Our data suggest that SGK-1 risk carriers are at increased risk of hypertension and are more sensitive to the blood pressure elevating effects associated with hyperinsulinemia.

ObjectiveNeuronal precursor cell expressed developmentally down-regulated 4-like (NEDD4L) is a regulator of the amiloride-sensitive epithelial sodium channel (ENaC), thus a candidate gene for salt sensitivity. Carriers of an intact NEDD4L C2-domain, encoded by the NEDD4L rs4149601 (G/A) GG genotype, together with the C-allele of the NEDD4L rs2288774 (C/T) polymorphism have previously been shown to have increased blood pressure. Our aim was to test if genetic variation in NEDD4L is associated with increased salt sensitivity.Methods39 normotensive subjects were studied. The difference in 24-hour systolic blood pressure after four weeks on 150 mmol/day NaCl intake and four weeks on 50 mmol/day NaCl was defined as salt sensitivity. The rs4149601 and rs2288774 polymorphisms were genotyped using PCR-based techniques.ResultsCarriers of the rs4149601 GG-genotype together with the rs2288774 CC-genotype had significantly higher salt sensitivity (median, IQR) (18.0, 7.5–20.0 mmHg vs 6.0, 0.0–10.0 mmHg, P = 0.007) and lower plasma renin concentration (P-renin) (6.0, 2.0–9.5 mU/L vs 15.0, 9.0–24.0 mU/L, P = 0.005) as compared to non-carriers of these genotypes. In carriers of the rs4149601 GG-genotype together with the rs2288774 CC- or CT-genotype, as compared to non-carriers, salt sensitivity was (8.0, 6.0–18.0 mmHg vs 5.0, 0.0–10.0 mmHg, P = 0.07) and P-renin (9.0, 6.0–16.0 mU/L vs 15.0, 9.0–28.0 mU/L, P = 0.03).ConclusionGenetic NEDD4L variation seems to affect salt sensitivity and P-renin in normotensive subjects, suggesting that genotyping of NEDD4L may be clinically useful in order to identify subjects who benefit from dietary salt restriction in the prevention of hypertension.

Numerous linkage studies have indicated chromosome 18q21-22 as a locus of importance for blood pressure regulation. This locus harbors the neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) gene, which is instrumental for the regulation of the amiloride-sensitive epithelial sodium channel (ENaC). In a linkage study of 16 markers (including two single nucleotide polymorphism markers located within the NEDD4L gene) on chromosome 18 between 70-104 cM and ambulatory blood pressure (ABP), in 118 families, the strongest evidence of linkage was found for 24 h and day-time systolic ABP at the NEDD4L locus (82.25 cM) (P=0.0014). In a large population sample (n=4001), we subsequently showed that a NEDD4L gene variant (rs4149601), which by alternative splicing leads to varying expression of a functionally crucial C2 domain, was associated with diastolic blood pressure (DBP) (P=0.03) and DBP progression over time (P=0.04). A genotype combination of the rs4149601 and an intronic NEDD4L marker (rs2288774) was associated with systolic blood pressure (SBP) (P=0.01), DBP (P=0.04), and progression of both SBP (P=0.03) and DBP (P=0.05) over time. A quantitative transmission disequilibrium test in the family material of the rs4149601 supported this NEDD4L variant as being at least partially causative of the linkage result. In conclusion, our findings suggest that the chromosome 18 linkage peak at 82.25 cM is explained by genetic NEDD4L variation affecting cross-sectional and longitudinal blood pressure, possibly as a consequence of altered NEDD4L interaction with ENaC.

Lowering of salt intake with 100 mmol/day induces clinically relevant ABP reductions. Renin and Nt-proANP, measured with individuals on their habitual diet, could be useful biomarkers to identify individuals with the greatest blood pressure-lowering benefit from reduced salt intake.

Abstract-In a genome-wide scan in Scandinavians, we found suggestive linkage between early-onset primary hypertension and a region on chromosome 2. The ␣ 2B -adrenoceptor gene, a candidate gene within this region, harbors a functional insertion/deletion (I/D) polymorphism of three glutamate residues. The aim of this study was to investigate if the DD genotype is associated with hypertension in Swedes. We performed an association study between the I/D polymorphism of the ␣ 2B -adrenoceptor and hypertension in the Skaraborg population. The material consists of all known patients with primary hypertension in Skara (nϭ772 nondiabetic subjects; nϭ171 normoalbuminuric type 2 diabetic subjects) and 817 population control subjects. We first compared genotype frequencies between patients with early-onset hypertension (aged 50 years or younger at onset) and subjects with normotension (blood pressure Ͻ120/80 mm Hg). Thereafter, the polymorphism was tested for association with hypertension at the population level. When comparing patients with early-onset hypertension and normotensive subjects, the DD versus II genotype was associated with early-onset hypertension when diabetic subjects were excluded from the analysis (ORϭ2.0; 95% CIϭ1.2 to 3.5) or when they were not excluded (ORϭ1.8; 95% CIϭ1.0 to 3.1). At the population level, the DD versus II genotype was weakly associated with nondiabetic hypertension (ORϭ1.4; 95% CIϭ1.0 to 1.8). Our data suggest that carriers of the DD versus II genotype of the ␣ 2B -adrenoceptor are at increased risk for hypertension. The genotypic effect is most evident when comparing groups corresponding to the upper and lower tails of the blood pressure distribution in the population; however, in nondiabetic hypertensive subjects it is weakly detectable even at the population level. Key Words: receptors Ⅲ adrenergic Ⅲ genetics Ⅲ hypertension H uman primary hypertension is likely to be of a complex nature, arising from environmental and genetic factors. A positive family history of hypertension strongly predicts early-onset hypertension, but the predictive value gradually decreases with increasing age at onset of the disease. 1 This suggests that hypertension susceptibility gene variants are more common in patients with early-onset primary hypertension (EOHT) than in patients with late-onset hypertension.To clarify the genetics behind blood pressure variation and the development of primary hypertension, a wide variety of techniques have been developed. Of these, the genome-wide scan method is the only one that can identify regions of the genome that are linked to variation in blood pressure and to primary hypertension independently of available physiological knowledge of blood pressure regulation. We recently published a genome-wide scan for EOHT in Scandinavian families and found suggestive evidence of linkage on chromosome 2 with a 1-LOD decrease interval stretching between Ϸ109 to 121 cM. 2 Interestingly, this locus overlaps with linkage results of several other genome-wide scans for hypertension ...