Leveraging data from a genome-wide association study of 344,182 individuals in the UK Biobank, we identified a missense variant in the SLC5A1 gene that associated with glycated haemoglobin (HbA1c) to proxy SGLT1i. Outcome genetic data comprised 13,179 gout cases and 750,634 controls, 457,690 individuals for serum urate levels, and up to 977,323 individuals for cardiovascular safety outcomes. We applied the Wald ratio method and investigated potential genetic confounding using colocalization.
The rs17683430 missense variant was selected to instrument SGLT1i. Genetically proxied SGLT1i was associated with 75% reduction in gout risk (OR 0.25; 95%CI 0.06, 0.99; p = 0.048) and 32.0 μmol/L reduction in serum urate (95%CI -56.7, -7.3; p = 0.01), per 6.7 mmol/mol reduction in HbA1c. SGLT1i was associated with increased levels of low-density lipoprotein cholesterol (0.37 mmol/L; 95%CI 0.17, 0.56; p = 0.0002) but not risk of coronary heart disease, stroke, or chronic kidney disease. Colocalization did not suggest that results are attributable to genetic confounding.
SGLT1 inhibition may represent a novel therapeutic option for preventing gout in people with or without comorbid diabetes. Randomised trials are needed to formally investigate efficacy and safety.
利用来自英国生物银行344,182个人的全基因组关联研究的数据,我们在SLC5A1基因中发现了一个与糖化血红蛋白(HbA1c)相关的错义变异,以替代SGLT1i.结果遗传数据包括13,179例痛风病例和750,634例对照,457,690人的血清尿酸水平,以及多达977,323人的心血管安全结果。我们应用了Wald比率方法,并使用共定位研究了潜在的遗传混杂因素。
选择rs17683430错义变体来检测SGLT1i。遗传代理SGLT1i与痛风风险降低75%(OR0.25;95CI0.06,0.99;p=0.048)和血清尿酸降低32.0μmol/L(95CI-56.7,-7.3;p=0.01)相关,每6.7mmol/molHbA1c降低。SGLT1i与低密度脂蛋白胆固醇水平升高(0.37mmol/L;95CI0.17,0.56;p=0.0002)相关,但与冠心病风险无关。中风,或慢性肾病.共同定位并不表明结果归因于遗传混杂。
SGLT1抑制可能是预防糖尿病合并或不合并糖尿病患者痛风的一种新的治疗选择。需要随机试验来正式研究疗效和安全性。