Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers
Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers
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DOI：
10.1002/hep.30996
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发表时间：
2020-05-20
期刊：
影响因子：
13.5
通讯作者：
Morgan, Marsha Y.
中科院分区：
文献类型：
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作者：
Stickel, Felix;Lutz, Philipp;Morgan, Marsha Y.
背景与目的PNPLA3基因携带rs738409：G与酒精性肝硬变和肝细胞癌的发病风险相关。最近，羟基类固醇17-β脱氢酶13(HSD17B13)中的rs72613567：Ta被证明与发生酒精性肝病的风险降低和携带PNPLA3 rs738409：G的风险降低相关。本研究探索了这两个基因变异与酒精性肝硬变和肝细胞癌发生的风险关联。方法和结果对6,171名参与者进行了HSD17B13和PNPLA3的基因分型，其中包括1,031例酒精性肝硬变和肝细胞癌，1,653例酒精性肝硬变而不是肝细胞癌，2,588名无肝病的酗酒者和899名健康对照组。用Logistic回归分析确定与发生酒精相关的肝硬变和肝细胞癌的风险的遗传关联。携带HSD17B13 rs72613567：TA与发生肝硬变(优势比[OR]，0.79；95%可信区间[CI]，0.72-0.88；P=8.13×10(-6))和肝细胞癌(OR，0.77；95%可信区间，0.68-0.89；P=2.27×10(-4))相关，而携带PNPLA3 rs738409：G与发展为肝硬变的风险增加(OR，1.70；95%CI，1.54-1.88；P=1.52×10(-26))和肝细胞癌(OR，1.77；95%CI，1.58~1.98；P=2.31×10(-23))。在对年龄、性别、体重指数、2型糖尿病和国家进行调整后，这些相关性仍然显著。携带HSD17B13 rs72613567：Ta可降低男性和女性发生PNPLA3 rs738409：G相关肝硬变的风险，但对肝癌的保护作用仅见于男性(OR等位基因，0.75；95%CI，0.64~0.87；P=1.72×10(-4))。结论携带PNPLA3和HSD17B13基因突变对晚期酒精性肝病的发生有不同程度的影响。基因/表型风险评分可能有助于该人群中肝细胞癌的早期诊断。
Background and Aims Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC.Approach and Results Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 x 10(-6)) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 x 10(-4)), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 x 10(-26)) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 x 10(-23)). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (ORallelic, 0.75; 95% CI, 0.64-0.87; P = 1.72 x 10(-4)).Conclusions Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.