Pain versus analgesia: TAOK3 as a pharmacogene

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We read with interest the recent work of Matic et al.8 investigating single nucleotide polymorphisms in select candidate genes for experimental pain, and were grateful for their inclusion and study of rs795484 within TAOK3. Using genome-wide association study (GWAS) methodology, we had previously shown this and other supporting SNPs at the TAOK3 locus to be associated with perioperative morphine requirement and postoperative pain in a healthy pediatric day surgery population.4 However, the rs795484 variant did not associate with cold and heat pain thresholds studied by Matic et al. Why might this be?
Were TAOK3 a “pain gene,” we might have anticipated congruent results. This expectation may be oversimplified for such a multifaceted, complex trait as pain, however, TAOK3 could yet be a relevant pain gene but phenotypic, racial, or prior pain and opioid exposure differences between studies may have precluded association replication. Although several experimental pain modalities, especially heat pain sensitivity, may correlate with acute postoperative pain, none entirely equates with the postincisional, postelectrocautery pain, and inflammatory conditions following tonsillectomy and adenoidectomy. Because the genetic contribution to pain response variability critically depends on the pain modality tested,1 lack of association here could well be the consequence of mismatched phenotype. In our study, the TAOK3 rs795484 minor allele was primarily associated with increased morphine dose requirement in children of European Caucasian (EC) ancestry, although it was disproportionately represented in children of either EC or African American ancestry who had high maximum postoperative pain scores. Although the Dutch study cohort was likely of EC-predominant ancestry, subject race was not recorded, such that underlying population stratification may have prevented association signals from appearing. Potential further evidence of the influence of race in the findings of Matic et al. was the strong association with rs1799971 minor allele variant (G) at OPRM1 and decreased thermal pain sensitivity, demonstrating opposite effect direction when compared with results in a recent meta-analysis heavily weighted with subjects of Asian descent.5 Finally, compared with our opioid-naive cohort, 59% of subjects in the Dutch study had extensive opioid exposure before testing and although their subpopulation analyses did not reveal response heterogeneity, the possibility of confounding experiential pain history and persistent alteration of pain pathways remains.
We believe the most likely explanation for the differences between the study findings is that TAOK3 functions not as a “pain gene,” but rather as an “analgesic gene,” more generally a pharmacogene. Although we were unable to prove this in our original study, there are several lines of evidence consistent with this theory. In that first study, the strongest GWAS signal had been for morphine dose as a quantitative trait (analgesia required to bring pain to a level suitable for hospital discharge) as opposed to an association signal for high pain phenotype. Importantly, there was no interaction between SNP genotype and maximum pain. For oral methadone, our collaborative group recently demonstrated that maintenance dose requirement was increased in opioid-dependent adults with a genetic scoring panel that included the rs795484 minor variant.9
From a mechanistic standpoint, TAO3, the serine/threonine kinase TAOK3 gene product, may phosphorylate and modify function of several key proteins in drug-induced analgesia pathways. We previously posited that TAO3 variants conferring analgesic resistance could alter mu opioid receptor (MOR) and/or beta arrestin phosphorylation patterns, changing signal transduction following morphine–mu opioid receptor binding. In a related paradigm, homologous murine Taok3Gt heterozygotes are more resistant to the acute sedative effects of ethanol,6 raising the possibility that TAO3 variants could also alter ethanol-induced analgesia.
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