Genetic Association of Albuminuria with Cardiometabolic Disease and Blood Pressure

Abstract

Excretion of albumin in urine, or albuminuria, is associated with the development of multiple cardiovascular and metabolic diseases. However, whether pathways leading to albuminuria are causal for cardiometabolic diseases is unclear. We addressed this question using a Mendelian randomization framework in the UK Biobank, a large population-based cohort. We first performed a genome-wide association study for albuminuria in 382,500 individuals and identified 32 new albuminuria loci. We constructed albuminuria genetic risk scores and tested for association with cardiometabolic diseases. Genetically elevated albuminuria was strongly associated with increased risk of hypertension (1.38 OR; 95% CI, 1.27-1.50 per 1 SD predicted increase in albuminuria, p = 7.01 × 10). We then examined bidirectional associations of albuminuria with blood pressure which suggested that genetically elevated albuminuria led to higher blood pressure (2.16 mmHg systolic blood pressure; 95% CI, 1.51-2.82 per 1 SD predicted increase in albuminuria, p = 1.22 × 10) and that genetically elevated blood pressure led to more albuminuria (0.005 SD; 95% CI 0.004-0.006 per 1 mmHg predicted increase in systolic blood pressure, p = 2.45 × 10). These results support the existence of a feed-forward loop between albuminuria and blood pressure and imply that albuminuria could increase risk of cardiovascular disease through blood pressure. Moreover, they suggest therapies that target albuminuria-increasing processes could have antihypertensive effects that are amplified through inhibition of this feed-forward loop.

Urinary biomarkers and cardiovascular outcomes in the UK Biobank: observational and Mendelian randomization analyses

“…Regarding albumin and blood pressure, our results are consistent with a recent previous study 15 which supported the existence of a bidirectional causal association between albuminuria and blood pressure.…”

“…Our results are consistent with previous literature which reported that high albumin is associated with higher susceptibility to CVD 13 and hypertension. 15 Previous studies have shown inconsistent results between sodium intake and the risk of CVD. The Scottish Heart Study, a population-based longitudinal study of 10,000 people, showed no consistent associations between sodium intake and cardiovascular or all-cause mortality.…”

“…In addition, we highlight a feed-back causal loop between albumin and T2D, and we also replicate the existence of a bidirectional causal association between albuminuria and blood pressure that was reported by a recent MR study. 15 The Potential Causal Role of Urinary Biomarkers in Blood Pressure and Type 2…”

“…11,12 Similarly, in observational epidemiologic studies, high albuminuria is associated with risk for cardiovascular events in individuals with or without diabetes mellitus. 13,14 One recent Mendelian randomization (MR) study 15 supported the existence of a bidirectional causal association between albuminuria and blood pressure, implying that albuminuria could increase risk of cardiovascular disease through blood pressure. There is a lack of prior studies comprehensively examining several urinary biomarkers reflecting different aspects of kidney function and their associations with blood pressure, type 2 diabetes (T2D) and CVD in a large study sample from the general population.…”

Whole genome sequencing analysis of the cardiometabolic proteome

“…We also leveraged summary statistics manually downloaded from recent large association studies for Chronic Kidney Disease 39 , blood lipids 40 , Atrial Fibrillation, Type-II Diabetes, Coronary Artery Disease, estimated glomerular filtration rate 41 , albuminuria 42 , and anthropometric traits 43 . Two proteins, PDL2 and TNFRSF10C, had both cis and trans associations where the trans did not fall in a highly pleiotropic gene.…”