Population genetic testing and SERPINA1 sequencing identifies unidentified alpha-1 antitrypsin deficiency alleles and gene-environment interaction with hepatitis C infection.
Population genetic testing and SERPINA1 sequencing identifies unidentified alpha-1 antitrypsin deficiency alleles and gene-environment interaction with hepatitis C infection.
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DOI：
10.1371/journal.pone.0286469
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
α -1抗胰蛋白酶缺乏症（AATD）是一种相对常见的常染色体隐性遗传疾病，在有症状的个体中诊断不足。我们试图比较AATD杂合子和纯合子丙型肝炎感染相关肝移植的风险，并确定SERPINA1测序是否可以识别未确诊的AATD。我们在一个与电子健康记录（EHR）相关的DNA生物库中进行了一项回顾性队列研究，其中有72,027个个体的SERPINA1基因分型为M、Z和S等位基因。我们按基因型组调查肝移植频率，并与丙型肝炎感染进行比较。我们对接受肝移植的致病性AATD等位基因携带者进行了SERPINA1测序。肝移植与Z等位基因（Z：比值比[OR] = 1.31, p<2e-16; MZ: OR = 1.02, p = 1.2e-13）和丙型肝炎（OR = 1.20, p<2e-16）相关。对于肝移植，基因型与丙型肝炎存在显著的相互作用（ZZ：相互作用OR = 1.23, p = 4.7e-4； MZ：相互作用OR = 1.11, p = 6.9e-13）。测序在133例肝移植且未患丙型肝炎的6例患者中发现了第二种罕见的致病性SERPINA1变异，肝移植在AATD风险等位基因（包括杂合子）患者中更为常见，AATD和丙型肝炎证明了与肝移植相关的基因-环境相互作用。目前的AATD筛查策略可能漏诊，而SERPINA1测序可能提高AATD的诊断率，对肝脏疾病的风险进行分层，并为具有AATD风险等位基因和肝脏疾病危险因素的个体提供临床管理信息。
Alpha-1 antitrypsin deficiency (AATD), a relatively common autosomal recessive genetic disorder, is underdiagnosed in symptomatic individuals. We sought to compare the risk of liver transplantation associated with hepatitis C infection with AATD heterozygotes and homozygotes and determine if SERPINA1 sequencing would identify undiagnosed AATD. We performed a retrospective cohort study in a deidentified Electronic Health Record (EHR)-linked DNA biobank with 72,027 individuals genotyped for the M, Z, and S alleles in SERPINA1. We investigated liver transplantation frequency by genotype group and compared with hepatitis C infection. We performed SERPINA1 sequencing in carriers of pathogenic AATD alleles who underwent liver transplantation. Liver transplantation was associated with the Z allele (ZZ: odds ratio [OR] = 1.31, p<2e-16; MZ: OR = 1.02, p = 1.2e-13) and with hepatitis C (OR = 1.20, p<2e-16). For liver transplantation, there was a significant interaction between genotype and hepatitis C (ZZ: interaction OR = 1.23, p = 4.7e-4; MZ: interaction OR = 1.11, p = 6.9e-13). Sequencing uncovered a second, rare, pathogenic SERPINA1 variant in six of 133 individuals with liver transplants and without hepatitis C. Liver transplantation was more common in individuals with AATD risk alleles (including heterozygotes), and AATD and hepatitis C demonstrated evidence of a gene-environment interaction in relation to liver transplantation. The current AATD screening strategy may miss diagnoses whereas SERPINA1 sequencing may increase diagnostic yield for AATD, stratify risk for liver disease, and inform clinical management for individuals with AATD risk alleles and liver disease risk factors.
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影响因子：
46.9
作者：
通讯作者：
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DOI：
10.1126/science.aal4043
发表时间：
2018-03-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bastarache L;Hughey JJ;Hebbring S;Marlo J;Zhao W;Ho WT;Van Driest SL;McGregor TL;Mosley JD;Wells QS;Temple M;Ramirez AH;Carroll R;Osterman T;Edwards T;Ruderfer D;Velez Edwards DR;Hamid R;Cogan J;Glazer A;Wei WQ;Feng Q;Brilliant M;Zhao ZJ;Cox NJ;Roden DM;Denny JC
通讯作者：
Denny JC
影响因子：
6.8
作者：
Balderacchi, Alice M.;Barzon, Valentina;Ferrarotti, Ilaria
通讯作者：
Ferrarotti, Ilaria
影响因子：
4.6
作者：
Carey, Elizabeth J.;Iyer, Vivek N.;Krowka, Michael J.
通讯作者：
Krowka, Michael J.
影响因子：
25.7
作者：
Malhi, Harmeet;Kaufman, Randal J.
通讯作者：
Kaufman, Randal J.