Abstract
Similar to a tsunami wave, a new surge of genome-wide association studies in common complex diseases has succeeded in identifying the causative genetic risk factors of hypertension. The current status of genomic studies in hypertension, however, remains disorganized, and there are no clear solutions in sight. One possible reason for this disorganization is the small effect of each genetic variant on the predisposition to hypertension. Another reason could be that the morbidity of hypertension is typically used as a target to assess genetic contribution, which could be resolved by introducing new technology into the classical genetic analysis. In this review, we reaffirm the genetic basis of hypertension and outline recent progress in genomics. In addition, we discuss both the possibility and usefulness of genomic information in the development of tailored medicine.
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Introduction
In Japan, physicians frequently refer to the guidelines of hypertension in daily clinical practice. The latest version of the guidelines was recently published by the Japanese Society of Hypertension (JSH2009).1 The number of hypertensive patients in Japan was estimated to be ∼40 million. It was also found that a 2 mm Hg decrease in systolic blood pressure (BP) led to a >5% decrease in the occurrence of stroke or ischemic heart disease. Thus, there is no question that the primary goal of hypertension treatment is to prevent cardiovascular disease by achieving a specific BP level. The response to antihypertensive treatment and the grade of targeted organ damage vary significantly among individuals, and the standard therapy described in the guidelines does not always achieve the final goal of treatment. A reason for this diversity is that a large proportion of hypertension cases are essential hypertension, of which the cause is not yet defined. This indicates that the identification of certain causes or predisposing factors for hypertension could lead to the development of more specific and efficient treatments. For example, if physicians could diagnose ‘salt-sensitive hypertension’ accurately, a reduction in the dietary intake of salt and a small dose of diuretics should be prescribed with confidence. In this study, we review publications with regard to the genetic basis of hypertension and discuss the clinical application of the results.
Heritability of BP
Both genetic and environmental factors are involved in the pathogenesis of hypertension. The genetic factors contribute to approximately 30–70% of disease susceptibility. The proportion of hypertensive patients with affected siblings was studied in 6000 Caucasian patients,2 showing a recurrence risk of ∼3.5 for hypertension. The heritability (H2) of systolic and diastolic BP in 6148 Sardinians was estimated to be 0.253 (0.156–0.651) and 0.186 (0.121–0.449), respectively.3 As aging has been found to be the most influential on BP in covariate analysis, the effect of genetic factors should be discussed after adjusting for age.
Previous studies with regard to monogenic hypertension and hypotension showed the importance of rare genetic variations in the electrolyte channels and transporters of renal tubules (Table 1). It is interesting that the same gene, such as the one encoding the β- and γ-subunit of the epithelial sodium channel (SNCC1B/G), contributes to both hypertension (Liddle's syndrome) and hypotension (pseudohypoaldosteronism type 1, or PHA1), depending on the mutation. The importance of rare genetic variations receives significant attention not only in cases of monogenic hypertension/hypotension but also in essential hypertension. In the Framingham Heart Study, rare genetic variations in three genes, solute carrier family 12 member 3(SLC12A3) (thiazide-sensitive Na–Cl co-transporter, TSC), SLC12A1 (NKCC2) and KCNJ1 (ROMK), were found to be associated with lower BP in the general population.4 Thus, rare genetic variations may explain, at least in part, the complex genetics of human hypertension.5 In JSH2009, Table 12-7 lists information regarding rare genetic variations in essential hypertension and includes a list of congenital diseases with BP abnormalities, the name of the causative genes and their clinical features.1
