Jinwala Zeal, Davis Christal N, SooHoo Jackson F, Gelernter Joel, Kember Rachel L, Vickers-Smith Rachel, Kranzler Henry R
Mental Illness Research, Education and Clinical Center, Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA.
Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
medRxiv. 2025 Jul 24:2025.07.23.25331996. doi: 10.1101/2025.07.23.25331996.
Opioid analgesics are commonly prescribed to manage acute postoperative pain. However, individuals vary in their opioid dosing needs, with no validated biomarkers to guide prescribing. We used electronic health records data from the Million Veteran Program sample to investigate individual differences in opioid analgesic dosing following knee (n=18,540) or hip (n=9,363) arthroplasty in a predominantly male (93%) veteran sample. We extracted data from pharmacy records on inpatient opioid medications dispensed to estimate each patient's average daily morphine milligram equivalent (MME) doses. We used genome-wide association studies (GWAS) stratified by arthroplasty type (i.e., knee or hip) and genetically inferred ancestry group (i.e., European-like (EUR), African-like (AFR), and Admixed American-like (AMR) to identify genetic variants associated with daily MME doses. Within-ancestry summary statistics from the knee and hip arthroplasty GWAS were meta-analyzed, followed by a cross-ancestry GWAS meta-analysis. We identified two genome-wide significant loci in the AFR hip arthroplasty GWAS and three in the AMR GWAS, through no variants were genome-wide significant in the cross-ancestry meta-analysis. Genes mapped to these loci were implicated in a wide range of biological functions, including T-cell activation, chromatin organization and epigenetic regulation, epidermal differentiation and cell adhesion, and cell growth and organ development. Tissue enrichment analysis revealed significant enrichment in brain tissue from early infancy developmental stage. This study provides a proof-of-concept framework for the use of electronic health records data to examine the genetics of opioid dosing in the management of post-operative pain.
阿片类镇痛药常用于控制术后急性疼痛。然而，个体对阿片类药物的剂量需求各不相同，且尚无经过验证的生物标志物来指导用药。我们使用了来自百万退伍军人计划样本的电子健康记录数据，在一个以男性为主（93%）的退伍军人样本中，研究膝关节置换术（n = 18,540）或髋关节置换术（n = 9,363）后阿片类镇痛药剂量的个体差异。我们从药房记录中提取了住院期间发放的阿片类药物数据，以估计每位患者的平均每日吗啡毫克当量（MME）剂量。我们使用了按关节置换类型（即膝关节或髋关节）和遗传推断的祖先群体（即欧洲裔（EUR）、非洲裔（AFR）和混血美洲裔（AMR））分层的全基因组关联研究（GWAS），以识别与每日MME剂量相关的基因变异。对膝关节和髋关节置换术GWAS的祖先内汇总统计数据进行了荟萃分析，随后进行了跨祖先GWAS荟萃分析。我们在AFR髋关节置换术GWAS中确定了两个全基因组显著位点，在AMR GWAS中确定了三个，但在跨祖先荟萃分析中没有变异达到全基因组显著水平。映射到这些位点的基因涉及广泛的生物学功能，包括T细胞活化、染色质组织和表观遗传调控、表皮分化和细胞粘附，以及细胞生长和器官发育。组织富集分析显示，在婴儿早期发育阶段的脑组织中有显著富集。本研究为利用电子健康记录数据来研究术后疼痛管理中阿片类药物剂量的遗传学提供了一个概念验证框架。
