Urine biomarkers reflecting kidney function and handling of dietary sodium and potassium are strongly associated with several common diseases including chronic kidney disease, cardiovascular disease, and diabetes mellitus. Knowledge about the genetic determinants of these biomarkers may shed light on pathophysiological mechanisms underlying the development of these diseases. We performed genome-wide association studies of urinary albumin: creatinine ratio (UACR), urinary potassium: creatinine ratio (UK/UCr), urinary sodium: creatinine ratio (UNa/UCr) and urinary sodium: potassium ratio (UNa/UK) in up to 218,450 (discovery) and 109,166 (replication) unrelated individuals of European ancestry from the UK Biobank. Further, we explored genetic correlations, tissue-specific gene expression, and possible genes implicated in the regulation of these biomarkers. After replication, we identified 19 genome-wide significant independent loci associated with UACR, 6 each with UK/UCr and UNa/UCr, and 4 with UNa/UK. In addition to 22 novel associations, we confirmed several established associations, including between the CUBN locus and microalbuminuria. We detected high pairwise genetic correlation across the urinary biomarkers, and between their levels and several physiological measurements. We highlight GIPR, a potential diabetes drug target, as possibly implicated in the genetic control of urinary potassium excretion, and NRBP1, a locus associated with gout, as plausibly involved in sodium and albumin excretion. Overall, we identified 22 novel genome-wide significant associations with urinary biomarkers and confirmed several previously established associations, providing new insights into the genetic basis of these traits and their connection to chronic diseases.
Causal associations of circulating biomarkers with cardiovascular disease
The overall goal of this project is to study the causal roles of the 36 biomarkers currently being assayed in UK Biobank for development of coronary heart disease, stroke and heart failure. Knowledge about causal relations of these 36 biomarkers with cardiovascular outcomes will give important insights regarding the etiological understanding of these diseases and accelerate development of new prevention strategies, including druggable targets. Hence, the proposed research does meet UK Biobank's stated purpose via improving the prevention and treatment of heart disease and stroke.
First, we will study associations of 36 circulating biomarkers representing different biological systems with incidence of coronary heart disease, stroke and heart failure.
Second, by combing data from the UK Biobank gene analyses with the biomarker data, we will perform genetic studies across the whole human genome for all 36 biomarkers to establish common genetic variation associated with respective biomarker.
Third, we will perform so called Mendelian randomization analyses to study whether the biomarkers are causally related to coronary heart disease, stroke and heart failure.
Full cohort (n=502,650).
|Lead investigator:||Prof. Themistocles Assimes|
|Lead institution:||Stanford University|