Genetics of hypertension: Implications of single nucleotide polymorphism(s) in African populations and beyond

Avoiding the devastating implications of the soaring global burden of hypertension has become the focus of a great deal of attention recently. Given these implications, significant effort has been paid to understand better the factors leading to this global public health crisis. Across the African continent, the prevalence of hypertension is on the rise, with reported rates as high as 46% in some populations in South Africa.1 This higher than average prevalence of hypertension has been reported across the African diaspora including populations within the United States, the United Kingdom, and the Caribbean.2, 3, 4 Thus, the increased prevalence of hypertension coupled with the enhanced sequelae of the target organ damage associated with an elevated blood pressure in persons of African ancestry calls into question the role that genetics might play in the preponderance of hypertension among African populations.

The genetics governing the phenotypic state, that is, raised blood pressure and hypertension, is fascinating but equally complex and enigmatic with several advances having been made over the last 30 years. On the one hand are rare monogenetic hypertensive syndromes, which at best account for less than 5% of all cases of hypertension. These syndromes frequently demonstrate traditional Mendelian genetics with the inherence of autosomal and X‐linked dominant and recessive traits. Key examples of these inherited secondary causes of hypertension include familial hyperaldosteronism, familial pheochromocytoma, and Bartter and Gitelman syndrome, among others.

On the other hand are the majority of cases of hypertension (frequently labeled primary or essential hypertension), for which no single culpable gene defect can be identified, but genetics still may play an underpinning role.5 In these cases, hypertension is thought to be the culmination of multiple inherited genes across the entire genome, which demonstrate varied levels of expression and interactions. However, teasing out and understanding these complex polygenetic inheritance patterns in essential hypertension is an elusive pursuit.

Through advances in genetics, such as genome‐wide mapping, has come the identification of subtle genetic variations among individuals. Notably, in some instances, clustering of these variations has been seen across populations and might provide insight into the inheritance of common diseases, such as cardiovascular disease, hypertension, and type 2 diabetes mellitus. One mechanism of genetic variation that has emerged is the common phenomenon of single nucleotide polymorphisms (SNPs) whose role in disease continues to be under examination. Single nucleotide polymorphisms are responsible for 90% of human genetic variation; SNP refers to changes (termed polymorphism) in specific nucleotides at fixed portions of the DNA sequence that occur approximately once in every 1000 nucleotide bases6 and are present in all individuals. These SNPs are passed on from generation to generation largely unaltered. Given their preponderance, the large majority of SNPs have no clinical significance, residing in noncoding parts of the genome, but with detailed analysis through population‐based studies, several key SNPs potentially involved in an elevation of blood pressure have emerged. These may both predispose individuals to hypertension and play important roles in how certain antihypertensive drugs, such as those that mediate the renin‐angiotensin‐aldosterone system (RAAS) system, lower blood pressure. However, in spite of our growing knowledge, the application of genetics to predicting persons at risk for hypertension has not lived up to expectations.7

To explore further the role that genetics may play in the development of hypertension, in this edition of the Journal, Yako, Balti, Matsha et al. present a timely and important article titled “Genetic Factors Contributing to Hypertension in African Based Populations: A Systematic Review and Meta‐Analysis,” which seeks to identify clinically significant SNPs in the development of hypertension among African populations. In this comprehensive review composed of 38 studies, the majority of which were case‐controlled trials, a number of SNPs were examined, with a varied impact on blood pressure in select African populations. For example, an initial observation of the article was that the AGT‐TI47M gene, a RAAS gene, was found to be associated with the raised blood pressure in Ghanaian populations but not Algerian populations. Notably the included studies did not feature genome‐wide analysis looking for novel associations but focused on key preestablished SNPs of interest. This limitation could result in the omission of several SNPs whose importance in the development of hypertension in African populations is unknown. Along a similar line is the underrepresentation of multiple African ethnic groups for whom SNPs of unknown significance to hypertension may exist but remain undetermined. This reinforces the notion that the role of SNPs in hypertension may be population specific and ultimately might have limited external validity to heterogenous population groups.

