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Background: A recently published genome wide association study identified 29 single nucleotide polymorphisms (SNPs) influencing blood pressure (BP). Case-control studies suggest that a genetic risk score (GRS) based on these 29 SNPs affect the risk of cardiovascular disease (CVD), but its role for CVD at population level is unknown. Here, we prospectively evaluate the impact of this polygenetic BP component on CVD morbidity and mortality in a large urban-based middle-aged population., Method: The 29 previously BP associated SNPs were genotyped in the Swedish Malmö Diet and Cancer Study; (n = 27,003 with at least 24 valid SNPs). The number of BP elevating alleles of each SNPs, weighted by their effect size in the discovery studies, was summed into a BP-GRS., Results: Using regression models, we found significant associations of the BP-GRS, cross-sectionally, with BP and hypertension prevalence, prospectively, with incident cardiovascular morbidity and mortality during 14.2 ± 3.2 years of follow-up. After adjustment for traditional cardiovascular risk factors (TRF), including hypertension, the BP-GRS remained significantly associated only with CVDs [in terms of strokes and coronary artery disease; hazard ratio 1.15; 95% confidence interval (CI) 1.06-1.24 comparing the third vs. first tertile; P = 0.003]. Calibration, discrimination and reclassification analyses did not show a meaningful increment in prediction using the BP-GRS in addition to the model encompassing only the TRF., Conclusion: The polygenetic component of BP influences risk of cardiovascular morbidity and mortality. However, the effect size is small and unlikely to be useful for prediction at the population level.

Objectives: We have previously shown that genetic variance in NEDD4L, a regulating protein of a sodium channel in the distal nephron, has been associated with marginally higher blood pressure and enhanced salt sensitivity. Here, we tested if the genetic NEDD4L variation previously associated with salt sensitivity is related to population blood pressure, incidence of cardiovascular disease (CVD) and mortality., Method: We genotyped the rs4149601 A→G and rs2288774 T→C NEDD4L variants in 27,564 participants of the Malmö Diet and Cancer Study. The genotype combination previously shown to be associated with salt sensitivity (rs4149601 GG+rs2288774 CC), which was present in 9.6% of participants, was related to cross sectional blood pressure as well as to CVD incidence and mortality during a median follow-up time of 14 years using Cox regression models., Results: Carriers of the NEDD4L salt sensitivity-associated genotype had (mean ± SEM) higher systolic (142 ± 0.4 vs. 141 ± 0.1 mmHg, P = 0.002) and diastolic (86.0 ± 0.5 vs. 85.6 ± 0.2 mmHg, P = 0.025) blood pressure and multivariate adjusted hazards ratio (95% confidence interval) of CVD 1.13 (1.02-1.25, P = 0.018), coronary events 1.20 (1.06-1.37; P = 0.005) and cardiovascular mortality 1.17 (0.99-1.37; P = 0.055) than noncarriers but there was no significant difference in the incidence of stroke and total mortality., Conclusion: The NEDD4L salt sensitivity-associated genotype was associated with higher blood pressure, which may translate into increased risk for CVD morbidity and mortality. Interestingly, there was no association with stroke suggesting that the association is partially blood pressure independent.