Identification of sex-specific genetic associations in response to opioid analgesics in a White, non-Hispanic cohort from Southeast Minnesota

Guilherme S Lopes,Suzette J Bielinski,Nicholas B Larson,Liwei Wang,Dana C Cavanaugh,Ye Zhu,Ruoxiang Jiang,Sebastian M Armasu,Ann M Moyer,Jaime L Lopes,Debra J Jacobson,Jennifer L St Sauver

doi:10.1038/s41397-022-00265-9

Guilherme S Lopes, Suzette J Bielinski + Show 10 more

Open Access

https://doi.org/10.1038/s41397-022-00265-9

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Abstract

The study of sex-specific genetic associations with opioid response may improve the understanding of inter-individual variability in pain treatments. We investigated sex-specific associations between genetic variation and opioid response. We identified participants in the RIGHT Study prescribed codeine, tramadol, hydrocodone, and oxycodone between 01/01/2005 and 12/31/2017. Prescriptions were collapsed into codeine/tramadol and hydrocodone/oxycodone. Outcomes included poor pain control and adverse reactions within six weeks after prescription date. We performed gene-level and single-variant association analyses stratified by sex. We included 7169 non-Hispanic white participants and a total of 1940 common and low-frequency variants (MAF > 0.01). Common variants in MACROD2 (rs76026520), CYP1B1 (rs1056837, rs1056836), and CYP2D6 (rs35742686) were associated with outcomes. At the gene level, FAAH, SCN1A, and TYMS had associations for men and women, and NAT2, CYP3A4, CYP1A2, and SLC22A2 had associations for men only. Our findings highlight the importance of considering sex in association studies on opioid response.

Highlights

Opioids are among the most commonly prescribed medications in the United States, with 51 opioid prescriptions per 100 persons filled in 2018 [1]
Genetic association studies have reported over 150 genes associated with chronic pain conditions [5], some of which are implicated in the risk of poor pain control and adverse reactions due to opioid analgesics [8]
Among participants prescribed hydrocodone/oxycodone (n = 6649), one intronic single nucleotide polymorphisms (SNPs) was associated with a decreased risk of poor pain control in the pooled sample

Summary

Introduction

Opioids are among the most commonly prescribed medications in the United States, with 51 opioid prescriptions per 100 persons filled in 2018 [1]. Despite the widespread use of opioids, there are important individual differences in opioid response in terms of pain relief, adverse reactions, and addiction [2,3,4]. Genetic factors have explained about 30–76% of the inter-individual variability in opioid response in animal models [7]. Genetic association studies have reported over 150 genes associated with chronic pain conditions [5], some of which are implicated in the risk of poor pain control and adverse reactions due to opioid analgesics [8]. Genetic variation in CYP2D6 directly affects CYP2D6 enzyme activity [9], which can predict a person’s likelihood to experience poor pain control and adverse reactions [10]. Identifying novel genetic risk factors associated with opioid metabolism may help explain this variability and lead to more optimized treatment regimens

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