Genetic study of intrahepatic cholestasis of pregnancy in Chinese women unveils East Asian etiology linked to historic HBV epidemic

IF 3.7 2区生物学 Q1 BIOCHEMICAL RESEARCH METHODS

ACS Synthetic Biology Pub Date : 2024-11-14 DOI:10.1016/j.jhep.2024.11.008

Yanhong Liu, Yuandan Wei, Xiaohang Chen, Shujia Huang, Yuqin Gu, Zijing Yang, Xinxin Guo, Hao Zheng, Hanxiao Feng, Mingxi Huang, Shangliang Chen, Tiantian Xiao, Liang Hu, Quanfu Zhang, Yang Zhang, Guo-Bo Chen, Xiu Qiu, Fengxiang Wei, Jianxin Zhen, Siyang Liu

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引用次数: 0

Abstract

Background & Aims

Intrahepatic cholestasis of pregnancy (ICP) is the most common and high-risk liver disorder during pregnancy, with varying prevalence across populations. Our understanding of the mechanisms underlying ICP and its population difference remains limited. This study delves into the genetic etiology of ICP in East Asians, drawing comparisons with Europeans to comprehend ICP etiology in the context of genetic background and evolution.

Methods

We conducted the hitherto largest-scale genome-wide association studies (GWAS) on fasting total serum bile acids (TBA) and ICP in 98,269 Chinese pregnancies. The findings were replicated in three cohorts and compared with European populations. Additionally, phenome-wide association and spatio-temporal evolution analyses were employed to investigate the function and evolutionary patterns of ICP-associated loci.

Results

We identified eight loci for fasting TBA and four for ICP, including ten novel loci. Notably, we discovered an East-Asian-specific locus within a 0.4Mbp region at 14q24.1, which increases fasting TBA by 6.12 μmol/L and ICP risk by 16.56-fold per risk allele (95% CI: 16.43 to 16.69, P = 7.06×10^-381). Phenome-wide association and spatial-temporal evolution analyses revealed that this 14q24.1 ICP risk locus confers resistance to hepatitis B and has become prevalent in East and Southeast Asia within the last 3,000 years.

Conclusions

We uncovered a distinct genetic etiology of ICP in East Asians, likely linked to a historic HBV epidemic in East and Southeast Asia within the last 3,000 years. These findings enhance our understanding of ICP pathophysiology and offer potential for more precise detection, assessment, and treatment of the disorder.

Impact and implications

This study provides novel insights into the genetic basis of intrahepatic cholestasis of pregnancy (ICP) in East Asian populations, where little was previously known. The identification of the East-Asian-specific 14q24.1 locus, associated with both fasting TBA and ICP, and its connection to a historical hepatitis B epidemic emphasize the importance of incorporating population-specific history into disease research. These findings are crucial for researchers studying pregnancy-related liver disorders and clinicians providing care to pregnant women, enabling more accurate screening, risk assessment, and targeted interventions for ICP.

Abstract Image

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对中国妇女妊娠期肝内胆汁淤积症的基因研究揭示了与历史上 HBV 流行有关的东亚病因

背景& 目的妊娠期肝内胆汁淤积症（ICP）是妊娠期最常见的高危肝脏疾病，在不同人群中的发病率各不相同。我们对 ICP 的发病机制及其人群差异的了解仍然有限。本研究深入探讨了东亚人ICP的遗传病因，并与欧洲人进行了比较，以便在遗传背景和进化的背景下理解ICP的病因。方法我们对98269名中国孕妇的空腹血清总胆汁酸（TBA）和ICP进行了迄今为止最大规模的全基因组关联研究（GWAS）。研究结果在三个队列中得到了重复，并与欧洲人群进行了比较。此外，我们还采用了全表型关联分析和时空进化分析来研究 ICP 相关位点的功能和进化模式。值得注意的是，我们在14q24.1的0.4Mbp区域内发现了一个东亚特异性位点，该位点使空腹TBA增加6.12 μmol/L，使每个风险等位基因的ICP风险增加16.56倍（95% CI：16.43至16.69，P = 7.06×10-381）。全表型关联分析和时空进化分析表明，14q24.1 ICP 风险位点赋予了对乙型肝炎的抵抗力，并在过去 3000 年间在东亚和东南亚流行起来。这些发现加深了我们对 ICP 病理生理学的了解，并为更精确地检测、评估和治疗该疾病提供了可能。影响和意义这项研究为以前鲜为人知的东亚人群妊娠期肝内胆汁淤积症（ICP）的遗传基础提供了新的见解。东亚特异性 14q24.1 位点的确定与空腹 TBA 和 ICP 都有关联，其与历史上乙型肝炎流行的联系强调了将特定人群的历史纳入疾病研究的重要性。这些发现对于研究妊娠相关肝脏疾病的研究人员和为孕妇提供护理的临床医生来说至关重要，可使ICP的筛查、风险评估和针对性干预更加准确。

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来源期刊

ACS Synthetic Biology 生物-

CiteScore

8.00

自引率

10.60%

发文量

380

审稿时长

6-12 weeks

期刊介绍： The journal is particularly interested in studies on the design and synthesis of new genetic circuits and gene products; computational methods in the design of systems; and integrative applied approaches to understanding disease and metabolism. Topics may include, but are not limited to: Design and optimization of genetic systems Genetic circuit design and their principles for their organization into programs Computational methods to aid the design of genetic systems Experimental methods to quantify genetic parts, circuits, and metabolic fluxes Genetic parts libraries: their creation, analysis, and ontological representation Protein engineering including computational design Metabolic engineering and cellular manufacturing, including biomass conversion Natural product access, engineering, and production Creative and innovative applications of cellular programming Medical applications, tissue engineering, and the programming of therapeutic cells Minimal cell design and construction Genomics and genome replacement strategies Viral engineering Automated and robotic assembly platforms for synthetic biology DNA synthesis methodologies Metagenomics and synthetic metagenomic analysis Bioinformatics applied to gene discovery, chemoinformatics, and pathway construction Gene optimization Methods for genome-scale measurements of transcription and metabolomics Systems biology and methods to integrate multiple data sources in vitro and cell-free synthetic biology and molecular programming Nucleic acid engineering.