Midregional proadrenomedullin predicts reduced blood pressure and glucose elevation over time despite enhanced progression of obesity markers.

OBJECTIVES: Elevated plasma levels of the vasodilating hormone adrenomedullin (ADM) predict cardiovascular disease and have been associated with hypertension and obesity. We aimed to examine the independent relationship between ADM and the progression of major cardiometabolic risk factors during long-term follow-up. METHODS: We studied midregional pro-ADM (MR-proADM) in fasting plasma in 3298 participants from the population-based Malmö Diet and Cancer Study - Cardiovascular Cohort, re-examined after 17 years of follow-up and related baseline MR-proADM to cardiometabolic risk factors cross-sectionally and longitudinally. RESULTS: At baseline, after full adjustment, each SD increment of MR-proADM was independently related to (beta ±â€Šstandard error, P value) higher SBP (0.956 ±â€Š0.319 mmHg, P = 0.003), BMI (0.912 ±â€Š0.061 kg/m, P = 1.42 × 10), waist (2.28 ±â€Š0.158 cm, P = 8.46 × 10) and fasting blood glucose (0.046 ±â€Š0.018 mmol/l, P = 0.01). After full adjustment, including the baseline level of the risk factor whose degree of progression was studied, each SD increment of MR-proADM predicted significantly reduced progression of SBP (-1.170 ±â€Š0.337 mmHg, P = 0.001) and fasting blood glucose (-0.055 ±â€Š0.023 mmol/l, P = 0.015), but greater increase of BMI (0.101 ±â€Š0.051 kg/m, P = 0.047) and waist (0.600 ±â€Š0.144 cm, P = 3.1 × 10). CONCLUSION: Despite cross-sectional associations with higher levels of blood pressure and glucose, high levels of MR-proADM predict a slower progression of blood pressure and glycemia during long-term follow-up. Conversely, the cross-sectional associations with higher levels of MR-proADM and obesity were paralleled by a faster progression of obesity markers over time. These results may be important for assessment of long-term effects of therapies modulating levels of ADM.

A stop-codon of the phosphodiesterase 11A gene is associated with elevated blood pressure and measures of obesity.

OBJECTIVE: To identify stop-codon variants associated with blood pressure (BP). METHODS: Illumina exome chip was genotyped in 5453 individuals of the population-based Malmö Diet and Cancer Study. We compared BP levels between carriers and noncarriers of all stop-codon variants found in at least 10 individuals and characterized these further based on literature evidence of functionality. Next, the association to ischemic stroke was evaluated in 2278 cases of ischemic stroke and 5969 controls. RESULTS: We identified 19 stop-codon variants with nominally significant BP associations (P < 0.05). One of these, located in the phosphodiesterase 11A (PDE11A) gene (R307X), has previously been reported to cause loss of PDE11A function and Cushing's syndrome in female carriers. In the Malmö Diet and Cancer Study, 1% of the population carried R307X and had age and sex-adjusted (mean, 95% confidence interval) 5.0, 0.29-9.7 (P = 0.038), and 3.3, 0.83-5.7 (P = 0.009) mmHg higher SBP and DBP than noncarriers and also significantly higher waist circumference and BMI. Among females, carriers of the R307X had age adjusted 8.3, 2.3-14 (P = 0.006) and 4.7, 1.7-7.7 (P = 0.002) mmHg higher SBP and DBP, 4.3, 0.84-7.8 (P = 0.015)  cm higher waist circumference and 1.7, 0.30-3.1 (P = 0.018)  kg/m higher BMI. In addition, carriers of the R307X mutation had an odds ratio of ischemic stroke of 1.73 (95% confidence interval 1.06-2.82); P = 0.028. CONCLUSION: One percent of the Swedish population carries a PDE11A loss-of-function mutation associated with elevated BP, abdominal obesity, and risk of ischemic stroke.

Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension.

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.

Cardiovascular consequences of a polygenetic component of blood pressure in an urban-based longitudinal study: the Malmö diet and cancer.

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.