Genetic Factors and Dietary Salt Intake as Determinants of Blood Pressure and Risk of Primary Hypertension

University dissertation from Medical Faculty, Lund University

Abstract: Blood pressure (BP) and development of hypertension (HT) are determined by both genetic and environmental factors. The specific genetic etiology of these two entities has remained enigmatic despite large efforts. In addition, daily salt intake seems to predispose for certain individuals to develop HT. The aims of the present study were to: (i) reveal where in the genome BP and early onset hypertension (EOHT) susceptibility genes reside by using linkage analysis and meta-analysis of several such studies (study I-II); (ii) investigate the effect on BP or HT of polymorphisms in genes selected either on basis of position derived from study I and II (alpha2B-Adrenergic Receptor gene (ADRA2B)), function (serum and glucocorticoid regulated kinase 1 gene (SGK-1)) or both (Neural precursor cell Expressed Developmentally Down regulated 4 like gene (NEDD4L)) (study III-V); (iii) investigate the role of dietary salt restriction on BP as well as to explore the possibility to predict this BP change by measuring plasma concentrations of renin (P-renin) and N-terminal pro-Atrial Natriuretic Peptide (P-Nt-proANP). Regions on chromosome 2, 3, and 14 revealed loci that are likely to harbor genes of importance for BP regulation and subsequent development of HT (study I-II). The ADRA2B, that resides directly underneath the peak on chromosome 2, contains a functional insertion/deletion (I/D) polymorphism of which the DD-genotype was found to be associated with EOHT and HT (study III). Two polymorphisms in the SGK-1 gene (SGK-1 risk) and two in the NEDD4L gene (NEDD4L risk) were found to be associated with elevations in BP and BP change over time (study IV-V). The SGK-1 risk did also lead to a strengthening of the insulin-diastolic BP correlation (study IV). Finally, we observed that by reducing daily salt intake from 150 to 50 mmol per day BP decreases significantly and this decrease correlated with base-line levels of P-renin and P-Nt-proANP (study VI).These results suggest that: (1) loci on chromosome 2, 3 and 14 could harbor genes of importance for BP regulation or the development of HT; (2) carriers of the DD versus II genotype of the a2B-adrenoceptor are at increased risk of HT; (3) SGK-1 risk carriers and NEDD4L risk carriers are at increased risk of HT and SGK-1 risk carriers are more sensitive to the BP elevating effects associated with hyperinsulinemia; (4) salt restriction from 150 to 50 mmol per day induces significant BP reductions and that P-renin and P-NtproANP, measured with subjects on their habitual diets, could be useful biomarkers to identify individuals benefiting most from reduced salt intake.