Salt sensitivity and genetic predisposition to hypertension
The most popular approach to identifying hypertensive genes involves genetic association studies, which are population-based and compare cases and controls. The candidate gene approach is a classical but powerful method to examine the predisposing genetic factor of hypertension. Many studies have examined the association between gene variants of the renin–angiotensin system and hypertension. Among these, M235T, T174M and G-6A polymorphisms of the angiotensinogen gene (AGT) have been determined to increase the genetic risk not only for hypertension but also for ischemic heart disease,6 lacunar infarction and non-dipper type of BP variation.7 These results suggest the possibility that a polymorphism in AGT modulates the sensitivity to salt through an enhancement of sympathetic nerve activity or insulin resistance, thereby increasing the risk for ischemic heart disease. Indeed, AGT is considered to be a thrifty gene that has the advantage of surviving in a harsh environment; however, it increases the risk for cardiovascular disease through sodium and body fluid retention. In addition to AGT, the risk allele frequencies of popular candidate gene polymorphisms of salt-sensitive hypertension, such as alpha adducin (ADD1), the G-protein beta-3 subunit gene (GNB3) and the aldosterone synthase gene (cytochrome P450, subfamily Y XIB, polypeptide 2, CYP11B2), are higher in the Japanese population than in Caucasians.8 Hunt et al.9 reported that the effect of salt reduction and weight loss on the prevention of hypertension in pre-hypertensive individuals with the risk allele was much greater than in individuals with the normal allele. Therefore, a reduction in salt or a small dose of diuretics should be an effective approach in the treatment of hypertension in Japanese patients. On the basis of the comparable effectiveness for the treatment of hypertension and the advantage of pharmaco-economics, JSH2009 encourages physicians to use diuretics more frequently.
The thiazide-sensitive Na–Cl co-transporter has an important function in the treatment of hypertension with diuretics. Kokubo et al.10 and our group11 have reported a positive association between the TSC gene (SLC12A3) and a predisposition to hypertension. Matayoshi et al.12 showed that the C1784T polymorphism of SLC12A3 was significantly associated with the antihypertensive effect of diuretics. As a functional single-nucleotide polymorphism (SNP) of SLC12A3, Keszei et al.13 showed the difference in renal tubular sodium transport by an Arg919Cys substitution of SLC12A3, using the Xenopus laevis oocyte expression system. The TSC gene not only indicates a genetic risk for hypertension but is also a causative gene for monogenic hypotensive disease (Gitelman's syndrome)14 (Table 1).
Molecules with similarly important functions in salt homeostasis are WNK kinases (WNK1 and WNK4), which are also causative genes for monogenic hypertension with hyperkalemia (Gordon's syndrome)15 (Table 1). WNK kinases bind and phosphorylate two Ste20-related protein kinases, OSR1 and STK39, which bind and phosphorylate TSC to increase their activity. This results in WNK kinases modulating the electrolyte and water transport pathways in the distal nephron.16, 17 A recent genome-wide association study (GWAS) in Amish and non-Amish Caucasians showed strong association signals with common variants in STK39, a serine/threonine kinase gene. STK39 interacts with WNK kinases and cation-chloride co-transporters, mutations of which cause monogenic forms of BP dysregulation.18 This indicates that TSC, STK39, OSR1 and WNK kinases are key molecules in the pathogenesis of hypertension and are the new targets of treatment for hypertension.
