Impacts of TCF7L2 gene polymorphisms on the susceptibility of hepatogenous diabetes and hepatocellular carcinoma in cirrhotic patients

• We revealed a genetic role in the pathogenesis of hepatogenous diabetes.
• TCF7L2 polymorphisms were independently associated with hepatogenous diabetes.
• The rs290487 C/C variant homozygote showed much higher insulin resistance.
• We provided first molecular association between diabetes and hepatocellular carcinoma.
• Three SNPs located near 3′ end of TCF7L2 gene were associated with cancer risk.

BackgroundHepatogenous diabetes (HD) occurs as a complication of cirrhosis. Whether genetic factors, rather than only liver damage, play roles in the development of HD is unknown. TCF7L2 gene has been reported to be associated with type 2 diabetes and also cancer risks. We aim to evaluate the impact of TCF7L2 gene on the susceptibility of HD and hepatocellular carcinoma (HCC) in a Chinese Han population.Patients and methodsA total of 367 adult liver transplant candidates with liver cirrhosis were included. Fifteen tag single nucleotide polymorphisms (SNPs) were selected from HapMap CHB database with a minor allele frequency of > 0.2 and r2 of > 0.8. Another three SNPs were also chosen because of their close association with type 2 diabetes in East Asian.ResultsPatients with HD presented significantly poorer liver function, higher incidence of cirrhotic complications and higher insulin resistance compared with non-HD patients. Three SNPs were differentially distributed between HD patients and non-HD patients. In multivariate logistic analysis, TCF7L2 rs290487 and rs6585194 polymorphisms were independently associated with HD after adjustment of clinical factors. The TCF7L2 rs290487 C/C variant homozygote showed much higher insulin resistance and significantly increased HD risk comparing with T/T and T/C genotypes, while the genetic variant of rs6585194 was protectively against HD. Three SNPs (rs290481, rs290487 and rs290489) located near the 3′ end of TCF7L2 gene were associated with HCC risk with marginal significance. Patients carrying G-C-A haplotype had a significantly higher HCC risk than those with A-T-G.ConclusionsTCF7L2 polymorphisms were associated with HD and maybe cancer risk as well. Further studies with large samples are needed to verify these results.