Role of candidate gene variants in modulating the risk and severity of alcoholic hepatitis.
Role of candidate gene variants in modulating the risk and severity of alcoholic hepatitis.
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DOI：
10.1111/acer.14581
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Gawrieh S
中科院分区：
文献类型：
--
作者：
Beaudoin JJ;Liang T;Tang Q;Banini BA;Shah VH;Sanyal AJ;Chalasani NP;Gawrieh S
酒精性肝炎（AH）是一种严重的、危及生命的酒精相关性肝病。只有少数重度饮酒者获得AH，这表明AH的易感性和严重性有遗传基础。一个由211名AH患者和176名重度饮酒对照组成的队列对先前与慢性肝病相关的五个候选基因中的五个变体进行基因分型：马铃薯糖蛋白样磷脂酶结构域蛋白3（PNPLA 3）中的rs738409，羟基类固醇17-β脱氢酶13中的rs72613567跨膜6超家族成员2（TM 6SF 2）中的rs 58542926、含膜结合O-酰基转移酶结构域7（MBOAT 7）中的rs641738和触珠蛋白（HP）基因中的拷贝数变体。我们测试了个体变异的影响以及变异对AH风险和严重程度的组合/相互作用影响。我们发现AH风险与rs738409（P=0.0081）和HP（P=0.0371）的风险等位基因之间存在显著相关性，但在调整患者的年龄和性别后，rs72613567（P=0.3132）、rs 58542926（P=0.2180）和rs641738（P=0.7630）均无相关性。多元回归模型显示PNPLA 3 rs738409：G [OR=1.59（95%CI：1.15-2.22），P=0.0055]和HP*2 [OR=1.38（95%CI：1.04-1.82），P=0.0245]结合并校正年龄和性别对重度饮酒者的AH风险也有很大影响。在整个队列中，PNPLA 3和HP的变异与总胆红素和终末期肝病模型（MELD）评分（AH严重程度的两个指标）增加相关。在携带PNPLA 3 rs738409 G等位基因的患者中，未发现HSD 17 B13 rs72613567：AA等位基因降低AH的风险（P=0.0921）。目前的研究表明，PNPLA 3和HP遗传变异增加了AH风险，并与总胆红素和MELD评分相关，这些评分是AH严重程度的替代指标。
Alcoholic hepatitis (AH) is a severe and life-threatening form of alcohol-associated liver disease. Only a minority of heavy drinkers acquires AH, suggesting a genetic basis for the susceptibility to and severity of AH. A cohort consisting of 211 patients with AH and 176 heavy drinking controls was genotyped for five variants in five candidate genes that previously had been associated with chronic liver diseases: rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3), rs72613567 in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), rs58542926 in transmembrane 6 superfamily member 2 (TM6SF2), rs641738 in membrane bound O-acyltransferase domain containing 7 (MBOAT7), and the copy number variant in the haptoglobin (HP) gene. We tested the effects of individual variants and the combined/interacting effects of variants on AH risk and severity. We found significant associations between AH risk and the risk alleles of rs738409 (P=0.0081) and HP (P=0.0371), but not rs72613567 (P=0.3132), rs58542926 (P=0.2180), nor rs641738 (P=0.7630), after adjusting for patient’s age and sex. A multiple regression model indicated that PNPLA3 rs738409:G [OR=1.59 (95% CI: 1.15–2.22), P=0.0055] and HP*2 [OR=1.38 (95% CI: 1.04–1.82), P=0.0245] combined and adjusted for age and sex also had a large influence on AH risk among heavy drinkers. In the entire cohort, variants in PNPLA3 and HP were associated with increased total bilirubin and Model for End-stage Liver Disease (MELD) score, two measures of AH severity. The HSD17B13 rs72613567:AA allele was not found to reduce risk of AH in patients carrying the G allele of PNPLA3 rs738409 (P=0.0921). The current study demonstrates that PNPLA3 and HP genetic variants increase AH risk and are associated with total bilirubin and MELD score, surrogates of AH severity.
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