MASLD Research Center, Division of Gastroenterology, University of California San Diego, La Jolla, California, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Aliment Pharmacol Ther. 2024 Aug;60(3):369-377. doi: 10.1111/apt.18099. Epub 2024 Jun 2.
Genetic factors contribute to the risk and severity of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the utility of genetic testing in risk stratification remains poorly characterised.
To examine the influence of genetic risk on advanced fibrosis and cirrhosis in patients with type 2 diabetes mellitus (T2DM) and the utility of a polygenic risk score (PRS) in screening guidelines.
We prospectively enrolled adults aged ≥50 years with T2DM recruited from clinics. PRS was the sum of risk alleles in PNPLA3, TM6SF2 and SERPINA1 minus the protective variant in HSD17B13. We performed magnetic resonance elastography and vibration-controlled transient elastography to assess for advanced fibrosis and cirrhosis.
Of 382 included patients, the mean age and BMI were 64.8 (±8.4) years and 31.7 (±6.2) kg/m respectively. The prevalence of advanced fibrosis and cirrhosis were 12.3% and 5.2% respectively; higher PRS was associated with increased risk of cirrhosis (2.7% vs. 7.5%, p = 0.037). High PRS was associated with increased risk of advanced fibrosis among those with fibrosis-4 index (FIB-4) index <1.3 (9.6% vs. 2.3%, p = 0.036) but was not significantly different in other FIB-4 categories. Incorporating PRS determination into the American Gastroenterological Association and American Association for the Study of Liver Diseases screening guidelines prevented approximately 20% of all participants with advanced fibrosis from being inappropriately classified as low risk.
Utilising a well-phenotyped, prospective cohort of adults with T2DM, we found that adding an assessment of genetic risk to recommendations to screen at-risk populations may improve risk prediction.
遗传因素导致代谢功能障碍相关脂肪性肝病（MASLD）的发病风险和严重程度增加。然而，遗传检测在风险分层中的作用仍未得到充分描述。
研究遗传风险对 2 型糖尿病（T2DM）患者肝纤维化和肝硬化的影响，并探讨多基因风险评分（PRS）在筛查指南中的应用价值。
我们前瞻性地招募了来自诊所的年龄≥50 岁的 T2DM 成年患者。PRS 为 PNPLA3、TM6SF2 和 SERPINA1 中的风险等位基因总和减去 HSD17B13 中的保护性变异。我们采用磁共振弹性成像和振动控制瞬时弹性成像来评估肝纤维化和肝硬化的严重程度。
在纳入的 382 例患者中，平均年龄和 BMI 分别为 64.8（±8.4）岁和 31.7（±6.2）kg/m2。肝纤维化和肝硬化的患病率分别为 12.3%和 5.2%；较高的 PRS 与肝硬化风险增加相关（2.7%比 7.5%，p=0.037）。在 FIB-4 指数<1.3 的患者中，PRS 升高与肝纤维化进展的风险增加相关（9.6%比 2.3%，p=0.036），但在其他 FIB-4 类别中无显著差异。将 PRS 检测纳入美国胃肠病学会和美国肝病研究协会的筛查指南中，可以避免约 20%的肝纤维化高危患者被错误地归类为低风险。
利用经过充分表型分析的前瞻性 T2DM 成年患者队列，我们发现，在建议对高危人群进行筛查时，评估遗传风险可能会改善风险预测。
