Liu Yanhong, Wei Yuandan, Chen Xiaohang, Huang Shujia, Gu Yuqin, Yang Zijing, Guo Xinxin, Zheng Hao, Feng Hanxiao, Huang Mingxi, Chen Shangliang, Xiao Tiantian, Hu Liang, Zhang Quanfu, Zhang Yang, Chen Guo-Bo, Qiu Xiu, Wei Fengxiang, Zhen Jianxin, Liu Siyang
School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong 518107, China.
School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong 518107, China; Central Laboratory, Shenzhen Baoan Women's and Children's Hospital, Shenzhen, Guangdong 518102, China.
J Hepatol. 2025 May;82(5):826-835. doi: 10.1016/j.jhep.2024.11.008. Epub 2024 Nov 14.
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 population-level differences 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.
We conducted the hitherto largest-scale genome-wide association study 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.
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 0.4 Mbp 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). 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.
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.
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 total serum bile acids 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.
妊娠期肝内胆汁淤积症（ICP）是孕期最常见的高风险肝脏疾病，不同人群中的患病率有所不同。我们对ICP潜在机制及人群水平差异的理解仍然有限。本研究深入探究东亚人群中ICP的遗传病因，并与欧洲人进行比较，以在遗传背景和进化的背景下理解ICP病因。
我们对98,269例中国孕妇的空腹总血清胆汁酸（TBA）和ICP进行了迄今为止最大规模的全基因组关联研究。研究结果在三个队列中进行了重复验证，并与欧洲人群进行了比较。此外，还采用了全表型组关联和时空进化分析来研究ICP相关基因座的功能和进化模式。
我们确定了8个空腹TBA相关基因座和4个ICP相关基因座，其中包括10个新基因座。值得注意的是，我们在14q24.1的一个0.4 Mbp区域内发现了一个东亚特异性基因座，每个风险等位基因使空腹TBA增加6.12 μmol/L，使ICP风险增加16.56倍（95% CI 16.43至16.69，p = 7.06×10）。全表型组关联和时空进化分析表明，这个14q24.1 ICP风险基因座赋予了对乙型肝炎的抵抗力，并且在过去3000年内在东亚和东南亚地区变得普遍。
我们发现了东亚人群中ICP独特的遗传病因，可能与过去3000年内在东亚和东南亚地区发生的历史性乙肝疫情有关。这些发现加深了我们对ICP病理生理学的理解，并为该疾病更精确的检测、评估和治疗提供了可能。
本研究为东亚人群中妊娠期肝内胆汁淤积症（ICP）的遗传基础提供了新的见解，此前该领域了解甚少。与空腹总血清胆汁酸和ICP均相关的东亚特异性14q24.1基因座的鉴定及其与历史性乙肝疫情的联系，强调了将特定人群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至关重要，能够实现对ICP更准确的筛查、风险评估和针对性干预。
