BACKGROUND Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. METHODS We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. RESULTS A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was associated with reduced levels of ALT (P=4.2×10-12) and AST (P=6.2×10-10). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. CONCLUSIONS A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis. (Funded by Regeneron Pharmaceuticals and others.).

中文翻译：

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截短蛋白的HSD17B13变体和对慢性肝病的保护作用。

背景技术阐明慢性肝病的遗传因素可能揭示新的治疗靶标。方法我们使用来自DiscovEHR人类遗传学研究的46,544名参与者的外显子组序列数据和电子健康记录，来鉴定与血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平相关的遗传变异。在DiscovEHR研究参与者和另外两个独立的队列（总计37,173人）中评估了在另外三个队列（12,527人）中复制的变异体与慢性肝病的临床诊断的相关性，并在2391个人类肝脏样本中评估了肝病的组织病理学严重程度。结果HSD17B13中有一个剪接变体（rs72613567：TA），编码肝脂质滴蛋白羟类固醇17-β脱氢酶13，与ALT（P = 4.2×10-12）和AST（P = 6.2×10-10）降低有关。在DiscovEHR研究参与者中，这种变异与酒精性肝病的风险降低相关（杂合子降低了42％[95％置信区间{CI}，20至58]，而杂合子降低了53％[95％CI，3至77]）。纯合子），非酒精性肝病（杂合子中为17％[95％CI，8至25]，纯合子中为30％[95％CI，13至43]），酒精性肝硬化（42％[95％CI，14]杂合子中分别有61％到61]和纯合子中的73％[95％CI，15到91]和非酒精性肝硬化（杂合子中有26％[95％CI，7至40]和49％[95％CI，15]至69]。在两个独立的队列中证实了关联。rs72613567：TA变体与降低非酒精性脂肪性肝炎的风险有关，但与脂肪变性无关，在人类肝脏样本中。rs72613567：TA变体减轻了与风险增加的PNPLA3 p.I148M等位基因相关的肝损伤，并导致酶活性降低的不稳定且截短的蛋白质。结论HSD17B13的功能丧失变异与降低慢性肝病风险以及从脂肪变性发展为脂肪性肝炎的风险有关。（由Regeneron Pharmaceuticals等资助）。