Rare Pathogenic Variants Predispose to Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease
Rare Pathogenic Variants Predispose to Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease
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DOI：
10.1038/s41598-019-39998-2
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发表时间：
2019-03-06
影响因子：
4.6
通讯作者：
Valenti, Luca Vittorio Carlo
中科院分区：
文献类型：
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作者：
Pelusi, Serena;Baselli, Guido;Valenti, Luca Vittorio Carlo
非酒精性脂肪性肝病（NAFLD）是肝细胞癌（HCC）的一个上升的原因。我们检查了候选基因（n = 181）中的遗传致病性变异是否在NAFLD-HCC患者中富集。为此，我们对142例NAFLD-HCC、59例晚期纤维化NAFLD和50例对照的外周血DNA进行了重新测序，并考虑了来自1000 G的404名健康个体。根据ClinVar定义致病性变体，可能致病性为预测改变蛋白质活性的罕见变体。在NAFLD-HCC患者中，我们检测到致病性（p = 0.024）和可能致病性变体（p = 1.9*10（-6））的富集，特别是APOB（p = 0.047）。APOB变异与较低的循环甘油三酯和较高的HDL胆固醇相关（p < 0.01）。遗传风险评分预测NAFLD-HCC（OR 4.96，3.29-7.55; p = 5.1*10（-16）），优于常见遗传风险变异和临床风险因素的诊断准确性（p < 0.05）。总之，涉及肝脏疾病和癌症易感性的基因中的罕见致病性变异与NAFLD-HCC的发展相关。
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.