Genetic contributions to alcohol use disorder treatment outcomes: a genome-wide pharmacogenomics study.
Genetic contributions to alcohol use disorder treatment outcomes: a genome-wide pharmacogenomics study.
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DOI：
10.1038/s41386-021-01097-0
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Karpyak VM
中科院分区：
文献类型：
--
作者：
Biernacka JM;Coombes BJ;Batzler A;Ho AM;Geske JR;Frank J;Hodgkinson C;Skime M;Colby C;Zillich L;Pozsonyiova S;Ho MF;Kiefer F;Rietschel M;Weinshilboum R;O'Malley SS;Mann K;Anton R;Goldman D;Karpyak VM
纳洛酮可以帮助减少酒精消耗，而阿坎酸支持禁欲;然而，并非所有酒精使用障碍（AUD）患者都能从这些治疗中获益。在这里，我们提出了第一个全基因组关联研究的AUD治疗结果的基础上，从阿坎酸和纳洛酮的联合收割机和预测研究的数据，和马约诊所CITA研究的阿坎酸。主要分析集中在治疗结果上，不考虑药物干预，随后进行药物分层分析，以确定阿坎酸和纳洛酮反应的治疗特异性药物基因组学预测因子。治疗结局定义为：（1）治疗前3个月内，至复发至任何饮酒的时间（TR）和（2）至复发至重度饮酒的时间（THR;男性每天饮酒≥ 5次，女性每天饮酒≥4次）。在每个数据集内进行分析，然后进行跨研究的荟萃分析（N = 1083名欧洲血统参与者）。在整个样本中，BRE基因的单核苷酸多态性（SNP）与THR相关（最小p = 1.6E−8），而两个基因间SNP与药物特异性结局相关（纳洛酮THR：rs 12749274，p = 3.9E−8;阿坎酸TR：rs77583603，p = 3.1E−9）。在纳洛酮治疗患者的THR（p = 6.1E−8）分析中，TR（p = 7.7E−8）和第二强信号的最高关联信号映射到PTPRD，这是一种先前在人类和动物研究中与成瘾表型有关的基因。留一法多基因风险评分分析显示与TR（p = 3.7E−4）和THR（p = 2.6E−4）显著相关。本研究提供了多基因效应对AUD治疗反应的第一个证据，并确定了与AUD治疗反应的潜在药物特异性效应相关的遗传变异。
Naltrexone can aid in reducing alcohol consumption, while acamprosate supports abstinence; however, not all patients with alcohol use disorder (AUD) benefit from these treatments. Here we present the first genome-wide association study of AUD treatment outcomes based on data from the COMBINE and PREDICT studies of acamprosate and naltrexone, and the Mayo Clinic CITA study of acamprosate. Primary analyses focused on treatment outcomes regardless of pharmacological intervention and were followed by drug-stratified analyses to identify treatment-specific pharmacogenomic predictors of acamprosate and naltrexone response. Treatment outcomes were defined as: (1) time until relapse to any drinking (TR) and (2) time until relapse to heavy drinking (THR; ≥ 5 drinks for men, ≥4 drinks for women in a day), during the first 3 months of treatment. Analyses were performed within each dataset, followed by meta-analysis across the studies (N = 1083 European ancestry participants). Single nucleotide polymorphisms (SNPs) in the BRE gene were associated with THR (min p = 1.6E−8) in the entire sample, while two intergenic SNPs were associated with medication-specific outcomes (naltrexone THR: rs12749274, p = 3.9E−8; acamprosate TR: rs77583603, p = 3.1E−9). The top association signal for TR (p = 7.7E−8) and second strongest signal in the THR (p = 6.1E−8) analysis of naltrexone-treated patients maps to PTPRD, a gene previously implicated in addiction phenotypes in human and animal studies. Leave-one-out polygenic risk score analyses showed significant associations with TR (p = 3.7E−4) and THR (p = 2.6E−4). This study provides the first evidence of a polygenic effect on AUD treatment response, and identifies genetic variants associated with potentially medication-specific effects on AUD treatment response.
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DOI：
10.1136/bmj.m3934
发表时间：
2020-11-25
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Cheng HY;McGuinness LA;Elbers RG;MacArthur GJ;Taylor A;McAleenan A;Dawson S;López-López JA;Higgins JPT;Cowlishaw S;Lingford-Hughes A;Hickman M;Kessler D
通讯作者：
Kessler D
影响因子：
9.2
作者：
Choi, Shing Wan;O'Reilly, Paul F.
通讯作者：
O'Reilly, Paul F.
影响因子：
3.9
作者：
Cox, Jiayi W.;Sherva, Richard M.;Farrer, Lindsay A.
通讯作者：
Farrer, Lindsay A.
影响因子：
11
作者：
Buchwald, Jadwiga;Chenoweth, Meghan J.;Tyndale, Rachel F.
通讯作者：
Tyndale, Rachel F.
影响因子：
2.8
作者：
Kiefer, F.;Witt, S. H.;Mann, K.
通讯作者：
Mann, K.