The impact of LEPR variants on risk of non-alcoholic fatty liver disease and its interaction with PNPLA3 variant.

J Gastroenterol Hepatol. 2012 Dec 27. doi: 10.1111/jgh.12104. [Epub ahead of print]


Zain SM, Mohamed Z, Mahadeva S, Cheah PL, Rampal S, Chin KF, Basu RC, Tan HL, Mohamed R.


The Pharmacogenomics Laboratory, University of Malaya, Kuala Lumpur, Malaysia; Department of Pharmacology, University of Malaya, Kuala Lumpur, Malaysia.


BACKGROUND AND AIM: Genetic polymorphism has been implicated as a factor for the occurence of non-alcoholic fatty liver diseasese (NAFLD). This study attempted to assess whether polymorphisms in the LEPR gene and its combined effect with PNPLA3 are associated with risk of NAFLD.

METHODS: A total of 144 biopsy-proven NAFLD and 198 controls were genotyped using the Sequenom MassARRAY platform.

RESULTS: We observed a significant association between the LEPR rs1137100 and rs1137101 with susceptibility to NAFLD (OR 1.64, 95% CI 1.18-2.28, p = 0.003; and OR 1.61, 95% CI 1.11-2.34, p = 0.013, respectively) and to non-alcoholic steatohepatitis (NASH) (OR 1.49, 95% CI 1.05-2.12, p = 0.026; and OR 1.57, 95% CI 1.05-2.35, p = 0.029, respectively). The LEPR rs1137100 is also associated with simple steatosis (OR 2.27, 95% CI 1.27-4.08, p = 0.006). Analysis of gene-gene interaction revealed a strong interaction between the LEPR and PNPLA3 genes (empirical p = 0.001). The joint effect of LEPR and PNPLA3 greatly exacerbated the risk of NAFLD (OR 3.73, 95% CI 1.84-7.55, p < 0.0001). The G allele of rs1137100 is associated with lower fibrosis score (OR 0.47, 95% CI 0.28-0.78, p = 0.001).

CONCLUSIONS: We report an association between variants of LEPR rs1137100 and rs1137101 with risk of NAFLD. This study suggests that rs1137100, specifically the G allele is associated with a less severe form of liver disease in patients with NAFLD. The interaction between LEPR and PNPLA3 genes showed increased risk of NAFLD compared to either gene alone.


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