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Association of glucokinase regulatory gene polymorphisms with risk and severity of non-alcoholic fatty liver disease: an interaction study with adiponutrin gene

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

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.

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Abbreviations

ALT:

Alanine aminotranferase

ANOVA:

Analysis of variance

AST:

Aspartate aminotranferase

BMI:

Body mass index

CI:

Confidence interval

GCKR :

Glucokinase regulatory

GGT:

Gamma-glutamyl transpeptidase

GMDR:

Generalized Multifactor Dimensionality Reduction

GWAS:

Genome-wide association study

HDL:

High density lipoprotein

HWE:

Hardy–Weinberg equilibrium

LDL:

Low density lipoprotein

NAFLD:

Non-alcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

OR:

Odds ratio

PNPLA3 :

Patatin-like phospholipase domain-containing protein 3

SD:

Standard deviation

SNP:

Single nucleotide polymorphism

UMMC:

University of Malaya Medical Center

US:

Ultrasonography

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Acknowledgments

This study was supported by University Malaya Research Grant RG069/09HTM and RG364/11HTM, and by the High Impact Research Ministry of Higher Education (HIRMOHE) Grant E000025-20001.

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Hwa-Li Tan, Shamsul Mohd Zain & Zahurin Mohamed

  2. Department of Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Rosmawati Mohamed & Sanjiv Mahadeva

  3. Department of Social and Preventive Medicine, Faculty of Medicine, Julius Centre University of Malaya, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Sanjay Rampal

  4. Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

    Kin-Fah Chin

  5. Clinical Investigation Centre, University Malaya Medical Centre, 50603, Kuala Lumpur, Malaysia

    Roma Choudhury Basu

  6. Department of Pathology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Phaik-Leng Cheah

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  1. Hwa-Li Tan
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Correspondence to Hwa-Li Tan.

Additional information

H.-L. Tan and S. M. Zain contributed equally to this project and should be considered co-first authors.

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Tan, HL., Zain, S.M., Mohamed, R. et al. Association of glucokinase regulatory gene polymorphisms with risk and severity of non-alcoholic fatty liver disease: an interaction study with adiponutrin gene. J Gastroenterol 49, 1056–1064 (2014). https://doi.org/10.1007/s00535-013-0850-x

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  • DOI: https://doi.org/10.1007/s00535-013-0850-x

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