Analysis of genetic and clinical factors associated with buprenorphine response

Buprenorphine, approved for treating opioid use disorder (OUD), is not equally efficacious for all patients. Candidate gene studies have shown limited success in identifying genetic moderators of buprenorphine treatment response.

We studied 1616 European-ancestry individuals enrolled in the Million Veteran Program, of whom 1609 had an ICD-9/10 code consistent with OUD, a 180-day buprenorphine treatment exposure, and genome-wide genotype data. We conducted a genome-wide association study (GWAS) of buprenorphine treatment response [defined as having no opioid-positive urine drug screens (UDS) following the first prescription]. We also examined correlates of buprenorphine treatment response in multivariable analyses.

Although no variants reached genome-wide significance, 6 loci were nominally significant (p < 1 × 10^-5), four of which were located near previously characterized genes: rs756770 (ADAMTSL2), rs11782370 (SLC25A37), rs7205113 (CRISPLD2), and rs13169373 (LINC01947). A higher maximum daily buprenorphine dosage (aOR = 0.98; 95 %CI: 0.97, 0.995), greater number of UDS (aOR = 0.97; 95 %CI: 0.96, 0.99), and history of hepatitis C (HCV) infection (aOR = 0.71; 95 %CI: 0.57, 0.88) were associated with a reduced odds of buprenorphine response. Older age (aOR: 1.01; 95 %CI: 1.000, 1.02) was associated with increased odds of buprenorphine response.

This study had limited statistical power to detect genetic variants associated with a complex human phenotype like buprenorphine treatment response. Meta-analysis of multiple data sets is needed to ensure adequate statistical power for a GWAS of buprenorphine treatment response. The most robust phenotypic predictor of buprenorphine treatment response was intravenous drug use, a proxy for which was HCV infection.