Differential Motif and Transcription Factor Binding Predictions Link to ULK4 Gene Polymorphisms and Associated with Essential Hypertension in Caucasian Females

Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) in the Unc51-like-kinase 4 (ULK4) gene, to be associated with blood pressure. Aims (i) to replicate and validate the previously reported associations between ULK4 gene and hypertension on hypertensive cases and normotensive controls, (ii) to identify in silico the potential functionality of the associated variants. A total of 558 genotyped Caucasian subjects (n=293 cases & n=265 controls) were recruited and clinically characterized at the Hypertension clinic, University of Ottawa Heart Institute and Institute of Cardiology in Warsaw, Poland. A total of 58 ULK4 SNPs were tested. Our study fails to find any significant association between ULK4 gene and hypertension. However, sex-specific categorization of data revealed strong quantitative association between (I) rs3897976 (p=0.0008) and blood potassium in hypertensive females and (ii) rs9818193 (p=0.0005) and urinary sodium in normotensive female. No signification association were found in males. In-silico motif search revealed differential affinity between the common and the rare allele of rs3897976 and Myocyte enhancer factor-2 (Mef2) and Forkhead box protein O1 (FOXO1) and of rs9818193 and Promyelocytic leukemia zinc finger protein (PLZF) and GATA binding protein 5 (GATA5). Our study unveils novel significant associations between blood potassium levels, urinary sodium levels and ULK4 gene in Caucasian females. Future work needs to confirm the functionality of rs3897976 and rs9818193 polymorphisms.