title: Associations between KCNJ6 (GIRK2) gene polymorphisms and pain-related phenotypes.
abstract: 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 single nucleotide polymorphism (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 white patients undergoing total knee arthroplasty in whom postsurgical oral opioid analgesic medication order data were available. Primary sample findings were then replicated in an independent white 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 < .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.
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN, USA Center for Human Genetics Research, Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Bruehl
authors.forename: Jerod S
authors.initials: JS
authors.lastname: Denton
authors.forename: Daniel
authors.initials: D
authors.lastname: Lonergan
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Koran
authors.forename: Melissa
authors.initials: M
authors.lastname: Chont
authors.forename: Christopher
authors.initials: C
authors.lastname: Sobey
authors.forename: Shanik
authors.initials: S
authors.lastname: Fernando
authors.forename: William S
authors.initials: WS
authors.lastname: Bush
authors.forename: Puneet
authors.initials: P
authors.lastname: Mishra
authors.forename: Tricia A
authors.initials: TA
authors.lastname: Thornton-Wells
mesh_terms: D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000627:therapeutic use; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C094401:KCNJ6 protein, human
keywords: Chronic pain; GIRK; Genetics; KCNJ3; KCNJ6; Pain; Polymorphism; Postsurgical Pain; Potassium channel