β-Arrestin 2 (ARRB2) Polymorphism is Associated With Adverse Consequences of Chronic Heroin Use

β-arrestin 2 is an intracellular protein recruited during the activation of G-protein-coupled receptors. In preclinical studies, β-arrestin 2 has been implicated in µ-opioid receptor desensitization and internalization and the development of opioid tolerance and dependence. The present study investigated relationships between variants in the gene encoding β-arrestin 2 (ARRB2) and clinically relevant phenotypes among individuals with opioid use disorder (OUD). We hypothesized that ARRB2 variants would be associated with the negative effects of long-term heroin use.

Chronic heroin users (N = 201; n = 103 African American; n = 98 Caucasian) were genotyped for ARRB2 r1045280 (synonymous, also affecting binding motif of transcription factor GTF2IRD1), rs2036657 (3'UTR) and rs3786047 (intron) and assessed for the past-month frequency of use, injection use, and lifetime duration of heroin use, number of heroin quit-attempts, and heroin use-related consequences.

Lifetime heroin-use consequences (especially occupational and health-related) were significantly lower for African American ARRB2 r1045280 C-allele carriers compared with the TT genotype. There was no significant genotype difference in the Caucasian group. ARRB2 rs2036657 was in strong linkage disequilibrium with rs1045280.

These results, consistent with extant data, illustrate a role for ancestry-dependent allelic variation in ARRB2 r1045280 on heroin-use consequences. The ARRB2 r1045280 C-allele played a protective role in African-descent participants.

These first-in-human findings, which should be replicated, provide support for mechanistic investigations of ARRB2 and related intracellular signaling molecules in OUD etiology, treatment, and relapse prevention. (Am J Addict 2021;00:00-00).