PDF(Pubmed)
Abstract：
Cohort studies have identified several genetic determinants that could predict the clinical response to allopurinol. However, they have not been commonly used for genome-wide investigations to identify genetic determinants on allopurinol metabolism and concentrations. We conducted a genome-wide association study of a prior cross-sectional investigation of patients from the Montreal Heart Institute Biobank undergoing allopurinol therapy. Four endpoints were investigated, namely plasma concentrations of oxypurinol, the active metabolite of allopurinol, allopurinol, and allopurinol-riboside, as well as allopurinol daily dosing. A total of 439 participants (mean age 69.4 years; 86.4% male) taking allopurinol (mean daily dose 194.5 mg) and who had quantifiable oxypurinol concentrations were included in the genome-wide analyses. Participants presented with multiple comorbidities and received concomitant cardiovascular medications. No association achieved the predefined genome-wide threshold values for any of the endpoints (all p > 5 × 10-8). Our results are consistent with prior findings regarding the difficulty in identifying genetic determinants of drug concentrations or pharmacokinetics of allopurinol and its metabolites, as well as allopurinol daily dosing. Given the size of this genome-wide study, collaborative investigations involving larger and diverse cohorts may be required to further identify pharmacogenomic determinants of allopurinol and measure their clinical relevance to personalize allopurinol therapy.
摘要：
队列研究已经确定了几种可以预测对别嘌呤醇的临床反应的遗传决定因素。然而,它们并不常用于全基因组调查,以确定别嘌醇代谢和浓度的遗传决定因素.我们对来自蒙特利尔心脏研究所生物库接受别嘌呤醇治疗的患者的先前横断面调查进行了全基因组关联研究。调查了四个终点，即血浆中的氧嘌呤醇浓度，别嘌醇的活性代谢产物,别嘌呤醇,和别嘌呤醇核苷，以及每天服用别嘌呤醇。共有439名参与者（平均年龄69.4岁；男性86.4％）服用别嘌呤醇（平均日剂量194.5mg），并且具有可量化的氧嘌呤醇浓度的参与者被纳入全基因组分析。参与者出现多种合并症，并接受合并心血管药物治疗。没有关联达到任何端点的预定义的全基因组阈值(所有p>5×10-8)。我们的结果与先前关于确定别嘌呤醇及其代谢物的药物浓度或药代动力学的遗传决定因素的困难的发现一致。以及每天服用别嘌呤醇。鉴于这项全基因组研究的规模，可能需要涉及更大和不同队列的协作研究，以进一步确定别嘌呤醇的药物基因组决定因素，并测量其与个性化别嘌呤醇治疗的临床相关性。