Genetic basis for hypertension
Blockade of the renin–angiotensin system improves not only hypertension but also insulin sensitivity and adipocytokine abnormalities.19 The recent TROPHY trials20 suggested that an early blockade of the renin–angiotensin system prevents the onset of hypertension. High normal BP, obesity and impaired glucose tolerance are independent predictors of the onset of hypertension.21 BP was shown to be significantly associated with lower adiponectin concentrations, regardless of insulin resistance. In individuals with a TC genotype of an I164T polymorphism of the adiponectin gene (ADIPOQ), adiponectin concentrations were one-third the normal level in individuals who had the homozygous wild allele. Moreover, these individuals were highly predisposed to cardiovascular diseases.22
Endothelial dysfunction due to reactive oxygen species (ROS) is also considered to be a cause of hypertension.23 The genetic variants of the endothelial nitric oxide synthase gene (NOS3) have been determined to increase the genetic risk for coronary spasms24 and to increase pulse pressure and senile cognitive dysfunction.25 The C677T polymorphism of the methyleneteterahydrofolate reductase (MTHFR) gene was also found to be significantly correlated with hyperhomocysteinemia and carotid atherosclerosis in Japanese women, and the significance increased when the women smoked.26 Thus, in individuals who are genetically sensitive to ROS, a recommendation to cease smoking and to modify lifestyle, or drug administration to reduce oxidative stress, should be given. Recent pharmacological studies have shown that the combination of pioglitazone and candesartan exerts more beneficial effects on hypertensive cardiovascular damage by increasing the suppression of ROS.27
The modulation of sympathetic nerve activity has a key function in the pathogenesis of cardiovascular diseases. We reported in a 5-year longitudinal study that beta2-adrenergic receptor gene (ADRB2) polymorphisms in association with exaggerated sympathetic nerve activity could predict the future onset of obesity and hypertension.28 Furthermore, higher plasma norepinephrine levels that are associated with β2-adrenoceptor polymorphisms predict future renal damage in non-obese, normotensive individuals.29 Leptin is another unique molecule to be considered as the common denominator between obesity and problems in the sympathetic nervous system. We have also pointed out that leptin-receptor gene (LEPR) polymorphisms have a function in the development of obesity through leptin resistance and blunted leptin-mediated sympathetic nerve activity.30 As the Gly16 allele of ADRB2 polymorphisms is linked to weight gain-induced BP elevation and is associated with leptin resistance,31 the genotype information of adrenoceptors and leptin receptor gene polymorphisms may be useful for determining optimal diet and exercise.
Recent progress of GWASs in hypertension genetics
In recent years, GWASs have surpassed classical genetic investigations using a candidate gene approach. First, a result obtained from the Wellcome Trust Case Control Consortium (WTCCC) using 14 000 cases of 7 common diseases and 3000 shared controls was published in Nature in 2007.32 Even though hypertension was included in the seven major diseases, no significant independent associations were detected in cases of hypertension. This was in contrast to diabetes, Crohn's disease, rheumatoid arthritis and coronary artery disease. Only haplotype analysis showed a marginal association with hypertension on the 15q26.2 locus, but this was unable to pass WTCCC's stringent genotype quality filters.33 Ehret et al. carried out a replication study using the top six SNPs from the WTCCC data in 11 433 individuals from the US National Heart, Lung, and Blood Institute-funded Family Blood Pressure Program. They found that only one SNP, rs1937506, was significantly associated with hypertension; however, its location was in a 500-kb gene desert on 13q21.34 In the Hypertension Genetic Epidemiology Network, Shi et al. examined gene–age interactions using genome-wide linkage analysis. The highest logarithm of odds score was identified on the chromosomal region 1p36, and supporting evidence was confirmed in three separate studies. This investigation also showed that genetic effects on BP varied by age.35
The Japanese Millennium Genome project succeeded in identifying several loci and genes responsible for hypertension. In this project, Japanese researchers shared the samples and examined the genetic variants using 18 977 microsatellite markers and 80 795 SNPs. This resulted in 19 allelic loci using the microsatellite approach,36 and 3 genes using the SNP approach37 were identified as susceptible genes for hypertension. The genes identified were the beta-adducin gene (ADD2) on 2p14-p13, KIAA0789 on 12q23.3 and the mannose-6-phospate gene (M6PR) on 12p13.
Recently, a GWAS in the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) S3 cohort study of 1644 Germans showed a significant association between BP and a common variant, rs11646213, upstream of CDH13. This gene encodes for an adhesion glycoprotein QJ;T-cadherin, a regulator of vascular wall remodeling and angiogenesis.38 The significant association was reconfirmed in KORA S4 (Germans) and HYPEST (Estonians), and a similar trend was observed in BRIGHT (British). It is interesting that T-cadherin is also a receptor for the hexameric and high-molecular-weight species of adiponectin, but not for the trimeric or globular species.39 In addition, methylation of the promoter region of CDH13 was found to be significantly associated with the recurrence of non-small-cell lung cancer.40 A similar association was observed in the cyclin-dependent kinase inhibitor 2A gene (CDKN2A) on 9p21, a current interest as the candidate locus of myocardial infarction.41 These results indicate that the genes considered to be candidates for tumorigenesis or metastasis also act as the modifiers of vascular remodeling, atherosclerosis and metabolic signals.
