A genetic variant in toll-like receptor 5 is linked to chemokine levels and hepatocellular carcinoma in steatohepatitis

Question Bacterial translocation from the intestine is an important mechanism of liver disease progression. In contrast to toll-like rececptor (TLR) 4, the receptor for lipopolysaccharide, the receptor for flagellin, another frequent component of Gram-negative bacteria, TLR5, has rarely been studied. We wondered whether functional genetic variants in TLR5 affect the risk to develop hepatocellular carcinoma (HCC) in patient with cirrhosis due to alcohol-associated and nonalcoholic steatohepatitis.

Methods Healthy controls (n=212), patients with alcohol abuse without liver disease (n=382), and three cohorts of patients with cirrhosis due to alcohol-associated (n=372 and n=355) and non-alcoholic steatohepatitis (NASH) (n=145), including 79, 132 and 62 patients with HCC, respectively, were genotyped for the TLR5 rs5744174 and rs5744168 polymorphisms. Chemokine levels were measured by ELISA in patients” sera and supernatants of flagellin-stimulated healthy monocytes.

Results Frequency of the TLR5 rs5744174 TT genotype was similar in healthy controls (33 %), controls with alcohol abuse (34 %), and patients with alcohol-associated cirrhosis in the discovery (28 %), validation (33 %) and NASH cohort (31 %). However, the TT genotype was enriched in cirrhotic patients with HCC compared to patients without HCC in the discovery, validation and NASH cohort (41 % vs 25 %; 39 % vs 29 %; 40 % vs 24 %; p < 0.05 each). The TT genotype remained a risk factor for HCC (OR = 1.9; CI 1.2 – 3.1; p = 0.01) after multivariate correction for age, gender, diabetes, and carriage of the PNPLA3 148M variant. In presence of the TT genotype, interleukin-8 induction in monocytes from healthy controls and serum levels of interleukin-8 and of CXCL1 from cirrhotic patients were significantly increased. Genetic variance of the TLR5 rs5744168 polymorphism was not linked to the occurrence of HCC.

Conclusion The proinflammatroy TT genotype of the TLR5 rs5744174 polymorphism is associated with an increased risk for for HCC in cirrhosis due to steatohepatitis.

Publication History

Article published online:
04 January 2021