Mendelian Randomization Analysis Of Uric Acid With Diabetic Vascular Disease In Chinese Patients With Type 2 Diabetes

As the major vascular complications of diabetes,diabetic macrovascular disease and diabetic kidney disease(DKD)have become the leading causes of mortality and disability in type 2 diabetes(T2DM).Among the risk factors for diabetic macrovascular disease and DKD,the role of uric acid is still controversial.To exclude the interferences from those confounding factors and the reverse causation,we aimed to confirm whether there is a causal relationship of uric acid with diabetic macrovascular disease and DKD through Mendelian randomization analysis.Firstly,we recruited 3,207 T2 DM patients,selected seventeen uric acid related SNPs(single nucleotide polymorphism),built uric acid related weighted genetic risk score(GRS)using selected SNPs and the strength of their effects on uric acid levels.As shown in this part,the weighted GRS was positively correlated with uric acid in total population,male patients and female patients(β = 0.203,p < 0.0001;β = 0.255,p < 0.0001;β = 0.142,p < 0.0001,respectively).Uric acid was significantly associated with diabetic macrovascular disease in the total population and females(OR = 1.068,95% CI = 1.005-1.136,p = 0.0349;OR = 1.122,95% CI = 1.022-1.231,p = 0.0158).The weighted GRS was significantly associated with diabetic macrovascular disease in female patients(OR = 1.184,95% CI = 1.056-1.327,p = 0.0039),and there were no significant difference between the observed association and the predicted association(OR = 1.016,95% CI = 0.906-1.140).Therefore,using the uric acid-related weighted GRS as an instrumental variable for Mendelian randomization analysis,our study provided an evidence for causal relationship between uric acid and diabetic macrovascular disease in Chinese females with T2 DM.Secondly,we recruited 2,749 T2 DM patients and built uric acid related weighted GRS,evaluated the associations between weighted GRS,uric acid and DKD.As shown in the result,in total population,male patients and female patients,uric acid was significantly associated with DKD(OR = 1.396,95% CI = 1.307-1.491,p = 2.60E-23;OR = 1.377,95% CI = 1.255-1.511,p = 1.50E-11;OR = 1.406,95% CI = 1.279-1.544,p = 1.30E-12),the weighted GRS was positively correlated with uric acid(β = 0.083 ± 0.027,p = 0.0018;β = 0.059 ± 0.041,p = 0.1540;β = 0.108 ± 0.034,p = 0.0015).However,there was no significant association between weighted GRS and DKD in any group.Therefore,our study found no evidence for causal relationship between uric acid and DKD in Chinese T2 DM patients.In summary,using the uric acid-related weighted GRS as an instrumental variable for Mendelian randomization analysis,our study confirmed the casual relationship of uric acid with diabetic macrovascular disease in Chinese females with T2 DM mellitus,however,no causal relationship between uric acid and DKD was certified by Mendelian randomization analysis in the present study.