The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

Introduction: Hypertension is a major risk factor for cardiac hypertrophy and heart failure. Genome wide association studies have recently identified single nucleotide polymorphisms in ATP2B1 , the gene encoding the calcium extrusion pump, plasma membrane calcium ATPase (PMCA1), as having a strong association with hypertension risk. Hypothesis: PMCA1 plays an important role in regulation of blood pressure and protection against hypertension and cardiac hypertrophy. Aims: We aim to examine whether there is a functional link between PMCA1 and blood pressure regulation, and the development of hypertension. And to determine the impact this link may have on cardiac structure and function. Methods and Results: To study the role of PMCA1 we generated a global PMCA1 heterozygous knockout mouse (PMCA1 Ht ). PMCA1 Ht mice had 46% to 52% reduction in PMCA1 protein expression compared to the WT, in aorta, heart, kidney and brain. To study the mice under hypertensive stress conditions, 3 month old PMCA1 Ht and wild type (WT) mice were infused via minipump with angiotensin II (1mg/Kg/daily) or water as a control. Upon angiotensin treatment, PMCA1 Ht mice showed a significantly greater increase in systolic (62.24±3.05 mmHg) and diastolic pressure (52.68±4.67 mmHg), in comparison to the WT (33.37±2.91 mmHg and 23.94±4.56 mmHg, respectively), P<0.001, n=12. Moreover, PMCA1 Ht mice showed a significantly greater hypertrophic response as indicated by a greater heart weight to tibia length ratio, cardiomyocyte cell size (410±18.7 μm 2 ), compared to WT mice (340.4±9.8 μm 2 ), and increased expression of B-type natriuretic peptide (BNP), 2.36 ± 0.25 fold change, n =5-6, P< 0.01. Echocardiography showed no significant changes between PMCA1 Ht and WT mice, in heart rate, and in cardiac function, as indicated by fractional shortening and ejection fraction. In addition, PMCA1 Ht mice showed no sign of lung congestion as indicated by lung weight to body weight ratio. Conclusion: ATP2B1 deletion leads to increased blood pressure and cardiac hypertrophy. This provides functional evidence that PMCA1 is involved in blood pressure regulation and protects against the development of hypertension and cardiac hypertrophy.

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What have genome-wide association studies taught us about cGMP and blood pressure regulation?

BMC Pharmacology and Toxicology ◽

10.1186/2050-6511-14-s1-o5 ◽

2013 ◽

Vol 14 (S1) ◽

Author(s):

Christopher Newton-Cheh

Keyword(s):

Blood Pressure ◽

Association Studies ◽

Blood Pressure Regulation ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Pressure Regulation ◽

Genome Wide

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Genetic mechanisms of human hypertension and their implications for blood pressure physiology

Physiological Genomics ◽

10.1152/physiolgenomics.00032.2017 ◽

2017 ◽

Vol 49 (11) ◽

pp. 630-652 ◽

Cited By ~ 13

Author(s):

Eric Seidel ◽

Ute I. Scholl

Keyword(s):

Blood Pressure ◽

Large Scale ◽

Association Studies ◽

Blood Pressure Regulation ◽

Genome Wide Association Studies ◽

Pressure Regulation ◽

Public Health Burden ◽

Sequencing Studies ◽

Hereditary Factors ◽

Genetic Mechanisms

Hypertension, or elevated blood pressure, constitutes a major public health burden that affects more than 1 billion people worldwide and contributes to ~9 million deaths annually. Hereditary factors are thought to contribute to up to 50% of interindividual blood pressure variability. Blood pressure in the general population approximately shows a normal distribution and is thought to be a polygenic trait. In rare cases, early-onset hypertension or hypotension are inherited as Mendelian traits. The identification of the underlying Mendelian genes and variants has contributed to our understanding of the physiology of blood pressure regulation, emphasizing renal salt handling and the renin angiotensin aldosterone system as players in the determination of blood pressure. Genome-wide association studies (GWAS) have revealed more than 100 variants that are associated with blood pressure, typically with small effect sizes, which cumulatively explain ~3.5% of blood pressure trait variability. Several GWAS associations point to a role of the vasculature in the pathogenesis of hypertension. Despite these advances, the majority of the genetic contributors to blood pressure regulation are currently unknown; whether large-scale exome or genome sequencing studies will unravel these factors remains to be determined.

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Hypertension, Kidney, and Transgenics: A Fresh Perspective

Physiological Reviews ◽

10.1152/physrev.00016.2005 ◽

2006 ◽

Vol 86 (2) ◽

pp. 709-746 ◽

Cited By ~ 72

Author(s):

Linda J. Mullins ◽

Matthew A. Bailey ◽

John J. Mullins

Keyword(s):

Blood Pressure ◽

Candidate Genes ◽

Association Studies ◽

Single Gene ◽

Underlying Mechanism ◽

Blood Pressure Regulation ◽

Laboratory Animals ◽

Pressure Regulation ◽

Transgenic Technology ◽

Starting Point

In this review, we outline the application and contribution of transgenic technology to establishing the genetic basis of blood pressure regulation and its dysfunction. Apart from a small number of examples where high blood pressure is the result of single gene mutation, essential hypertension is the sum of interactions between multiple environmental and genetic factors. Candidate genes can be identified by a variety of means including linkage analysis, quantitative trait locus analysis, association studies, and genome-wide scans. To test the validity of candidate genes, it is valuable to model hypertension in laboratory animals. Animal models generated through selective breeding strategies are often complex, and the underlying mechanism of hypertension is not clear. A complementary strategy has been the use of transgenic technology. Here one gene can be selectively, tissue specifically, or developmentally overexpressed, knocked down, or knocked out. Although resulting phenotypes may still be complicated, the underlying genetic perturbation is a starting point for identifying interactions that lead to hypertension. We recognize that the development and maintenance of hypertension may involve many systems including the vascular, cardiac, and central nervous systems. However, given the central role of the kidney in normal and abnormal blood pressure regulation, we intend to limit our review to models with a broadly renal perspective.

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