Back
The tendency for Afro-descendant individuals with hypertension to retain salt and water can lead to low-renin hypertension. Different mutations have been described that give rise to a gain of function of the epithelial sodium channel (ENaC) and eventually Liddle syndrome. Furthermore, functional variant T8590C, located in the CYP4A11 gene which regulates salt and water homeostasis at multiple sites within the kidney, has been associated with hypertension. In order to evaluate these mutations, a prevalence study was conducted.
Adult patients from south-west Colombia diagnosed with hypertension were recruited as volunteers in a primary care centre from Cali, Valle del Cauca. Their serum levels of total renin and aldosterone concentration were measured, and their phenotypes were classified based on their renin and aldosterone levels. The phenotypes were categorized into low renin and aldosterone phenotype, low renin and high aldosterone phenotype, and high renin and aldosterone phenotype. The buffy coat samples for DNA extraction and the associated data from the same individuals diagnosed with hypertension were provided by the Biorrepositorio from Fundación Valle de Lili with the appropriate approval of the IRB Biomedical Research Ethics Committee. The following mutations were genotyped through sanger sequencing: SCNN1B:p.T594M (rs1799979), CYP4A11:p.F434S (rs1126742) and exon 13 of SCNN1G. African ancestry was determined according to the genetic sequence of the mitochondrial DNA D-Loop via sanger sequencing.
79 patients were included in the study (mean age 55 [SD 8], 47% male). The study found a prevalence of 41% of patients with low renin and aldosterone phenotype, 25% with low renin and high aldosterone phenotype, and 34% of patients with high renin and aldosterone phenotype. The patient's sodium intake was found to be 8200 mg/day. The study also found that 39% of patients were taking less than 3 medications despite being formulated with more.
None of the literature reported gene variants associated with hypertensive phenotypes were found. However, the synonym polymorphism rs5723 (Leu649Leu) was present on 45.56% of the patients; from these, 19.44% were homozygous. Even though synonymous variant rs5723 is classified by in silico predictors as benign, it has been significantly associated with office diastolic blood pressure response (Turner et al 2005) (Barbosa et al 2014) and weaker diuresis (Vormfelde et al 2007). Although there was no significant difference between the groups, homozygous vs heterozigous rs5723 showed a 2 g/day higher sodium consumption (9.96 vs 7.89, p value 0.086), and 57% of patients exhibited the Liddle phenotype (57% vs 38%, p value 0.4). Moreover, one patient carried the Thr604Pro variant (rs528262449) in heterozygous state. This variant has only been found in populations from african ancestry according to population databases. Also, in silico tool PolyPhen-2 classifies it as probably damaging.
No mutations associated with hypertension were found. Nonetheless, rs5723, an already reported polymorphism, was present in our study population. Yang et al (2018) reported in their korean cohort a Minor Allele Frecuency (MAF) of 6% for the rs5723 mutation, however we had a MAF of 27.2% in our colombian sample. Previously, Vormfelde et al (2007) described individuals with this synonymous variant as having weaker diuresis, indicating higher activity of Epithelial sodium channel (ENaC). Whether this polymorphism can explain a functional gain of function of ENaC is not known, and further studies must be done to answer this question.