Cook-Sather Scott D, Li Jin, Goebel Theodora K, Sussman Emily M, Rehman Mohamed A, Hakonarson Hakon
Department of Anesthesiology and Critical Care, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Pain. 2014 Sep;155(9):1773-1783. doi: 10.1016/j.pain.2014.05.032. Epub 2014 Jun 5.
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 4-18years 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.
候选基因研究揭示了阿片类镇痛反应变异性的有限遗传基础。全基因组关联研究有助于对常见基因变异进行公正的查询，从而能够识别出对药物效应有新的遗传贡献。使用Illumina（美国加利福尼亚州圣地亚哥市Illumina公司）单核苷酸多态性（SNP）阵列，在一个回顾性队列中，对4至18岁未使用过阿片类药物的儿童进行日间手术扁桃体切除术和腺样体切除术后，研究SNP与作为数量性状位点的总吗啡需求量以及术后疼痛之间的关联。在一个独立的重复队列中，使用TaqMan探针检测全基因组关联研究中确定的显著SNP。在617名经过全面表型分析的儿童中，277名具有欧洲白种人（EC）血统的受试者显示，在TAOK3基因座处，吗啡剂量与一系列新的SNP（最显著的是rs795484，P = 1.01×10⁻⁶；rs1277441，P = 2.77×10⁻⁶）之间存在名义上的关联。年龄、体重指数和身体状况作为协变量纳入分析。吗啡需求量平均为132.4μg/kg（标准差40.9）。rs795484（鸟嘌呤[G]>腺嘌呤[A]）的每个次要等位基因使剂量增加17.6μg/kg（95%置信区间[CI] 10.7 - 24.4）。效应方向和幅度在一个由75名EC儿童组成的独立队列中得到重复验证（P < 0.05）。在非裔美国人（AA）（n = 241）中未检测到与吗啡剂量的关联。在EC队列中，术后疼痛评分≥7/10与rs795484（G>A）相关（优势比2.35，95% CI 1.56 - 3.52，P < 0.00005），并且这种关联在AA儿童中也得到了重复验证（优势比1.76，95% CI 1.14 - 2.71，P < 0.01）。编码丝氨酸/苏氨酸蛋白激酶TAO3的TAOK3基因变异与EC血统儿童的吗啡需求量增加以及EC和AA受试者的急性术后疼痛增加有关。
