Analysis of genetic factors associated with fatty liver disease-related hepatocellular carcinoma

Aim: Single-nucleotide polymorphisms (SNPs) in PNPLA3 and hydroxysteroid 17 -beta dehydrogenase 13 (HSD17B13) genes are associated with fatty liver disease (FLD) progression and carcinogenesis. In the present study, we evaluated the characteristics of Japanese FLD patients according to HSD17B13 polymorphisms.Methods: We enrolled 402 patients who were clinically and pathologically diagnosed with FLD (alcoholic: 63 cases, nonalcoholic: 339 cases) at our hospital in 1990- 2018 (228 males; median age: 54.9 [14.6- 83.6] years). FLD patients with HSD17B13 A/A (212 cases) and others (A/AA or AA/AA; 190 cases) were compared.Results: Compared to patients with HSD17B13 A/A and others, those with the A/A genotype showed increased incidence of hepatocellular carcinoma (HCC) (A/A vs. others; 18.4% vs. 9.5%, p = 0.01), cardiovascular diseases (14.2% vs. 4.2%, p < 0.01), and hypertension (56.6% vs. 47.4%, p = 0.06). In patients without A/A, the HCC incidence was significantly reduced in those with alcohol-related FLD, fibrosis-4 index <2.67, and the PNPLA3 CC genotype; however, there was no significant difference in nonalcoholic- FLD. Patients without HSD17B13 A/A showed severe steatosis (77% vs. 88.6%, p < 0.01). New HCC developed in 11 cases and the 5- year incidence rate of HCC was 3.3% in patients with both PNPLA3 GG/GC and HSD17B13 A/A, which was significantly higher than the rate for those with other SNP profiles (0.6%, p = 0.03).Conclusions: Inhibiting HSD17B13 activity may prevent HCC development, particularly in alcohol-related FLD and low- risk patients. Therefore, combinations of SNPs and other risk factors can be used for screening FLD- HCC.

Automated summary

This study examined the association between HSD17B13 gene polymorphisms and the characteristics of Japanese fatty liver disease (FLD) patients. Patients with the HSD17B13 A/A genotype had a higher incidence of hepatocellular carcinoma, cardiovascular diseases, and hypertension. Patients without the HSD17B13 A/A genotype had more severe steatosis. Combining SNP profiles with other risk factors can be beneficial in screening FLD-HCC.