Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Cardiac Genetics Group, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Nat Genet. 2024 May;56(5):827-837. doi: 10.1038/s41588-024-01720-y. Epub 2024 Apr 17.
We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.
我们报告了一项多血统全基因组关联研究，研究对象为肝硬化及其相关表型，包括丙氨酸氨基转移酶（ALT）和γ-谷氨酰转移酶。该研究使用了来自 12 个队列的数据，包括 18265 例肝硬化病例、1782047 名对照者、多达 100 万人的肝功能检查数据，以及一个包含 21689 例病例和 617729 名对照者的验证队列。我们鉴定和验证了 14 个与肝硬化相关的风险关联。许多变异位于与肝内脂质代谢相关的基因附近。其中一个，PNPLA3 p.Ile148Met，与饮酒、肥胖和糖尿病共同作用，增加肝硬化和肝细胞癌（HCC）的风险。我们开发了一种与肝硬化向 HCC 进展相关的多基因风险评分。通过关注常见变异分析中的优先基因，我们发现 GPAM 中的罕见编码变异与较低的 ALT 相关，支持将 GPAM 作为潜在的治疗靶点。总之，这项研究为肝硬化的遗传基础提供了新的见解。
