Abstract
Nonalcoholic fatty liver disease (NAFLD) is a rising cause of hepatocellular carcinoma (HCC). We examined whether inherited pathogenic variants in candidate genes (n = 181) were enriched in patients with NAFLD-HCC. To this end, we resequenced peripheral blood DNA of 142 NAFLD-HCC, 59 NAFLD with advanced fibrosis, and 50 controls, and considered 404 healthy individuals from 1000 G. Pathogenic variants were defined according to ClinVar, likely pathogenic as rare variants predicted to alter protein activity. In NAFLD-HCC patients, we detected an enrichment in pathogenic (p = 0.024), and likely pathogenic variants (p = 1.9*10−6), particularly in APOB (p = 0.047). APOB variants were associated with lower circulating triglycerides and higher HDL cholesterol (p < 0.01). A genetic risk score predicted NAFLD-HCC (OR 4.96, 3.29–7.55; p = 5.1*10−16), outperforming the diagnostic accuracy of common genetic risk variants, and of clinical risk factors (p < 0.05). In conclusion, rare pathogenic variants in genes involved in liver disease and cancer predisposition are associated with NAFLD-HCC development.
Highlights
Pathogenic variants were defined according to ClinVar, likely pathogenic as rare variants predicted to alter protein activity
There was an enrichment in the number of pathogenic variants per individual in candidate genes in Nonalcoholic fatty liver disease (NAFLD)-HCC patients, as compared to patients with advanced fibrosis, healthy individuals and the 1000 genomes project phase 3 (1000 G) cohort (Fig. 2a and Supplementary Table 2; OR 1.4, 95% c.i. 1.1-infinite, p = 0.024)
We found a significant enrichment of variants in the APOB gene predisposing to familial hypobetalipoproteinemia
Summary
Pathogenic variants were defined according to ClinVar, likely pathogenic as rare variants predicted to alter protein activity. Rare pathogenic variants in genes involved in liver disease and cancer predisposition are associated with NAFLD-HCC development. Heritability is involved in HCC predisposition[7], and NAFLD has a strong genetic component[8], as does its progression to advanced disease[9]. We have showed that other common genetic variants influencing hepatic fat accumulation, namely those in TM6SF2 and MBOAT7, may improve the ability to discriminate NAFLD patients at risk of HCC11. Possibly because of the still large fraction of missing heritability, carriage of these variants was not specific enough to identify patients at risk of NAFLD-HCC to be implemented in clinical practice[12,13]. A systematic evaluation of candidate genes in a large number of affected individuals has not been performed so far
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