Genetics of Blood Pressure: New Insights Into a Complex Trait

High blood pressure is a leading modifiable cause of cardiovascular morbidity and mortality worldwide. About 80 million US adults have high blood pressure, and studies indicate that it is highly heritable (about 40%–50%), meaning that of the total phenotypic variation in the trait, genetics are estimated to account for that percentage.^1–5 Despite the high degree of heritability, known genetic variants identified to date explain only a small percentage (~<3%) of the inter individual variation in blood pressure.^1,6,7 Although safe and effective antihypertensive medications have been available for decades, blood pressure control rates remain low, and about 28 million US adults have uncontrolled high blood pressure.⁸ The effectiveness of antihypertensive medication, assessed by the magnitude they lower blood pressure, varies by ancestral group (eg, African, Asian, and European ancestry), which may be related in part to genetic factors that vary in frequency according to historical geographic separations (ie, Europeans, Asians, and Africans living in a relatively isolated manner in unique environments for tens of thousands of years).⁹ There is a need to better understand the genetic and mechanistic pathways underlying blood pressure regulation in order to identify new therapeutic targets for the prevention and treatment of high blood pressure. A recent study in Nature Genetics provides new information on the genetic basis of blood pressure regulation in humans.

WHAT DOES THIS IMPORTANT STUDY SHOW?

Ehret et al¹⁰ used a custom genotyping array that contains nearly 200,000 specific genetic markers for metabolic and cardiovascular traits¹¹ to conduct a genetic association study of systolic and diastolic blood pressure in 342,415 individuals of European ancestry with replication populations of South Asian (n = 20,875), East Asian (n = 9,637), and African ancestry (n = 33,909). A total of 89 separate studies were pooled for this analysis. The blood pressure measurement method and procedure varied among studies. This is important because blood pressure measurement method and technique can affect systolic blood pressure readings by as much as 20 mm Hg.¹² Most studies used the mean of at least 2 measurements using a mercury sphygmomanometer. However, some studies used only one measurement and some used random zero and automated oscillometric devices. The studies included participants both not using and using antihypertensive medications. For those using antihypertensive medication, a correction factor of 15 and 10 mm Hg was added to systolic and diastolic blood pressures, respectively. Because there is substantial variation between out-of-office and in- office blood pressure measurements, it is important to note that no ambulatory blood pressure measurements were used in any of the included studies.¹³

The authors identified 66 genetic loci that met genome-wide significance (P < 5×10⁻⁸), 17 of which had not been previously identified. The variants identified were enriched for cis-acting regulatory elements, especially in vascular endothelial cells. These are noncoding regions of DNA that regulate the transcription of nearby genes. This means that the variants identified may affect gene expression that could alter vascular smooth muscle cell function and contractility, which could lead to phenotypic changes in blood pressure regulation. Mean minor allele frequencies were similar between the 17 new variants and 49 established variants, 0.32 (range, 0.05–0.50) and 0.29 (range, 0.07–0.49), respectively. However, effect sizes for systolic blood pressure were smaller on average for the 17 newly identified variants; range, 0.09 to 0.59 (mean, 0.34) mm Hg compared with the 49 previously known variants; range, 0.07 to 1.13 (mean, 0.5) mm Hg, respectively. Together, the 66 genetic variants explained ~3.5% of the variation in both systolic and diastolic blood pressure and were also associated with target-organ damage in the heart, kidney, eye, and cerebral vessels. The genetic blood pressure risk score created by Ehret et al is a useful tool for assessing the cumulative impact that the identified blood pressure variants have on health outcomes. For each 1–mm Hg higher systolic blood pressure predicted from the genetic risk score composed of the 66 variants, the odds of coronary artery disease and stroke increased by about 4% and 6%, respectively. However, of 6 kidney phenotypes studied (ie, chronic kidney disease, glomerular filtration rate estimated from both creatinine and cystatin levels, serum creatinine level, microalbuminuria, and urinary albumin-creatinine ratio), higher blood pressure predicted from the genetic risk score was only significantly (P < 0.0028) associated with urinary albumin-creatinine ratio. Effect sizes of the identified variants on systolic and diastolic blood pressure were similar in individuals of South Asian, East Asian, and African ancestry, but many variants did not reach genome-wide significance, likely owing to the smaller sample size in these populations. The 66 variants were in genes globally expressed and hence did not show that a single organ (eg, the kidney) or gene has a dominant effect on blood pressure regulation. Because the 17 new variants identified were enriched in regions coding for genes expressed in widely distributed vascular endothelial cells, the results shed new light on the role of noncoding and regulatory variants affecting gene expression of vascular endothelial cells. Taken together, this study points in the direction that no single genetic or organ pathway dominates blood pressure regulation. Rather, it is more likely that a confluence of many genes, tissues, and organs regulate blood pressure.

HOW DOES THIS STUDY COMPARE WITH PRIOR STUDIES?

The analysis by Ehret et al was conducted in one of the largest sample sizes for a genetic association study of blood pressure in individuals of European ancestry. The large sample size allowed for identification of previously undetected variants that have smaller effect sizes on blood pressure. Identifying variants with small effect sizes is important for complex traits such as blood pressure because it is likely affected by many genes and variants, each with relatively small effects that taken together (eg, in a genetic risk score), can explain a substantial amount of the inter individual variation in blood pressure. The analysis by Ehret et al used relatively large replication sample sizes in individuals of East and South Asian and African ancestry. Despite the rigor of this study, more comprehensive investigation of the genome will be needed to continue to improve our understanding of the genetic background of blood pressure regulation. A limitation of the data used by Ehret et al is the difference in blood pressure measurement techniques used across the different studies. These differences, along with the biological variation in blood pressure, may have attenuated the effect of the genetic variants studied. Last, blood pressure is a critical component of human health that is regulated by multiple complex biological systems so that compensation can occur if one system fails. It is likely that genetic variants associated with blood pressure might be single steps in a complex biological system. The association could be masked if the effect of the variant is overcome by activation of a compensatory biological system. This potential phenomenon poses a challenge for studying genetics of blood pressure regulation.

WHAT ARE THE IMPLICATIONS FOR NEPHROLOGISTS?

Hypertension is common and blood pressure control is more challenging in patients with chronic kidney disease.¹⁴ This rigorously conducted very large genetic study of blood pressure confirms that although blood pressure appears to be highly heritable, known genetic variants explain a small amount (<4%) of the inter individual variation in blood pressure. Despite impressive statistical significance, genetic variants are not ready for clinical translation. We need to wait for more comprehensive studies of the genome (eg, exome sequencing and whole-genome sequencing), gene-by-gene and/or gene-by-environment interaction studies, to help explain a larger portion of the heritability of blood pressure. Results of large whole-genome sequencing studies of blood pressure in multiethnic populations are for the first time on the horizon, spearheaded by the National Heart, Lung and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) Program and the National Human Genome Research Institute’s Genome Sequencing Program. In the interim, it remains judicious to focus on modifiable nongenetic factors, including weight loss, physical activity, alcohol reduction, stress, and diet, to prevent the development of hypertension and improve blood pressure control among those with established hypertension in chronic kidney disease. Additionally, continued research is needed to determine whether there are genetic effect modifiers (eg, pharmacogenomics) of established therapies for the treatment of high blood pressure in chronic kidney disease, such as reduced sodium consumption, angiotensin-converting enzyme inhibitor or angiotensin II receptor blockers, and other medications. Finally, high-quality clinic and out-of-clinic blood pressure measurements are critical to optimally manage high blood pressure in chronic kidney disease.