Associations between KCNJ6 (GIRK2) gene polymorphisms and pain-related phenotypes

Abstract

Summary Variations in the KCNJ6 gene appear to influence both acute and chronic pain phenotypes. G-protein coupled inwardly rectifying potassium (GIRK) channels are effectors determining degree of analgesia experienced upon opioid receptor activation by endogenous and exogenous opioids. The impact of GIRK-related genetic variation on human pain responses has received little research attention. We used a tag SNP approach to comprehensively examine pain-related effects of KCNJ3 (GIRK1) and KCNJ6 (GIRK2) gene variation. Forty-one KCNJ3 and 69 KCNJ6 tag SNPs were selected, capturing the known variability in each gene. The primary sample included 311 Caucasian patients undergoing total knee arthroplasty in whom post-surgical oral opioid analgesic medication order data were available. Primary sample findings were then replicated in an independent Caucasian sample of 63 healthy pain-free individuals and 75 individuals with chronic low back pain (CLBP) who provided data regarding laboratory acute pain responsiveness (ischemic task) and chronic pain intensity and unpleasantness (CLBP Only). Univariate quantitative trait analyses in the primary sample revealed that 8 KCNJ6 SNPs were significantly associated with the medication order phenotype (p < 0.05); overall effects of the KCNJ6 gene (gene set-based analysis) just failed to reach significance (p=.054). No significant KCNJ3 effects were observed. A continuous GIRK Related Risk Score (GRRS) was derived in the primary sample to summarize each individual's number of KCNJ6 “pain risk” alleles. This GRRS was applied to the replication sample, which revealed significant associations (p<.05) between higher GRRS values and lower acute pain tolerance and higher CLBP intensity and unpleasantness. Results suggest further exploration of the impact of KCNJ6 genetic variation on pain outcomes is warranted.

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

“…In contrast to the adult postoperative study with the combined Ϫ1250G/1032A haplotype (66 ), preterm infants with the Ϫ1250AA genotype who received either morphine or remifentanil needed more time to reach a pain-free state after endotracheal intubation (64 ). In an explorative analysis in 311 adult white patients undergoing total knee arthroplasty, both Ϫ1250GϾA and 1032AϾG were not associated with opioid dose (68 ). Of the 69 SNPs identified and analyzed in this study, significant hits were found with 8 other polymorphisms (rs1543754, rs858035, rs9981629, rs928723, rs2835925, rs2211843, rs1787337, rs2835930).…”

Molecular Pharmacology ofδ-Opioid Receptors

“…Moreover, Kir3 contribution to the clinical response of opioid analgesics has been confirmed in association studies showing that genetic variations of different Kir3 subunits influence opioid dose requirements for pain management (Lötsch et al, 2010;Bruehl et al, 2013). For DOPrs in particular, Kir3 contribution to peripheral (Chung et al, 2014) and spinal analgesia (Marker et al, 2005) has been clearly documented in preclinical models.…”

Association Between KCNJ6 (GIRK2) Gene Polymorphism rs2835859 and Post-operative Analgesia, Pain Sensitivity, and Nicotine Dependence

“…One of these studies was conducted by our group (31), in which we sought to reveal the relationship between single-nucleotide polymorphisms (SNPs) in the KCNJ6 gene that encodes human GIRK2, especially within the exonic and 5′-flanking regions, and individual differences in opioid analgesic sensitivity. Another recent study found an association between KCNJ6 SNPs and pain-related phenotypes, reconfirming that the KCNJ6 gene is a promising target for investigating the genetic factors that contribute to pain and analgesia (29).…”

“…In these studies, the rs2835859 SNP was not investigated. In another recent study, Bruehl et al (29) revealed that eight KCNJ6 SNPs were significantly associated with the pain-related phenotype in Caucasian patients who underwent total knee arthroplasty (TKA) with postsurgical oral opioid analgesic medication (29). However, these SNPs and other SNPs reportedly tagged by these SNPs were not included in our candidate SNPs in the exploratory stage of the present study (Supplementary Table 4).…”