Risk of hepatocellular carcinoma and death among cirrhotics who carry genetic variants of epidermal growth factor, Adiponutrin and 17β-Hydroxysteroid Dehydrogenase-13: a long-term cohort study

Background and aims: Single nucleotide polymorphisms (SNPs) of genes coding for epidermal growth factor (EGF; rs4444903), adiponutrin (PNPLA3; rs738409), and 17β-hydroxysteroid dehydro- genase-13 (HSD17B13; s72613567) are among the genetic factors thought to be involved in hepatocarcinogenesis. Whether carriage of these SNPs still modulates the risk of developing hepatocellular carcinoma (HCC) and/or survival of patients after they had progressed to cirrhosis is unknown. Method: A retrospective cohort of 303 adults (183 males, median age 62 years) with any stage of all-cause liver cirrhosis was studied at a single center. All were initially free of HCC and underwent HCC surveillance. Follow-up data were censored at the last follow-up visit. Each patient was genotyped for rs738409, rs72613567, and rs4444903. The results of genotyping were included as predictor variables in two multivariate models. Results: Etiologies, not mutually exclusive, were as follows: HCV, 150 (50%); HBV, 25 (8%); alcoholic liver disease, 118 (39%); metabolic dysfunction associated steatotic liver disease, 24 (8%); other, 21 (7%). The distribution for Child-Pugh Class at baseline was as follows: Class A, 228/303 (75%), Class B 64/303 (21%), Class C 11/303 (4%). The median observation time from the diagnosis of cirrhosis was 9.9 years (min 1 year, max 26 years, 2793 person-years). At the end of follow- up, 83/303 patients (27%) had developed HCC (incidence rate 0.032 per year), 160/303 (53%) patients had died and 11/303 (4%) had been transplanted. In a Cox proportional hazards model, with age at diagnosis, history of alcohol use, body mass index, diabetes, Child- Pugh class at baseline, HBV positivity, HCV positivity, as well as rs738409, rs72613567 and rs4444903 genotypes as predictor variables, the factors independently associated with development of HCC were: age (HR 1.04, 95% CI = 1.01–1.06, p < 0.001), alcohol (HR 1.74, 95% CI = 1.06–2.84, p = 0.026) and HCV (HR 1.95, 95%CI = 1.09– 3.05, p = 0.023). No statistically significant association was found between the development of HCC and the presence of the allelic variants described above. Instead, in a model having the same predictor variables as above, the factors independently associated with death or transplant were age (HR = 1.07, 95%CI = 1.05–1.09, p < 0.001), alcohol (HR = 1.63, 95% CI = 1.15–2.31, p = 0.006), Child-Pugh class (HR = 1.95, 95%CI = 1.45–2.60, p < 0.001), HBV (HR = 0.48, 95%CI 0.24–0.95, p = 0.038) and rs72613567 (HR = 0.76, 95%CI = 0.58–0.98, p = 0.042). Conclusion: Among cirrhotics initially free of HCC followed for nearly 10 years, none of the three SNPs appeared to modulate the risk of developing HCC, suggesting that their postulated hepatocarcinoge- netic effect is exerted earlier in the natural history of chronic liver disease. Carriage of the rs72613567:TA allelic variant appears to exert a mild protective effect on transplant-free survival of cirrhotics.