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

Abstract

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.

Keywords: 17-beta dehydrogenase 13; fatty liver disease; hepatocellular carcinoma; patatin-like phospholipase 3.

FIGURE 1

HCC complications stratified according to genetic factors. HCC incidence by (A) PNPLA3 GG/GC and (B) PNPLA3 CC according to the HSD17B13 SNP, (C) combinations of risk SNPs, and (D) combinations of non‐risk SNPs. HCC was frequently observed in patients with HSD17B13 A/A in PNPLA3 GG/GC (A, p = 0.047). Among cases with PNPLA3 CC, no HCC was observed among those with HSD17B13 variants (B, p = 0.15). The incidence of HCC was significantly increased in patients with PNPLA3 GG/GC and HSD17B13 A/A (C, p < 0.01). Conversely, there were no HCC cases among patients with PNPLA3 CC and HSD17B13 variants (D, p = 0.05). HCC, hepatocellular carcinoma; HSD17B13, 17‐beta dehydrogenase 13; PNPLA3, patatin‐like phospholipase 3; SNP, single‐nucleotide polymorphism.

FIGURE 2

HCC incidence stratified by (A) alcohol‐related and (B) nonalcohol‐related pathology, and the presence and absence of (C, D) liver fibrosis, (E, F) obesity, (G, H) diabetes, (I, J) hypertension, and (K, L) dyslipidemia, according to HSD17B13 SNP status. In patients without the HSD17B13 A/A genotype, HCC incidence was significantly reduced among those with alcohol‐related FLD (A, p = 0.02), but not among those with nonalcoholic FLD (B, p = 0.37). HCC was more common in patients with HSD17B13 A/A compared to HSD17B13 variants and a FIB‐4 index <2.67 (C, p = 0.04), normal weight (E, p = 0.04), and normal lipid level (K, p = 0.03). However, there were no such significant differences among those with a FIB‐4 index ≥2.67 (D, p = 0.18, D), obesity (F, p = 0.12), or dyslipidemia (L, p = 0.12). The incidence of HCC was increased in patients with diabetes (H, p = 0.04) and hypertension (J, p = 0.03) among those with the HSD17B13 A/A genotype compared to those with HSD17B13 variants (G, p = 0.12, and I, p = 0.36, respectively). FIB‐4, fibrosis‐4; HCC, hepatocellular carcinoma; HSD17B13, 17‐beta dehydrogenase 13; PNPLA3, patatin‐like phospholipase 3.

FIGURE 3

New‐onset HCC rate according to (A) PNPLA3, (B) HSD17B13, and (C) both PNPLA3 + HSD17B13 SNP status, as determined by Kaplan–Meier curves. There were no significant differences and a trend toward an increased risk of HCC development in patients with the PNPLA3 genotype (A, p = 0.17) and HSD17B13 genotype (B, p = 0.07), respectively. The incidence of de novo HCC was significantly increased in patients with PNPLA3 GG/GC and HSD17B13 A/A (log‐rank = 4.93, p = 0.03). HCC, hepatocellular carcinoma; HSD17B13, 17‐beta dehydrogenase 13; PNPLA3, patatin‐like phospholipase 3; SNP, single‐nucleotide polymorphism.