TY - JOUR
T1 - TAOK3, a novel genome-wide association study locus associated with morphine requirement and postoperative pain in a retrospective pediatric day surgery population
AU - Cook-Sather, Scott D.
AU - Li, Jin
AU - Goebel, Theodora K.
AU - Sussman, Emily M.
AU - Rehman, Mohamed A.
AU - Hakonarson, Hakon
N1 - Funding Information:
We wish to thank the patients and their families for participating in our study. Dr. Jin Li contributed as co-first author in data analysis and manuscript preparation. We thank Lisa Morse, data analyst for the Department of Anesthesiology and Critical Care Medicine, for compiling data from Compurecord (Phillips Medical Systems, Andover, MA, USA.) Carole A. Marcus, MD, Professor of Pediatrics, Department of Pediatrics, Division of Pulmonary Medicine, kindly provided us with access to and interpretation of the Children’s Hospital of Philadelphia Sleep Laboratory database. Research assistants Renata Pellegrino, PhD, and Tiancheng Wang from the Center for Applied Genomics were invaluable for their help in completing the TaqMan assays (Life Technologies, Carlsbad, CA, USA). Finally, we gratefully recognize the help of Professor Gordon Barr, PhD, Associate Professor Lynne G. Maxwell, MD, Clinical Professor Alan Jay Schwartz, MD, and Assistant Professor Paul A. Stricker, MD from the Department of Anesthesiology and Critical Care Medicine for their thoughtful review and suggestions in preparing the manuscript. All acknowledged are staff members at the Children’s Hospital of Philadelphia (Philadelphia, PA, USA.) Funding was provided by the Department of Anesthesiology and Critical Care Medicine through Children’s Anesthesia Associates, Ltd. (Philadelphia, PA, USA) and by The Children’s Hospital of Philadelphia (Philadelphia, PA, USA) through a grant from the Institutional Development Fund to The Center for Applied Genomics.
PY - 2014
Y1 - 2014
N2 - Candidate gene studies have revealed limited genetic bases for opioid analgesic response variability. Genome-wide association studies facilitate impartial queries of common genetic variants, allowing identification of novel genetic contributions to drug effect. Illumina (Illumina Inc, San Diego, CA, USA) single nucleotide polymorphism (SNP) arrays were used to investigate SNP associations with total morphine requirement as a quantitative trait locus and with postoperative pain in a retrospective population of opioid- naïve children ages 4-18 years who had undergone day surgery tonsillectomy and adenoidectomy. In an independent replication cohort, significant genome-wide association studies-identified SNPs were assayed using TaqMan probes. Among 617 comprehensively phenotyped children, the 277 subjects of European Caucasian (EC) ancestry demonstrated nominal association between morphine dose and a series of novel SNPs (top rs795484, P = 1.01 × 10-6 and rs1277441, P = 2.77 × 10-6) at the TAOK3 locus. Age, body mass index, and physical status were included covariates. Morphine requirement averaged 132.4 μg/kg (SD 40.9). Each minor allele at rs795484 (guanine [G] > adenine [A]) contributed +17.6 μg/kg (95% confidence interval [CI] 10.7-24.4) to dose. Effect direction and magnitude were replicated in an independent cohort of 75 EC children (P < 0.05). No association with morphine dose was detected in African Americans (AA) (n = 241). Postoperative pain scores ≥7/10 were associated with rs795484 (G > A) in the EC cohort (odds ratio 2.35, 95% CI 1.56-3.52, P < 0.00005) and this association replicated in AA children (odds ratio 1.76, 95% CI 1.14-2.71, P < 0.01). Variants in TAOK3 encoding the serine/ threonine-protein kinase, TAO3, are associated with increased morphine requirement in children of EC ancestry and with increased acute postoperative pain in both EC and AA subjects.
AB - Candidate gene studies have revealed limited genetic bases for opioid analgesic response variability. Genome-wide association studies facilitate impartial queries of common genetic variants, allowing identification of novel genetic contributions to drug effect. Illumina (Illumina Inc, San Diego, CA, USA) single nucleotide polymorphism (SNP) arrays were used to investigate SNP associations with total morphine requirement as a quantitative trait locus and with postoperative pain in a retrospective population of opioid- naïve children ages 4-18 years who had undergone day surgery tonsillectomy and adenoidectomy. In an independent replication cohort, significant genome-wide association studies-identified SNPs were assayed using TaqMan probes. Among 617 comprehensively phenotyped children, the 277 subjects of European Caucasian (EC) ancestry demonstrated nominal association between morphine dose and a series of novel SNPs (top rs795484, P = 1.01 × 10-6 and rs1277441, P = 2.77 × 10-6) at the TAOK3 locus. Age, body mass index, and physical status were included covariates. Morphine requirement averaged 132.4 μg/kg (SD 40.9). Each minor allele at rs795484 (guanine [G] > adenine [A]) contributed +17.6 μg/kg (95% confidence interval [CI] 10.7-24.4) to dose. Effect direction and magnitude were replicated in an independent cohort of 75 EC children (P < 0.05). No association with morphine dose was detected in African Americans (AA) (n = 241). Postoperative pain scores ≥7/10 were associated with rs795484 (G > A) in the EC cohort (odds ratio 2.35, 95% CI 1.56-3.52, P < 0.00005) and this association replicated in AA children (odds ratio 1.76, 95% CI 1.14-2.71, P < 0.01). Variants in TAOK3 encoding the serine/ threonine-protein kinase, TAO3, are associated with increased morphine requirement in children of EC ancestry and with increased acute postoperative pain in both EC and AA subjects.
KW - Morphine
KW - Pediatric anesthesia
KW - Pharmacogenomics
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U2 - 10.1016/j.pain.2014.05.032
DO - 10.1016/j.pain.2014.05.032
M3 - Article
C2 - 24909733
AN - SCOPUS:84923625451
SN - 0304-3959
VL - 155
SP - 1773
EP - 1783
JO - Pain
JF - Pain
IS - 9
ER -