Background and Aims: Identification of noninvasive biomarkers to detect patients with dysmetabolism at risk of nonalcoholic fatty liver disease (NAFLD), severe fibrosis and hepatocellular carcinoma (HCC) is a priority. Progression of NAFLD is genetically conditioned. We previously developed a polygenic risk score (GRS) based on common variants that are involved in inherited predisposition to fat accumulation, namely PNPLA3, TM6SF2, MBOAT7 and GCKR. The aim of this cross-sectional multicenter study was to evaluate the accuracy of GRS to stratify the risk of NAFLD, advanced fibrosis and HCC. Methods: A total of 2021 individuals (464 without liver disease, 1034 with histological NAFLD without severe fibrosis, 275 with NAFLD and severe fibrosis without HCC, and 248 with NAFLD-HCC) were genotyped for the rs738409 (PNPLA3 I148 M), rs58542926 (TM6SF2 E167K), rs641738 C > T at MBOAT7 and rs1260326 (GCKR P446L). The GRS was computed for each subject. The association between GRS and disease risk was tested using multivariate logistic regression models, adjusted for age, sex, presence of diabetes, BMI and fibrosis. Results: In the overall cohort, GRS was associated with NAFLD (p<10ˆ-11, OR for the upper quartile: 4.22, 95%CI 2.72–6.54) independently of confounders. In NAFLD, GRS was also an independent predictor of severe fibrosis (p<10ˆ-14, OR for the upper quartile 2.96, 95%CI 1.55–5.65). Moreover, GRS was independently associated with HCC (p=10ˆ-6, OR for the upper quartile 2.41, 95%CI1.28–4.54) in NAFLD patients, but the association was lost after correction for fibrosis. The AUROC was 0.604, better than the single variants alone. Conclusion: The GRS was more accurate in discriminating NAFLD, severe fibrosis and HCC compared to single variants. Genetic heritability and hepatic fat accumulation determine liver fibrosis, that remains the major risk factor for HCC, although we can not exclude a pleiotropic effect of specific variants in hepatocarcinogenesis.
Noninvasive risk stratification in non-alcoholic fatty liver disease: a polygenic risk score
Bugianesi E;
2020-01-01
Abstract
Background and Aims: Identification of noninvasive biomarkers to detect patients with dysmetabolism at risk of nonalcoholic fatty liver disease (NAFLD), severe fibrosis and hepatocellular carcinoma (HCC) is a priority. Progression of NAFLD is genetically conditioned. We previously developed a polygenic risk score (GRS) based on common variants that are involved in inherited predisposition to fat accumulation, namely PNPLA3, TM6SF2, MBOAT7 and GCKR. The aim of this cross-sectional multicenter study was to evaluate the accuracy of GRS to stratify the risk of NAFLD, advanced fibrosis and HCC. Methods: A total of 2021 individuals (464 without liver disease, 1034 with histological NAFLD without severe fibrosis, 275 with NAFLD and severe fibrosis without HCC, and 248 with NAFLD-HCC) were genotyped for the rs738409 (PNPLA3 I148 M), rs58542926 (TM6SF2 E167K), rs641738 C > T at MBOAT7 and rs1260326 (GCKR P446L). The GRS was computed for each subject. The association between GRS and disease risk was tested using multivariate logistic regression models, adjusted for age, sex, presence of diabetes, BMI and fibrosis. Results: In the overall cohort, GRS was associated with NAFLD (p<10ˆ-11, OR for the upper quartile: 4.22, 95%CI 2.72–6.54) independently of confounders. In NAFLD, GRS was also an independent predictor of severe fibrosis (p<10ˆ-14, OR for the upper quartile 2.96, 95%CI 1.55–5.65). Moreover, GRS was independently associated with HCC (p=10ˆ-6, OR for the upper quartile 2.41, 95%CI1.28–4.54) in NAFLD patients, but the association was lost after correction for fibrosis. The AUROC was 0.604, better than the single variants alone. Conclusion: The GRS was more accurate in discriminating NAFLD, severe fibrosis and HCC compared to single variants. Genetic heritability and hepatic fat accumulation determine liver fibrosis, that remains the major risk factor for HCC, although we can not exclude a pleiotropic effect of specific variants in hepatocarcinogenesis.
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