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 (LASSO), 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 five to six time points, 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 sulfurase, 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 中罕见和常见的遗传变异与对别嘌呤醇反应不足的关联


目的 常见 rs2231142 ABCG2 变体的次要等位基因预测对别嘌呤醇尿酸盐降低治疗的反应不足。我们假设编码尿酸盐转运蛋白和别嘌呤醇-氧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 本研究包括来自评估痛风患者预后的长期别嘌呤醇安全性研究 （LASSO） 的痛风参与者子集，其全基因组被测序 （n = 563）。在 5 到 6 个时间点上，良好反应者在别嘌呤醇 ≤300 mg/d） 上血清尿酸盐 （SU） <0.36 mmol/l] 与差 （SU ≥0.36 mmol/l，尽管别嘌呤醇 >300 mg/d） 反应的比例为 4：1 或 5：1，而不足反应者的良好反应与不良反应之比为 1：4 或 1：5。对别嘌呤醇的依从性由药丸计数确定，对于亚组 （n = 303），由血浆氧嘌呤醇 >20μmol/l 确定。使用序列核关联测试 （SKAT），我们估计了尿酸盐分泌型 （ABCC4、ABCC5、ABCG2、SLC17A1、SLC17A3、SLC22A6、SLC22A8） 和再摄取基因 （SLC2A9、SLC22A11） 和别嘌呤醇-氧嘌呤醇代谢基因 （AOX1、MOCOS、XDH） 中罕见和常见变异的综合影响对别嘌呤醇反应。结果 别嘌呤醇-氧嘌呤醇基因组 （PSKAT-C = 0.019） 和编码钼辅因子硫酸酶的 MOCOS 与别嘌呤醇反应 （PSKAT-C = 0.011） 存在罕见和常见变异的关联。当血浆氧嘌呤醇证实对别嘌呤醇治疗的依从性时，别嘌呤醇对氧嘌呤醇基因组 （PSKAT-C = 0.002） 和 MOCOS （PSKAT-C < 0.001） 中别嘌呤醇反应的遗传关联证据更强。结论 我们为与别嘌呤醇反应相关的 MOCOS 中常见和罕见的遗传变异提供了证据。