Objectives The minor allele of the common rs2231142 ABCG2 variant predicts inadequate response to allopurinol urate lowering therapy. We hypothesize that additional variants in genes encoding urate transporters and allopurinol-to-oxypurinol metabolic enzymes also predict allopurinol response. Methods This study included a subset of participants with gout from the Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients, whose whole genome was sequenced (n = 563). Good responders had a 4:1 or 5:1 ratio of good (serum urate (SU) <0.36 mmol/l on allopurinol ≤300 mg/day) to poor (SU ≥ 0.36 mmol/l despite allopurinol >300 mg/day) responses over 5–6 timepoints, while inadequate responders had a 1:4 or 1:5 ratio of good to poor responses. Adherence to allopurinol was determined by pill counts, and for a subgroup (n = 303), by plasma oxypurinol >20μmol/l. Using the sequence kernel association test (SKAT) we estimated the combined effect of rare and common variants in urate secretory (ABCC4, ABCC5, ABCG2, SLC17A1, SLC17A3, SLC22A6, SLC22A8) and reuptake genes (SLC2A9, SLC22A11) and in allopurinol-to-oxypurinol metabolic genes (AOX1, MOCOS, XDH) on allopurinol response. Results There was an association of rare and common variants in the allopurinol-to-oxypurinol gene group (PSKAT-C = 0.019), and in MOCOS, encoding molybdenum cofactor sulphurase, with allopurinol response (PSKAT-C = 0.011). Evidence for genetic association with allopurinol response in the allopurinol-to-oxypurinol gene group (PSKAT-C = 0.002) and MOCOS (PSKAT-C < 0.001) was stronger when adherence to allopurinol therapy was confirmed by plasma oxypurinol. Conclusion We provide evidence for common and rare genetic variation in MOCOS associating with allopurinol response.

中文翻译：

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MOCOS 中罕见和常见遗传变异与别嘌呤醇反应不足的关联


目的 常见 rs2231142 ABCG2 变异的次要等位基因预测对别嘌呤醇降尿酸治疗的反应不足。我们假设编码尿酸转运蛋白和别嘌呤醇到羟嘌呤醇代谢酶的基因中的其他变异也可以预测别嘌呤醇反应。方法 本研究纳入了评估痛风患者结局的长期别嘌呤醇安全性研究中的一部分痛风参与者，对他们的全基因组进行了测序（n = 563）。良好反应者的良好（别嘌呤醇 ≤300 mg/天时血清尿酸盐 (SU) <0.36 mmol/l）与较差（尽管别嘌呤醇 >300 mg/天，SU ≥ 0.36 mmol/l）的比例为 4:1 或 5:1天）超过 5-6 个时间点的响应，而响应不足的人的好响应与差响应的比例为 1:4 或 1:5。别嘌呤醇的依从性通过药丸计数来确定，对于亚组（n = 303），通过血浆奥嘌呤醇％3E20μmol/l来确定。使用序列核关联测试（SKAT），我们估计了尿酸盐分泌基因（ABCC4、ABCC5、ABCG2、SLC17A1、SLC17A3、SLC22A6、SLC22A8）和再摄取基因（SLC2A9、SLC22A11）以及别嘌呤醇中罕见和常见变异的综合影响。 -羟基嘌呤醇代谢基因（AOX1、MOCOS、XDH）对别嘌呤醇反应的影响。结果 别嘌呤醇至羟嘌呤醇基因组 (PSKAT-C = 0.019) 以及编码钼辅因子硫酸化酶的 MOCOS 中的罕见和常见变异与别嘌呤醇反应 (PSKAT-C = 0.011) 存在关联。当通过血浆奥嘌呤醇证实对别嘌呤醇治疗的依从性时，别嘌呤醇-奥昔嘌呤醇基因组 (PSKAT-C = 0.002) 和 MOCOS (PSKAT-C < 0.001) 与别嘌呤醇反应的遗传相关性的证据更强。结论 我们为 MOCOS 中常见和罕见的遗传变异与别嘌呤醇反应相关提供了证据。