A second component of this work by Yako et al. was to conduct a meta‐analysis designed to determine the impact, if any, of known SNPs thought to be involved in hypertension based on the findings of previous multiple studies in African populations. Three such specific SNPs met criteria for inclusion in the meta‐analysis. These included the rs5186, r699, and rs4340 SNPs of the ACE, AGT, and AGTR1 genes, which have been previously implicated in hypertension. Of these SNPs, the meta‐analysis found that rs5186 showed a significant association with hypertension (OR 1.63 [95% CI, 1.04‐2.54]) for allele contrast and 4.01 [1.17‐13.80)] for homozygous codominant models, but this association was lost when some of the constituent studies were excluded. Meta‐analyses of the rs4340 and rs699 failed to demonstrate significant association with hypertension. Based on these inconsistent findings, the authors concluded that larger and more robust and specific genetic studies were needed to define better the role of SNPs in the development and prevalence of hypertension in African populations.

A key contribution of the paper by Yako and colleagues is that it opens the door for the exploration of likely factors that may have contributed to the failure of the meta‐analysis to show stronger associations of the identified SNPs with hypertension in these African populations. In addition to the reasons identified previously, with meta‐analyses in general, the conclusions drawn are dependent on the studies included. Regrettably, because of a paucity of robust genetic studies in African populationsrelated to hypertension, there is limited ability to perform meta‐analysis of a wide cross‐section of SNPs, mediating several aspects of the pathophysiology of hypertension. This finding could and should be a call to action to the global research and clinical community to plan and implement more robust studies in this critical area.

The ubiquitous nature of SNPs and the extremely high prevalence and heterogeneity of hypertension make it particularly difficult to tease out true associations in not just African but global populations as a whole. However, some links between hypertension and SNPs have been defined through genome‐wide examination in many settings. In Europe for example, the Cohorts for Heart and Aging Genome Epidemiology (CHARGE) consortium, which included almost 30 000 participants of European descent, identified 13 SNPs associated with systolic blood pressure, 20 SNPs associated with diastolic BP, and 10 SNPs associated with hypertension.8 In the United States, smaller studies, such as a recently conducted discovery study of just over 1000 African Americans, highlighted several SNPs near or within genes known to be associated with increased systolic blood pressure.9 Along similar lines, in a Chinese‐based population, 2 SNPs of the gene that codes for renalase, an amino‐acid flavoprotein that regulates blood pressure through catecholamine metabolism, have been shown to confer increased risk of the development of hypertension.10 Similarly, SNPs affecting the coding regions for genes governing renal sodium and potassium handling and calcium channels have been shown to be associated with increased rates of hypertension.9

Another area of interest is the genetic factors influencing the interaction between hypertension and other risk factors for cardiovascular disease. Notably, a genome analysis of 6889 participants of the Framingham Heart Study showed several loci associated with blood pressure, many of which were enhanced by cigarette smoking.11 Similarly, specific SNPs have been shown to be associated with increased susceptibility for cardiovascular disease. In another analysis of the Framingham cohort, several SNPs were associated with increased risk for the development of atherosclerosis.12

Going somewhat further, with potential clinical implications, a number of SNPs have been identified that encode for key receptors targeted by antihypertensive therapy. Namely, the CHANGE consortium identified SNPs that when present alter the likelihood of beta blockers as well as components of the renin‐angiotensin pathway being effective.13 Similar studies have identified SNPs that affect an individual's response to diuretics.14 The clinical implications of the discovery of these SNPs are obvious, as they introduce the possibility of selecting antihypertensive drugs based on the genetic properties, thereby leading to increased likelihood of achieving pharmacologic blood pressure control and ultimately reducing the cardiovascular complications of the hypertensive process.

There is rapidly emerging evidence surrounding the role and use of genetics in general and SNPs specifically in hypertension in specific geographic, racial, and ethnic populations, including the identification of persons at risk for developing hypertension and guidance in the selection of antihypertensive drugs. As is the case for African populations and the results of the study reported in this issue of the Journal, further exploration of the genetic basis of hypertension is essential, as it might provide key answers to solving the emerging global challenge being posed by hypertension.

Skeete J, DiPette DJ. Genetics of hypertension: Implications of single nucleotide polymorphism(s) in African populations and beyond. J Clin Hypertens. 2018;20:496–498. 10.1111/jch.13249