Department of Medicine, University of Otago, Christchurch, Aotearoa, New Zealand.
Department of Biochemistry, University of Otago, Dunedin, Aotearoa, New Zealand.
Rheumatology (Oxford). 2024 Nov 1;63(11):3025-3032. doi: 10.1093/rheumatology/keae420.
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.
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.
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.
We provide evidence for common and rare genetic variation in MOCOS associating with allopurinol response.
常见的 rs2231142 ABCG2 变异的次要等位基因预测别嘌呤醇降低尿酸治疗的反应不足。我们假设，尿酸转运蛋白和别嘌呤醇转化为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的反应。
这项研究包括来自长期别嘌呤醇安全性研究评估痛风患者结局（LASSO）的痛风患者亚组参与者，他们的全基因组进行了测序（n=563）。良好反应者在 5 至 6 个时间点上具有 4:1 或 5:1 的良好[血清尿酸（SU）<0.36mmol/l ，别嘌呤醇≤300mg/天]与不良[SU≥0.36mmol/l ，尽管别嘌呤醇>300mg/天]反应的比值，而反应不足者具有 1:4 或 1:5 的良好与不良反应的比值。通过药丸计数确定别嘌呤醇的依从性，对于亚组（n=303），通过血浆氧嘌呤醇>20μmol/l 确定。使用序列核关联测试（SKAT），我们估计了尿酸分泌（ABCC4、ABCC5、ABCG2、SLC17A1、SLC17A3、SLC22A6、SLC22A8）和再摄取基因（SLC2A9、SLC22A11）以及别嘌呤醇转化为氧嘌呤醇代谢基因（AOX1、MOCOS、XDH）中稀有和常见变异在别嘌呤醇反应中的综合作用。
别嘌呤醇转化为氧嘌呤醇基因组（PSKAT-C=0.019）和编码钼辅助因子硫代酶的 MOCOS 中稀有和常见变异与别嘌呤醇反应存在关联（PSKAT-C=0.011）。当别嘌呤醇治疗的依从性通过血浆氧嘌呤醇得到证实时，别嘌呤醇转化为氧嘌呤醇基因组（PSKAT-C=0.002）和 MOCOS（PSKAT-C<0.001）中与别嘌呤醇反应相关的遗传关联证据更强。
我们提供了 MOCOS 中常见和罕见遗传变异与别嘌呤醇反应相关的证据。
