmohamed M, Tan HL, Alshawsh MA, Mahadeva S, et al.

Sci Rep, 2015 Aug 21;5:13306.
PMID: 26293807 DOI: 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

Matched MeSH terms: Non-alcoholic Fatty Liver Disease/genetics*