载脂蛋白基因 PNPLA3、TM6SF2 和 HSD17B13 变异与普通人群肝硬化和肝细胞癌风险的联合作用。
Combined Effect of PNPLA3, TM6SF2, and HSD17B13 Variants on Risk of Cirrhosis and Hepatocellular Carcinoma in the General Population.
机构信息
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
出版信息
Hepatology. 2020 Sep;72(3):845-856. doi: 10.1002/hep.31238.
BACKGROUND AND AIMS
We hypothesized that a genetic risk score (GRS) for fatty liver disease influences the risk of cirrhosis and hepatocellular carcinoma (HCC). Three genetic variants (patatin-like phospholipase domain-containing protein 3 [PNPLA3] p.I148M; transmembrane 6, superfamily member 2 [TM6SF2] p.E167K; and hydroxysteroid 17-beta dehydrogenase 13 [HSD17B13] rs72613567) were combined into a risk score, ranging from 0 to 6 for risk-increasing alleles.
APPROACH AND RESULTS
We examined the association of the risk score with plasma markers of liver disease and with cirrhosis and HCC in 110,761 individuals from Copenhagen, Denmark, and 334,691 individuals from the UK Biobank. The frequencies of risk scores of 0, 1, 2, 3, 4, and 5 or 6 were 5%, 25%, 41%, 23%, 5.5%, and 0.5%, respectively. A higher GRS was associated with an increase in plasma alanine aminotransferase (ALT) level of 26% in those with score 5 or 6 versus 0. In meta-analysis of the Copenhagen studies and the UK Biobank, individuals with scores 1, 2, 3, 4, and 5 or 6 had odds ratios (ORs) for cirrhosis of 1.6 (95% confidence interval [CI], 1.3, 1.9), 2.0 (95% CI, 1.8, 2.2), 3.1 (95% CI, 2.7, 3.5), 5.2 (95% CI, 4.2, 6.4), and 12 (95% CI, 7.7, 19), respectively, as compared with those with a score of 0. The corresponding ORs for HCC were 1.2 (95% CI, 0.9, 1.7), 1.0 (95% CI, 0.7, 1.3), 2.4 (95% CI, 1.9, 3.0), 3.3 (95% CI, 2.2, 5.0), and 29 (95% CI, 17, 51).
CONCLUSION
A GRS for fatty liver disease confers up to a 12-fold higher risk of cirrhosis and up to a 29-fold higher risk of HCC in individuals from the general population.
背景与目的
我们假设脂肪肝疾病的遗传风险评分（GRS）会影响肝硬化和肝细胞癌（HCC）的风险。三个遗传变异（载脂蛋白样磷脂酶结构域包含蛋白 3 [PNPLA3] p.I148M；跨膜 6，超家族成员 2 [TM6SF2] p.E167K；和羟甾体 17-β 脱氢酶 13 [HSD17B13] rs72613567）被组合成一个风险评分，风险增加的等位基因范围从 0 到 6。
方法和结果
我们在丹麦哥本哈根的 110761 人和英国生物银行的 334691 人中检查了风险评分与肝病的血浆标志物之间的关联，以及与肝硬化和 HCC 的关联。风险评分为 0、1、2、3、4 和 5 或 6 的频率分别为 5%、25%、41%、23%、5.5%和 0.5%。在哥本哈根研究和英国生物银行的荟萃分析中，评分 5 或 6 的个体与评分 0 的个体相比，血浆丙氨酸氨基转移酶（ALT）水平升高 26%。在肝硬化方面，1、2、3、4 和 5 或 6 分的个体比值比（OR）分别为 1.6（95%置信区间[CI]，1.3，1.9）、2.0（95%CI，1.8，2.2）、3.1（95%CI，2.7，3.5）、5.2（95%CI，4.2，6.4）和 12（95%CI，7.7，19），与评分 0 的个体相比。在 HCC 方面，相应的 OR 分别为 1.2（95%CI，0.9，1.7）、1.0（95%CI，0.7，1.3）、2.4（95%CI，1.9，3.0）、3.3（95%CI，2.2，5.0）和 29（95%CI，17，51）。
结论
在普通人群中，脂肪肝疾病的 GRS 使肝硬化的风险增加了 12 倍，使 HCC 的风险增加了 29 倍。
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