Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
Nonalcoholic Fatty Liver Disease Research Center, Department of Medicine, University of California San Diego, La Jolla, California.
Gastroenterology. 2021 Apr;160(5):1620-1633.e13. doi: 10.1053/j.gastro.2020.12.011. Epub 2020 Dec 11.
BACKGROUND & AIMS: In contrast to most other common diseases, few genetic variants have been identified that impact risk of cirrhosis. We aimed to identify new genetic variants that predispose to cirrhosis, to test whether such variants, aggregated into a polygenic score, enable genomic risk stratification, and to test whether alcohol intake or body mass index interacts with polygenic predisposition.
We conducted a multi-trait genome-wide association study combining cirrhosis and alanine aminotransferase levels performed in 5 discovery studies (UK Biobank, Vanderbilt BioVU, Atherosclerosis Risk in Communities study, and 2 case-control studies including 4829 individuals with cirrhosis and 72,705 controls and 362,539 individuals with alanine aminotransferase levels). Identified variants were replicated in 3 studies (Partners HealthCare Biobank, FinnGen, and Biobank Japan including 3554 individuals with cirrhosis and 343,826 controls). A polygenic score was tested in Partners HealthCare Biobank.
Five previously reported and 7 newly identified genetic variants were associated with cirrhosis in both the discovery studies multi-trait genome-wide association study (P < 5 × 10) and the replication studies (P < .05), including a missense variant in the APOE gene and a noncoding variant near EFN1A. These 12 variants were used to generate a polygenic score. Among Partners HealthCare Biobank individuals, high polygenic score-defined as the top quintile of the distribution-was associated with significantly increased risk of cirrhosis (odds ratio, 2.26; P < .001) and related comorbidities compared with the lowest quintile. Risk was even more pronounced among those with extreme polygenic risk (top 1% of the distribution, odds ratio, 3.16; P < .001). The impact of extreme polygenic risk was substantially more pronounced in those with elevated alcohol consumption or body mass index. Modeled as risk by age 75 years, probability of cirrhosis with extreme polygenic risk was 13.7%, 20.1%, and 48.2% among individuals with no or modest, moderate, and increased alcohol consumption, respectively (P < .001). Similarly, probability among those with extreme polygenic risk was 6.5%, 10.3%, and 19.5% among individuals with normal weight, overweight, and obesity, respectively (P < .001).
Twelve independent genetic variants, 7 of which are newly identified in this study, conferred risk for cirrhosis. Aggregated into a polygenic score, these variants identified a subset of the population at substantially increased risk who are most susceptible to the hepatotoxic effects of excess alcohol consumption or obesity.
与大多数其他常见疾病不同，仅有少数遗传变异被确定可影响肝硬化风险。我们旨在鉴定新的遗传变异，这些变异易导致肝硬化，检验此类变异是否可汇总为多基因风险评分，从而实现基因组风险分层，并检验酒精摄入或体重指数是否与多基因易感性相互作用。
我们进行了一项多性状全基因组关联研究，结合了在 5 项发现研究（英国生物库、范德比尔特生物库、社区动脉粥样硬化风险研究和包括 4829 例肝硬化患者和 72705 例对照以及 362539 例丙氨酸氨基转移酶水平的 2 项病例对照研究）中进行的肝硬化和丙氨酸氨基转移酶水平。在包括 3554 例肝硬化患者和 343826 例对照的 3 项研究（合作伙伴健康护理生物库、芬兰遗传研究和日本生物库）中对鉴定的变异进行了复制。在合作伙伴健康护理生物库中检验了多基因风险评分。
在发现研究的多性状全基因组关联研究（P < 5 × 10）和复制研究中（P <.05），5 个先前报道的和 7 个新鉴定的遗传变异与肝硬化相关，包括载脂蛋白 E 基因中的错义变异和 EFN1A 附近的非编码变异。这 12 个变异用于生成多基因风险评分。在合作伙伴健康护理生物库个体中，高多基因评分（定义为分布的最高五分位数）与肝硬化相关的风险显著增加（优势比，2.26；P <.001），与最低五分位数相比，还与相关合并症相关。在具有极端多基因风险的个体中，风险更为显著（分布的前 1%，优势比，3.16；P <.001）。在那些酒精摄入量或体重指数较高的个体中，极端多基因风险的影响更为显著。在 75 岁时建模为风险，在没有或适度、中度和增加酒精摄入的个体中，具有极端多基因风险的肝硬化概率分别为 13.7%、20.1%和 48.2%（P <.001）。同样，在具有极端多基因风险的个体中，在体重正常、超重和肥胖的个体中，概率分别为 6.5%、10.3%和 19.5%（P <.001）。
12 个独立的遗传变异，其中 7 个是本研究中首次鉴定的，为肝硬化风险提供了依据。将这些变异汇总为多基因风险评分，可以确定风险显著增加的人群亚组，这些人群对过量饮酒或肥胖的肝毒性作用最敏感。
