The rs10781468 Genetic Polymorphism of the Gαq ( <scp>GNAQ</scp> ) Gene Is Associated With Responsiveness to Opioid Analgesics in Patients With Postoperative and Cancer Pain: An Exploratory Study

BACKGROUND: G protein-coupled receptors, the largest class of cell surface receptors, are ubiquitously expressed throughout the body. Different subtypes of G protein α subunits activate distinct intracellular signaling pathways and mediate opioid analgesic effects. However, the contributions of these Gα subunits remain unclear. We conducted a hypothesis-generating, two-stage candidate gene association study to identify potential genetic loci related to pain processing and opioid analgesia, focusing on genes encoding G protein α subunits. METHODS: To identify candidate single-nucleotide polymorphisms (SNPs) in seven genes encoding G protein α subunits, we analyzed postoperative opioid consumption, pain intensity, and opioid responsiveness in two exploratory cohorts [laparoscopy-assisted colectomy (n = 350) and mandibular plastic surgery (n = 354)]. For identified candidate SNPs, we further evaluated opioid responsiveness in a confirmatory cohort of 89 patients with cancer pain. We also conducted a preliminary sensitivity analysis adjusting for relevant covariates. RESULTS: Two SNPs (rs10781468 in the GNAQ gene and rs308049 in the GNA11 gene) showed significant associations in both exploratory cohorts. Patients with postoperative pain who were homozygous for the minor allele of rs10781468 exhibited higher opioid sensitivity or lower pain severity. In the confirmatory cohort, homozygosity for the major allele of rs10781468 was significantly associated with increased opioid sensitivity for cancer pain management under the dominant model (p = 0.025) and the genotypic model (p = 0.020), whereas rs308049 was not. The observed phenotypes and associated genetic models differed across cohorts, and sensitivity analyses continued to demonstrate some significant associations. CONCLUSIONS: As a hypothesis-generating investigation, we suggest that rs10781468 may serve as a potential candidate marker of responsiveness to opioid analgesics. Our findings should be validated in a large-scale study with a homogeneous pain type in which the opioid administration protocol is controlled to further examine the association observed in this exploratory study.