目的:常见rs2231142ABCG2变体的次要等位基因预测对别嘌呤醇降低尿酸治疗的反应不足。我们假设编码尿酸盐转运蛋白和别嘌呤醇至氧嘌呤醇代谢酶的基因中的其他变体也可以预测别嘌呤醇反应。
方法:这项研究纳入了一部分痛风患者的长期别嘌呤醇安全性研究,评估痛风患者的预后。其全基因组测序(n=563)。良好反应者在5-6个时间点的良好(别嘌呤醇≤300mg/天的血清尿酸(SU)<0.36mmol/l)与差(尽管别嘌呤醇>300mg/天,但SU≥0.36mmol/l)的反应比例为4:1或5:1。而应答不足者的好与差的反应比例为1:4或1:5。通过药丸计数确定对别嘌醇的依从性,对于一个子组(n=303),通过血浆氧天青醇>20μmol/l。使用序列内核关联测试(SKAT),我们估计了罕见和常见变体在尿酸分泌(ABCC4,ABCC5,ABCG2,SLC17A1,SLC17A3,SLC22A6,SLC22A8)和再摄取基因(SLC2A9,SLC22A11)中的联合作用。在别嘌醇至氧嘌呤代谢基因(AOX1,MOCOS,XDH)对别嘌醇的响应。
结果:在别嘌呤醇-氧代嘌呤醇基因群(PSKAT-C=0.019)中存在罕见和常见变异的关联,而在MOCOS,编码钼辅因子硫化酶,别嘌醇反应(PSKAT-C=0.011)。当血浆氧嘌呤醇证实对别嘌醇治疗的依从性时,别嘌醇对氧嘌呤醇基因组(PSKAT-C=0.002)和MOCOS(PSKAT-C<0.001)中与别嘌醇反应的遗传关联的证据更强。
结论:我们提供了与别嘌呤醇反应相关的MOCOS中常见和罕见遗传变异的证据。
OBJECTIVE: 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.
CONCLUSIONS: We provide evidence for common and rare genetic variation in MOCOS associating with allopurinol response.