Luukkonen Panu K, Färkkilä Martti, Jula Antti, Salomaa Veikko, Männistö Satu, Lundqvist Annamari, Perola Markus, Åberg Fredrik
Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Abdominal Center, Helsinki University Hospital, Helsinki, Finland.
Liver Int. 2023 May;43(5):1035-1045. doi: 10.1111/liv.15554. Epub 2023 Mar 8.
BACKGROUND & AIMS: Genetic variants, abdominal obesity and alcohol use are risk factors for incident liver disease (ILD). We aimed to study whether variants either alone or when aggregated into genetic risk scores (GRSs) associate with ILD, and whether waist-hip ratio (WHR) or alcohol use interacts with this risk.
Our study included 33 770 persons (mean age 50 years, 47% men) who participated in health-examination surveys (FINRISK 1992-2012 or Health 2000) with data on alcohol use, WHR and 63 genotypes associated with liver disease. Data were linked with national health registers for liver-related outcomes (hospitalizations, malignancies and death). Exclusions were baseline clinical liver disease. Mean follow-up time was 12.2 years. Cox regression analyses between variants and ILD were adjusted for age, sex and BMI.
Variants in PNPLA3, IFNL4, TM6SF2, FDFT1, PPP1R3B, SERPINA1 and HSD17B13 were associated with ILD. GRSs calculated from these variants were not associated with WHR or alcohol use, but were exponentially associated with ILD (up to 25-fold higher risk in high versus low score). The risk of ILD in individuals with high GRS and high WHR or alcohol use compared with those with none of these risk factors was increased by up to 90-fold. GRSs provided new prognostic information particularly in individuals with high WHR.
The effect of multiple genetic variants on the risk of ILD is potentiated by abdominal obesity and alcohol use. Simple GRSs may help to identify individuals with adverse lifestyle who are at a particularly high risk of ILD.
基因变异、腹型肥胖和饮酒是新发肝病（ILD）的危险因素。我们旨在研究这些变异单独存在或汇总为遗传风险评分（GRS）时是否与ILD相关，以及腰臀比（WHR）或饮酒是否会与这种风险产生相互作用。
我们的研究纳入了33770人（平均年龄50岁，47%为男性），他们参与了健康检查调查（芬兰1992 - 2012年心血管疾病风险因素队列研究或2000年健康调查），提供了饮酒情况、WHR以及63种与肝病相关的基因型数据。数据与国家卫生登记系统中与肝脏相关的结局（住院、恶性肿瘤和死亡）相链接。排除标准为基线临床肝病。平均随访时间为12.2年。对变异与ILD之间进行的Cox回归分析对年龄、性别和体重指数进行了校正。
PNPLA3、IFNL4、TM6SF2、FDFT1、PPP1R3B、SERPINA1和HSD17B13基因的变异与ILD相关。根据这些变异计算出的GRS与WHR或饮酒无关，但与ILD呈指数关联（高分与低分相比，风险高出25倍）。与无这些风险因素的个体相比，GRS高且WHR高或饮酒的个体患ILD的风险增加了90倍。GRS尤其能为WHR高的个体提供新的预后信息。
腹型肥胖和饮酒会增强多种基因变异对ILD风险的影响。简单的GRS可能有助于识别生活方式不良且患ILD风险特别高的个体。
