Association between KCNJ6 (GIRK2) gene polymorphisms and postoperative analgesic requirements after major abdominal surgery.
- Authors
- Nishizawa, Daisuke; Nagashima, Makoto; Katoh, Ryoji; Satoh, Yasuo; Tagami, Megumi; Kasai, Shinya; Ogai, Yasukazu; Han, Wenhua; Hasegawa, Junko; Shimoyama, Naohito; Sora, Ichiro; Hayashida, Masakazu; Ikeda, Kazutaka
- Year
- 2009
- Journal
- PloS one
- PMID
- 19756153
- DOI
- 10.1371/journal.pone.0007060
- PMCID
- PMC2738941
Opioids are commonly used as effective analgesics for the treatment of acute and chronic pain. However, considerable individual differences have been widely observed in sensitivity to opioid analgesics. We focused on a G-protein-activated inwardly rectifying potassium (GIRK) channel subunit, GIRK2, that is an important molecule in opioid transmission. In our initial polymorphism search, a total of nine single-nucleotide polymorphisms (SNPs) were identified in the whole exon, 5'-flanking, and exon-intron boundary regions of the KCNJ6 gene encoding GIRK2. Among them, G-1250A and A1032G were selected as representative SNPs for further association studies. In an association study of 129 subjects who underwent major open abdominal surgery, the A/A genotype in the A1032G SNP and -1250G/1032A haplotype were significantly associated with increased postoperative analgesic requirements compared with other genotypes and haplotypes. The total dose (mean+/-SEM) of rescue analgesics converted to equivalent oral morphine doses was 20.45+/-9.27 mg, 10.84+/-2.24 mg, and 13.07+/-2.39 mg for the A/A, A/G, and G/G genotypes in the A1032G SNP, respectively. Additionally, KCNJ6 gene expression levels in the 1032A/A subjects were significantly decreased compared with the 1032A/G and 1032G/G subjects in a real-time quantitative PCR analysis using human brain tissues, suggesting that the 1032A/A subjects required more analgesics because of lower KCNJ6 gene expression levels and consequently insufficient analgesic effects. The results indicate that the A1032G SNP and G-1250A/A1032G haplotype could serve as markers that predict increased analgesic requirements. Our findings will provide valuable information for achieving satisfactory pain control and open new avenues for personalized pain treatment.
The position of the SNPs identified in the polymorphism screening for the KCNJ6 gene.The filled box and striped box represent the coding region and untranslated region, respectively. The horizontal arrows indicate the screened regions. The numbers above the boxes and in the exonic SNPs are relative positions from the transcription start site (+1) in the KCNJ6 mRNA, and the number “75167” in the IVS1C75167T SNP is the relative position from the intron 1 start site in the genomic DNA. The underlined SNPs show absolute linkage disequilibrium between one another (D' = 1, r2 = 1).
Association analysis between requirements for rescue analgesics and SNPs.The results for the frequency of analgesic administration (A) and the total dose of analgesics administered per weight (B) during the 24 h postoperative period are shown for the KCNJ6 A1032G SNP. The white, striped, and filled boxes indicate results for male, female, and all subjects, respectively. (A) *: significantly more frequent administration for the A/A genotype compared with the A/G and G/G genotypes in all subjects, †: significantly more frequent administration for the A/A genotype compared with the A/G and G/G genotypes in female subjects. (B) †: significantly greater dose of analgesic administration for the A/A genotype compared with the A/G genotype in female subjects.
Relative KCNJ6 mRNA expression level between each genotype subgroup of the SMRI samples.*: significantly lower expression level between the A/A genotype and combined A/G and G/G genotypes in all subjects.
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