BACKGROUND AND AIMS Alcohol-associated hepatitis (AH) is a clinically severe, acute disease that afflicts only a fraction of patients with alcohol use disorder. Genomic studies of alcohol-associated cirrhosis (AC) have identified several genes of large effect, but the genetic and environmental factors that lead to AH and AC, and their degree of genetic overlap, remain largely unknown. This study aims to identify genes and genetic variations that contribute to the development of AH. APPROACH AND RESULTS Exome-sequencing of patients with AH (N=784) and heavy drinking controls (N=951) identified an exome-wide significant association for AH at patalin-like phospholipase domain containing 3, as previously observed for AC in genome-wide association study, although with a much lower effect size. Single nucleotide polymorphisms (SNPs) of large effect size at inducible T cell costimulatory ligand ( ICOSLG ) (Chr 21) and TOX4/RAB2B (Chr 14) were also exome-wide significant. ICOSLG encodes a co-stimulatory signal for T-cell proliferation and cytokine secretion and induces B-cell proliferation and differentiation. TOX high mobility group box family member 4 ( TOX4 ) was previously implicated in diabetes and immune system function. Other genes previously implicated in AC did not strongly contribute to AH, and the only prominently implicated (but not exome-wide significant) gene overlapping with alcohol use disorder was alcohol dehydrogenase 1B ( ADH1B ). Polygenic signals for AH were observed in both common and rare variant analysis and identified genes with roles associated with inflammation. CONCLUSIONS This study has identified 2 new genes of high effect size with a previously unknown contribution to alcohol-associated liver disease and highlights both the overlap in etiology between liver diseases and the unique origins of AH.

中文翻译：

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外显子组范围关联分析确定了酒精相关性肝炎的新风险位点。


背景和目标 酒精相关性肝炎 （AH） 是一种临床上严重的急性疾病，仅折磨一小部分酒精使用障碍患者。酒精相关性肝硬化 （AC） 的基因组研究已经确定了几个具有很大影响的基因，但导致 AH 和 AC 的遗传和环境因素以及它们的遗传重叠程度在很大程度上仍然未知。本研究旨在确定导致 AH 发展的基因和遗传变异。方法和结果 AH （N=784） 和酗酒对照者 （N=951） 患者的外显子组测序确定了 AH 在含有 3 的巴塔林样磷脂酶结构域的外显子组显着关联，正如之前在全基因组关联研究中观察到的 AC，尽管效应量要小得多。在诱导型 T 细胞共刺激配体 （ICOSLG） （Chr 21） 和 TOX4/RAB2B （Chr 14） 处具有大效应量的单核苷酸多态性 （SNP） 在外显子组范围内也显著。ICOSLG 编码 T 细胞增殖和细胞因子分泌的共刺激信号，并诱导 B 细胞增殖和分化。TOX 高迁移率组盒家族成员 4 （ TOX4 ） 以前与糖尿病和免疫系统功能有关。以前与 AC 相关的其他基因对 AH 没有太大贡献，唯一与酒精使用障碍重叠的突出相关（但不是外显子组范围显着的）基因是酒精脱氢酶 1B （ADH1B）。在常见和罕见变异分析中均观察到 AH 的多基因信号，并鉴定了与炎症相关作用的基因。 结论 本研究确定了 2 个高效应量的新基因，这些基因对酒精相关性肝病的贡献以前未知，并强调了肝病之间病因的重叠和 AH 的独特起源。