Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, University of Bristol, Bristol, UK.
Int J Epidemiol. 2023 Oct 5;52(5):1341-1349. doi: 10.1093/ije/dyad048.
Genetic factors influence the risk of fatty liver disease (FLD) in adults. The aim of this study was to test if, and when, genetic risk factors known to affect FLD in adults begin to exert their deleterious effects during childhood, adolescence and early adulthood.
We included up to 4018 British children and adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Three genetic variants known to associate robustly with FLD in adults (PNPLA3 rs738409, TM6SF2 rs58542926 and HSD17B13 rs72613567) were tested for association with plasma levels of alanine transaminase (ALT) and aspartate transaminase (AST) during childhood (mean age: 9.9 years), early adolescence (15.5 years), late adolescence (17.8 years), and early adulthood (24.5 years). We also tested the associations of a 17-variant score and whole-genome polygenic risk scores (PRS) derived from associations in adults with plasma ALT and AST at the same four time points. Associations with elastography-derived liver steatosis and fibrosis were tested in early adulthood.
Genetic risk factors for FLD (individually, combined into a 3-variant score, a 17-variant score and as a genome-wide PRS), were associated with higher liver enzymes, beginning in childhood and throughout adolescence and early adulthood. The ALT-increasing effects of the genetic risk variants became larger with increasing age. The ALT-PRS was associated with liver steatosis in early adulthood. No genetic associations with fibrosis were observed.
Genetic factors that promote FLD in adults associate with elevated liver enzymes already during childhood, and their effects get amplified with increasing age.
遗传因素影响成人脂肪肝（FLD）的风险。本研究旨在测试已知会影响成人 FLD 的遗传风险因素何时以及何时开始在儿童、青少年和成年早期发挥其有害作用。
我们纳入了多达 4018 名来自英国阿冯纵向研究父母和孩子（ALSPAC）队列的儿童和青少年。测试了三个与成人 FLD 密切相关的遗传变异（PNPLA3 rs738409、TM6SF2 rs58542926 和 HSD17B13 rs72613567）与儿童期（平均年龄：9.9 岁）、青少年早期（15.5 岁）、青少年晚期（17.8 岁）和成年早期（24.5 岁）期间血浆丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平之间的关联。我们还测试了来自成人关联的 17 个变异评分和全基因组多基因风险评分（PRS）与四个时间点的血浆 ALT 和 AST 之间的关联。在成年早期测试了与弹性成像衍生的肝脂肪变性和纤维化的关联。
FLD 的遗传风险因素（单独、组合成 3 个变异评分、17 个变异评分和全基因组 PRS）与较高的肝酶相关，从儿童期开始，并贯穿整个青春期和成年早期。遗传风险变异对 ALT 的影响随着年龄的增长而增大。ALT-PRS 与成年早期的肝脂肪变性有关。未观察到与纤维化相关的遗传关联。
在成人中促进 FLD 的遗传因素与儿童时期已经升高的肝酶相关，并且随着年龄的增长，其影响会放大。
