A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers.
A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers.
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DOI：
10.1016/j.jhep.2021.10.005
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发表时间：
2022-03
影响因子：
25.7
通讯作者：
GenomALC Consortium
中科院分区：
文献类型：
--
作者：
Whitfield JB;Schwantes-An TH;Darlay R;Aithal GP;Atkinson SR;Bataller R;Botwin G;Chalasani NP;Cordell HJ;Daly AK;Day CP;Eyer F;Foroud T;Gleeson D;Goldman D;Haber PS;Jacquet JM;Liang T;Liangpunsakul S;Masson S;Mathurin P;Moirand R;McQuillin A;Moreno C;Morgan MY;Mueller S;Müllhaupt B;Nagy LE;Nahon P;Nalpas B;Naveau S;Perney P;Pirmohamed M;Seitz HK;Soyka M;Stickel F;Thompson A;Thursz MR;Trépo E;Morgan TR;Seth D;GenomALC Consortium
只有少数过量饮酒者会发展为肝硬化。我们开发并评估了风险分层评分，以确定那些风险最高的患者。三个队列（GenomALC-1：n=1690，GenomALC-2：n=3037，UK Biobank：相关n=6898），有重度饮酒史（≥80 g/天（男性），≥50 g/天（女性），≥10年）。例为酒精性肝硬化患者。对照组有类似的饮酒史，但没有肝脏疾病的证据。风险评分是根据先前确定的与酒精相关肝硬化相关的8个遗传位点和3个临床风险因素计算的。对酒精相关性肝硬化风险分层的评分性能进行了评估，并在酒精相关性肝病谱（包括肝细胞癌（HCC））中进行了比较。三个单核苷酸多态性（SNPs）（PNPLA 3：rs738409，SUGP 1-TM 6SF 2：rs 10401969，HSD 17 B13：rs6834314）和糖尿病状态的组合最能区分肝硬化风险。基于独立等位基因效应大小估计，3-SNP评分的极端评分五分位数（Q1-Q5）的比值比（OR）和95%置信区间（CI）分别为5.99（4.18;8.60）（GenomALC-1）、2.81（2.03;3.89）（GenomALC-2）和3.10（2.32;4.14）（UK Biobank）。与无糖尿病和低风险评分的患者相比，糖尿病和高风险评分的患者的OR增加至14.7（7.69;28.1）（GenomALC-1）和17.1（11.3;25.7）（UK Biobank）。肝硬化合并HCC患者的平均风险评分显著高于单纯肝硬化患者（0.76±0.06 vs 0.61±0.02，p=0.007）。得分表现没有显着提高额外的遗传风险变异，体重指数或咖啡消费的信息。基于三种遗传风险变异和糖尿病状态的风险评分可以为过量饮酒者的肝硬化提供有意义的风险分层，从而允许早期预防计划，包括强化干预。长期过量饮酒会导致一些人出现肝硬化，但到目前为止，还没有办法确定那些发展这种使人衰弱的疾病的高风险人群。我们的研究开发了一种遗传风险评分（GRS）测试，可以识别高风险患者，并显示肝硬化的风险增加>10倍，只有两个风险因素-糖尿病和高GRS。使用该检测进行风险评估，有可能对高风险患者的这种疾病进行早期和个性化管理。
Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk. Three cohorts (GenomALC-1: n=1690, GenomALC-2: n=3037, UK Biobank: relevant n=6898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to eight genetic loci identified previously as associated with alcohol-related cirrhosis and three clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC). A combination of three single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated for cirrhosis risk. The odds ratio (OR) and 95% confidence intervals (CI) for the extreme score quintiles (Q1-Q5) of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18;8.60) (GenomALC-1); 2.81 (2.03;3.89) (GenomALC-2); and 3.10 (2.32;4.14) (UK Biobank). Patients with diabetes and high-risk score, compared to those without diabetes and a low-risk score, had ORs increased to 14.7 (7.69;28.1) (GenomALC-1) and 17.1 (11.3;25.7) (UK Biobank). Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76±0.06 versus 0.61±0.02, p=0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption. A risk score based on three genetic risk variants and diabetes status can provide meaningful risk stratification for cirrhosis in excess drinkers, allowing earlier prevention planning including intensive intervention. Excessive chronic drinking leads to liver cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. Our study has developed a genetic risk score (GRS) test that can identify patients at high risk and shows that the risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and high GRS. Risk assessment using this test has potential for early and personalised management of this disease in high-risk patients.
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影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
6
作者：
Corrao, G;Bagnardi, V;Arico, S
通讯作者：
Arico, S
影响因子：
29.4
作者：
Innes, Hamish;Buch, Stephan;Stickel, Felix
通讯作者：
Stickel, Felix
影响因子：
13.5
作者：
Askgaard, Gro;Leon, David A.;Tolstrup, Janne S.
通讯作者：
Tolstrup, Janne S.
影响因子：
9.8
作者：
Salameh, Habeeb;Raff, Evan;Singal, Ashwani K.
通讯作者：
Singal, Ashwani K.