A Mendelian Randomization Study Provides Evidence that Adiposity and Dyslipidemia Lead to Lower Urinary Albumin Creatinine Ratio, a Marker of Microvascular Function.

Urinary albumin-creatinine ratio is a marker of diabetic nephropathy and microvascular damage. Metabolic-related traits are observationally associated with ACR but their causal role is uncertain. Here, we confirmed ACR as a marker of microvascular damage and tested whether metabolic-related traits have causal relationships with ACR.The association between ACR and microvascular function (responses to acetylcholine and sodium nitroprusside) were tested in the SUMMIT study. Two sample Mendelian randomization (MR) was used to infer the causal effects of eleven metabolic risk factors, including glycemic, lipid and adiposity traits on ACR. MR was performed in up to 440,000 UK Biobank and 54,451 CKDGen participants.ACR was robustly associated with microvascular function measures in SUMMIT. Using MR we inferred that higher triglyceride and LDL-cholesterol levels caused elevated ACR. A one standard deviation (SD) higher triglyceride and LDL-C level caused a 0.062 [95%CI: 0.040, 0.083] and a 0.026 [95%CI: 0.008, 0.044] SD higher ACR respectively. There was evidence that higher body fat and visceral body fat distribution caused elevated ACR, whilst a metabolically "favourable adiposity" phenotype lowered ACR.ACR is a valid marker for microvascular function. MR suggested that 7 traits have causal effects on ACR, highlighting the role of adiposity related traits in causing lower microvascular function.