High blood pressure is a major risk factor for cardiovascular diseases. Genome-wide
association studies have identified single-nucleotide polymorphisms (SNPs) in the
Unc51-like-kinase 4 (ULK4) gene, to be associated with blood pressure. The present
study aims to replicate and validate the previously reported associations between
ULK4 gene and hypertension on a sample of precisely defined early onset hypertensive
cases and normotensive controls.
METHODS AND RESULTS
The association was evaluated in 558 genotyped Caucasian subjects (n=293cases and
n=265 controls) recruited and clinically characterized at the Hypertension clinic
at the University of Ottawa Heart Institute, and the Institute of Cardiology in Warsaw,
Poland. Blood pressure was measured by 24hr ambulatory blood pressure monitoring.
A total of 58 SNPs were tested in association with hypertension. Strategic categorization
of data revealed a strong quantitative association between (i) rs3897976 (p= 0.0008,)
and blood potassium in female (cases) and pooled data (case and controls), (ii) rs4016425(p=
0.0001) and Urinary creatinine in Caucasian females. Whereas, a protective effect
against urinary sodium and rs9818193 (0.0005) was seen in female (controls), Urinary
Potassium and rs11129908 (p= 0.0001), rs1691974 (p= 0.0003), rs6780145(p= 0.0003),
rs1795348(p= 0.0003), rs2029254 (p=0.0004), rs9818193 (p= 0.0008), rs9876441(p=0.0008),
rs12638414 (p=0.0008), rs6599155(p= 0.0009), rs9841301(p=0.0012) in normotensives.
All the associations remained significant on the application of stringent multiple
Our study unveils significant associations between blood potassium, urinary creatinine,
urinary sodium, urine potassium and ULK4 gene. To the best of our knowledge these
associations have not been reported previously. The significant associations found
for urinary creatinine and blood potassium in hypertensive females in this study,
may represent a genetic predisposition towards the risk of developing kidney or muscle
diseases later in their life. On the other hand, a strong protective effect against
urinary sodium and urinary potassium seems to protect and lower the risk of developing
cardiovascular and kidney diseases in normotensives and normotensive females. The
future work needs to identify the functionality of these SNPs to confirm their role
in blood pressure regulation.