Identifying Opioid-Related Pharmacogenomic Variants in High-Risk Hospitalized Infants: A Pilot Study

Abstract

Introduction: Pharmacogenomic (PGx) variants impact the pharmacodynamics and pharmacokinetics of opioids and the brain's reward, cognition, stress, and pain pathways. This study examines the prevalence of PGx variants impacting opioid response among a cohort of high-risk infants. Methods: This retrospective study was conducted at a quaternary children's hospital from 2009-2020. Infants <1y with one or more high-risk condition (congenital heart disease (CHD), medical or surgical necrotizing enterocolitis (NEC), thoracoabdominal surgery, very or extremely low birthweight, hypoxic ischemic encephalopathy, or extracorporeal membrane oxygenation) with exome sequencing were included. Prevalence of opioid-related variants (COMT, DRD2/ANKK1, ABCB1, OPRM1, CYP2B6, CYP2D6) were compared to Ensembl, a database of published genomic cohorts. Results: Overall, 111 high-risk infants were identified (62.2% male, 47.7% Hispanic/Latino, 18.0% premature, and 82.0% CHD). Most underwent surgery (68.2%), with 37.8% undergoing CHD surgery. Overall, 81.1% of infants were homozygous for more than one opioid-related variant(s). Compared to Ensembl, high-risk infants had a significantly higher frequency of homozygosity for ABCB1: rs1045642 (43.6% vs. 18.7%, p<0.001) and rs2032582 (42.7% vs. 15.9%, p<0.001). Conversely, high-risk infants had a lower frequency of homozygosity for COMT: rs4818 (2.7% vs. 10.3%, p<0.001) and OPRM1: rs1799971 (2.7% vs. 7.1%, p<0.001). All infants with surgical NEC (N=5) were homozygous for one or more opioid-related variant. The most common metabolizer phenotypes were intermediate (CYP2B6: 35.5%, CYP2D6: 20.0%) and normal (CYP2B6: 53.9%, CYP2D6: 70.9%). Conclusion: Most high-risk infants carried at least one opioid-related variant, with frequencies that are significantly different from broader genetic cohorts. Larger studies inclusive of intronic PGx variants using ancestrally comparable controls are needed.