There is considerable evidence supporting the presence of a modest genetic contribution to the common essential hypertension which poses the significant public health problem as described above. Studies of blood pressure in twins and familial aggregation of blood pressure indicate a heritable component to non-Mendelian hypertension. Hypertension is about twice as common in individuals who have one or two hypertensive parents, and blood pressure is more closely correlated in identical (monozygotic) than non-identical (dizygotic) twins [
26,
27]. In the Montreal Adoption Study investigators compared blood pressure correlation between biological sibling pairs and adoptive sibling pairs (as well as parent-child correlations). Systolic BP (SBP) correlation coefficients were 0.38 and 0.16 for biological and adopted siblings respectively, and Diastolic BP (DBP) coefficients were 0.53 compared with 0.29 respectively [
28]. Genome-wide linkage approach with microsatellites has shown evidence for existence of several chromosomal regions that are linked to BP or essential hypertension on almost all chromosomes [
29,
30]. However linkage mapping has been difficult because of the polygenic nature of hypertension, possibly involving multiple pleiotropic variants of low penetrance, epistasis, ethnic diversity of human populations, phenotypic heterogeneity and the inability to control for environmental factors. In addition, linkage analysis has poor power for detecting common alleles that have low penetrance. All these factors hinder the replication of results and decrease the likelihood of success of linkage studies in general. The Medical Research Council funded British Genetics of Hypertension (MRC BRIGHT) study, [
31] demonstrated a successful attempt at reducing heterogeneity by using antihypertensive drug response to partition different pathways of hypertension [
32]. In the BRIGHT population, hypertensive sib-pairs who were non-responsive to ACE inhibitors, ARBs or beta-blockers showed significant linkage on chromosome 2p (LOD = 4.84 at 90.68 Kosambi cM). This susceptibility locus co-localises to a region found in African-American hypertensive patients in the Family Blood Pressure Program, who showed evidence of linkage with hypertension status at 93 cM with a LOD score of 2.84 [
33]. Thus the chromosomal 2p locus independently identified in different populations may contain a gene or genes for the salt-sensitive form of hypertension which is common among Africans, and the same mechanism may be operative in a subset of white European hypertensive patients identified by unresponsiveness to beta blockers and ACE inhibitors. However, this study needs to be replicated and the underlying causative gene identified before translation.
There are numerous small candidate gene association studies that have tried to determine if common polymorphisms in genes can predict response to antihypertensive agents. The candidate gene association study approach involves the selection of candidate genes based on a mechanistic understanding of the roles of the encoded proteins in blood pressure regulation, or drug target. However this will, at best, identify only a fraction of genetic risk loci even if the pathway is relatively well understood. Candidate genes studied fall into the following categories—the Renin-Angiotensin-Aldosterone-System, adrenergic system and genes involved in sodium transport in the kidneys. None of the candidate gene studies have so far shown reproducible associations. Some of the limitations of the candidate gene approach are as follows: first, the choice of candidate genes may be inappropriate. Second, the causative genes might be either upstream of the points of action or in the downstream signalling pathways of the selected candidates. Third, the SNPs selected for association studies may provide incomplete coverage of all the variants within the genes studied. Fourth, most studies are underpowered and problems due to population stratification, phenotypic and locus heterogeneity. Finally, candidate gene studies rely on prior hypotheses about disease mechanisms, so that discovery of genetic variants in previously unknown pathways is precluded [
34]. The most convincing candidate gene study is the
ACE I/D polymorphism in the pharmacogenetic substudy of ALLHAT, called GenHAT. This study tested the association of various outcomes in ALLHAT with the I/D polymorphism in 37,939 patients. No association was found between this polymorphism and BP lowering (with lisinopril or any other study drugs) nor with any of the study outcomes, either when considered in combination or stratified by drug therapy [
35]. Similarly in the large INVEST study, no genetic association was found between
AGTR1 1166A→C genotype and BP response [
36]. In an association study of 585 subjects, between diuretic response and genes in renal sodium transport systems, polymorphisms in
WNK1,
ADRB2, and the epithelial sodium channel-subunit gene (
SCNN1G) predicted interindividual differences in antihypertensive responses to hydrochlorothiazide [
37]. The association between BP lowering with beta-blockers and genetic polymorphisms in the beta1-adrenergic receptor gene (
ADRB1)- Ser49Gly and Arg389Gly, suggest greater BP lowering in the Arg389Arg individuals. The commonly studied is the Arg389Gly polymorphism, for which many, but not all, studies show a significant association with antihypertensive response to beta-blockers and two independent studies have suggested an association between treatment related hypertensive outcomes and ADRB1 SNPs [
38,
39,
40]. There is some evidence that the Ser49Gly polymorphism alone does not importantly influence BP response, but when considered in combination with the Arg389Gly polymorphism, it may be more informative than Arg389Gly alone [
41,
42]. The Gly460Trp polymorphism of the alpha Adducin (
ADD1) gene is another extensively studied candidate gene and one study showed differential outcomes (myocardial infarction or stroke) with thiazide treatment based on the Gly460Trp genotype [
43]. But, subsequent outcomes-based analyses from controlled clinical trials did not replicate this finding [
44,
45]. However,
ADD1 gene remains an interesting candidate and recently
ADD1 considered together with
NEDD4L revealed a significant association with BP response to a thiazide, while neither gene alone showed such an association [
46]. In addition to epistasis, interactions among the three adducin subunits as well as tissue-specific splicing isoforms need to be considered for a more thorough dissection of adducin and its role in antihypertensive response [
47]. This supports the polygenic nature of antihypertensive response and highlights the challenges to dissect this trait. Another potential candidate gene is
KCNMB1, for which SNPs have been associated with BP response in three independent populations, and treatment-related outcomes in one [
48,
49].