Another recent breakthrough of the GWAS in hypertension appeared as three articles in an issue of Nature Genetics.42, 43, 44 The first paper42 identified the association of the common variants in the natriuretic peptide precursor A and B genes (NPPA, NPPB) with circulating natriuretic peptide and BP. The second43 examined 34 433 individuals of European ancestry from the Global BPgen consortium and found that common variants in eight loci were significantly associated with systolic or diastolic BP. In the third paper,44 10–20 loci were identified as the candidates responsible for BP and hypertension using the participants of the CHARGE consortium (n=29 136). Some of these loci were found to be significantly associated with BP or hypertension in a joint meta-analysis with the Global BPgen Consortium. The final candidate genes obtained from GWAS are listed in Table 2.
Antihypertensive medication based on pharmacogenomics
Salt sensitivity and genetic predisposition to hypertension are different between races. In the United States, for example, BiDil (isosorbide dinitrate and hydralazine, NitroMed. Inc., Lexington, MA, USA) is currently a standard therapy for African Americans, but not for other races, with heart failure.45 Thus, it is not difficult to anticipate that the response to antihypertensive medication also varies greatly between individuals with different racial or genetic backgrounds. Brown46 pointed out the function of ethnicity in the pathogenesis of hypertension, and emphasized the usefulness of measuring renin activity in choosing the most appropriate antihypertensive drug.46 In this review, age was discussed as a critical modifier in the response to antihypertensive medication. For example, usage of diltiazem or diuretics is recommended for senile African Americans, but not for young Caucasians. In individuals with the salt-sensitive allele of ADD1, diuretic therapy was preferred to reduce the risk of myocardial infarction or stroke compared with other antihypertensive therapies.47
The racial difference in the response to antihypertensive medication affected the results of major clinical trials, such as the ALLHAT or INSIGHT trial. The genetic background of the participants in ALLHAT was examined as a GenHAT study. It was found that the G-6A polymorphism of AGT was significantly associated with pulse pressure change after 6 months of antihypertensive treatment in a gender-specific manner.48 Another interesting result in GenHAT was obtained from the genotype determination of the two polymorphisms in the precursor of the atrial natriuretic polypeptide gene (NPPA).49 The C-allele carriers of the NPPA T2238C polymorphism experienced more favorable cardiovascular disease outcomes when randomized to receive a diuretic, whereas the TT-allele carriers had more favorable outcomes when randomized to receive a calcium channel blocker. Most candidate gene polymorphisms, however, did not show any significant association in response to antihypertensive treatment in the GenHAT study.
In contrast, there are many reports suggesting the effect of adrenoceptor gene polymorphisms on β-blocker treatment, cardiovascular risk and mortality. For example, Pacanowski et al.50 reported in the INVEST study that the ADRB1 haplotype variation was associated with mortality risk, and β-blockers may be preferred in subgroups of patients defined by β1- or β2-adrenoceptor gene polymorphisms.
Genome-wide association studies are already incorporated into pharmacogenomic investigations. Turner et al. compared the genetic background between good and poor responders for thiazide diuretic treatment using Affymetrix GeneChip Human Mapping 100K arrays (Affymetrix, Santa Clara, CA, USA). Haplotype trend regression analysis showed that the 12q15 locus was significantly associated with diastolic BP response.51 The same group also proposed a new investigation, known as the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study, by recruiting 800 hypertensive individuals and randomizing them to atenorol or hydrochlorothiazide.52
In Japan, two major pharmacogenomic cohort studies of antihypertensive therapy are currently in progress. One is the Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP) Study, which is a large-scale intervention trial using a PROBE design to determine an optimal target BP level on the basis of self-measured BP with an optimal initial dose of antihypertensive medication.53 We are carrying out a sub-study of HOMED-BP, known as the HOMED-BP-GENE study, which is a GWAS to examine the genetic background of the response to antihypertensive medication. The preliminary results after a month of treatment suggest that different genes may be responsible for a reduction in BP in the morning and in the evening. Another GWAS is the GEANE (Gene Evaluation for Antihypertensive Effect of drugs) study, which is a multicenter trial to examine the response to a 3-month treatment of diuretics, an angiotensin II receptor blocker and a calcium channel blocker.
