De Vincentis Antonio, Tavaglione Federica, Jamialahmadi Oveis, Picardi Antonio, Antonelli Incalzi Raffaele, Valenti Luca, Romeo Stefano, Vespasiani-Gentilucci Umberto
Internal Medicine Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy; Internal Medicine, Saint Camillus International University of Health and Medical Sciences, Rome, Italy.
Clinical Medicine and Hepatology Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy; Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Clin Gastroenterol Hepatol. 2022 Mar;20(3):658-673. doi: 10.1016/j.cgh.2021.05.056. Epub 2021 Jun 4.
BACKGROUND & AIMS: A polygenic risk score based on well-known genetic variants in PNPLA3, TM6SF2, MBOAT7, and GCKR predicts hepatic fat content (polygenic risk score-hepatic fat content [PRS-HFC]). Here, we hypothesized that the addition of PRS-HFC to clinical fibrosis scores may improve risk stratification and prediction of severe liver disease (SLD).
We used data from 266,687 individuals in the UK Biobank, evaluating the incidence of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation during a median follow-up period of 9 years. Nonalcoholic fatty liver disease fibrosis score, Fibrosis-4, aspartate aminotransferase-to-platelet ratio, BARD, and Forns scores, and PRS-HFC, were computed. All analyses were stratified according to the presence of diabetes, obesity, and a positive fatty liver index (≥60).
Unfavorable genetics (PRS-HFC, ≥0.396) further stratified the risk of SLD in subjects in intermediate-/high-risk classes of fibrosis scores, with a higher effect in those with metabolic risk factors, and the prediction was improved by integrating PRS-HFC (areas under the receiver operating characteristic increased for all scores with a P value of approximately 10 to 10, except for the aspartate aminotransferase-to-platelet ratio in the overall population and in subjects with obesity). PRS-HFC improved diagnostic accuracies and positive predictive values for SLD in intermediate-high clinical score risk classes. Risk stratification and prediction were not affected or were poorly affected by unfavorable genetics in subjects without metabolic risk factors.
Integration of genetics with clinical fibrosis scores refines individual risk and prediction for SLD, mainly in individuals at risk for nonalcoholic fatty liver disease. These data provide evidence from a prospective cohort that common genetic variants capture additional prognostic insights not conveyed by validated clinical/biochemical parameters.
基于PNPLA3、TM6SF2、MBOAT7和GCKR中知名基因变异的多基因风险评分可预测肝脏脂肪含量（多基因风险评分-肝脏脂肪含量[PRS-HFC]）。在此，我们假设将PRS-HFC添加到临床纤维化评分中可能会改善严重肝病（SLD）的风险分层和预测。
我们使用了英国生物银行中266,687名个体的数据，评估了在中位随访期9年期间肝硬化、失代偿性肝病、肝细胞癌和/或肝移植的发生率。计算了非酒精性脂肪性肝病纤维化评分、Fibrosis-4、天冬氨酸转氨酶与血小板比值、BARD和Forns评分以及PRS-HFC。所有分析均根据糖尿病、肥胖和脂肪肝指数阳性（≥60）进行分层。
不良遗传学（PRS-HFC≥0.396）进一步对纤维化评分处于中/高风险类别的受试者的SLD风险进行分层，对有代谢风险因素的受试者影响更大，并且通过整合PRS-HFC可改善预测（所有评分的受试者工作特征曲线下面积增加，P值约为10至10，总体人群和肥胖受试者中的天冬氨酸转氨酶与血小板比值除外）。PRS-HFC提高了中高临床评分风险类别中SLD的诊断准确性和阳性预测值。在没有代谢风险因素的受试者中，不良遗传学对风险分层和预测没有影响或影响很小。
将遗传学与临床纤维化评分相结合可优化个体对SLD的风险和预测，主要是在非酒精性脂肪性肝病风险个体中。这些数据提供了来自前瞻性队列的证据，表明常见基因变异可获得经验证的临床/生化参数未传达的额外预后见解。