Conclusions
In comparison with the recent surge of positive results in other common complex diseases, a clear answer has not yet been elucidated for the genetic etiology of hypertension. The continuous efforts of researchers, however, will make progress by small, incremental advances (Figure 1). The chaos observed in hypertension genomics is resolvable by the introduction of new technologies in the place of classical genetic analysis. GWASs, epigenetics, pharmacogenomics and accurate phenotyping of clinical features (for example, home BP measurement) are issues that are critical to the success of investigations. In addition, fresh ideas are also crucial in finding a novel way to clarify the pathogenesis of hypertension. To consider hypertension from the viewpoint of aging, arteriosclerosis and volume retention, paying close attention to salt sensitivity, the renin–angiotensin system, atherosclerosis, ROS and sympathetic nerve activation, as well as cell growth, apoptosis, immune reaction and adipocyte differentiation, could be the solution for resolving hypertension genomics.
Prevalence of hypertension increases with age. Various genes, indicated in italics as gene symbols, affect the onset and development of hypertension. *Other candidate genes from GWAS are listed in Table 2. SNS, sympathetic nervous system; ROS, reactive oxygen species; RAS, renin–angiotensin system, GWAS, genome-wide association study. Gene symbols: LEPR, leptin receptor; ADRB2, beta-2-adrenergic receptor; ADRB3, beta-3-adrenergic receptor; MTHFR, 5,10-methlenetetrahydrofolate reductase; OGG1, 8-oxoguanine DNA glycosylase; CYP11B2, cytochrome P450, subfamily Y XIB, polypeptide 2; GNB3, guanine nucleotide-binding protein, beta-3; ADD1, alpha-adducin; ADD2, beta-adducin; SLC12A3, solute carrier family 12 (sodium–chloride transporter), member 3; WNK1, protein kinase, lysine-deficient 1; WNK4, protein kinase, lysine-deficient 4; STK39, serine/threonine protein kinase 39; AGT, angiotensinogen; ACE, angiotensin I-converting enzyme (peptidyl-dipeptidase A) 1; AGTR1, angiotensin II receptor, type 1; KIAA0789 (WSCD2), WSC domain containing 2; M6PR, mannose-6-phosphate receptor (cation dependent); CDH13, cadherin 13 (H-cadherin (heart)).
Conflict of interest
The authors declare no conflict of interest.
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Acknowledgements
The authors thank Ms. Kazuko Iwasa and Ms. Eriko Nagata for their continuous support to our investigations. The authors also thank all collaborators and participants of the Ohasama Study, the Tanno-Sobetsu Study, the Amagasaki Study, the Suita Study, the HOMED-BP-GENE Study and the Hypertension Task Force of the Japanese Millennium Genome Project (Chief: Professor Tetsuro Miki). Our previous investigations were supported by a Grant-in-Aid for Scientific Research (H17-pharmaco-common-003) from the Japanese Ministry of Health, Labor, and Welfare, Grants-in-Aid for Scientific Research (18590265, 18590811, 19650188, 21390223) from the Ministry of Education, Science, Sports and Culture of Japan and by research grants from the Japan Research Foundation for Clinical Pharmacology.
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Katsuya, T., Morishita, R., Rakugi, H. et al. Genetic basis of hypertension for the development of tailored medicine. Hypertens Res 32, 643–648 (2009). https://doi.org/10.1038/hr.2009.87
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DOI: https://doi.org/10.1038/hr.2009.87
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