The Health Outcome
Hypertension, or high blood pressure, is a complex polygenic disease that affects approximately one in four adults in the United States , and is responsible for an enormous global disease burden. In 2001, hypertension resulted in millions of hospital visits and 8.7 deaths per 100,000 in the U.S. population. Risk factors for hypertension include sedentary behavior and obesity, excessive alcohol intake, and diets high in sodium. Clinical hypertension may be defined as consistent elevation in blood pressure (bp), with systolic bp greater than or equal to 120 mmHg and diastolic bp greater than or equal to 90 mmHg. Hypertension is a risk factor for many other health outcomes such as heart failure, stroke, and kidney dysfunction, as well as left ventricular hypertrophy (1,2,6).
Left ventricular hypertrophy (LVH) is a thickening of the myocardium due to chronic cardiac stress, often resulting from prolonged hypertension, and leads to a decrease in the size of the heart cavity. The result is increased stress due to the heart’s decreased capacity to meet the demands of normal blood circulation, exacerbating the effects of the original hypertension. Prevalence of LVH has been estimated to be 15-20% among hypertensives, but may vary dramatically when controlling for age, gender, and/or ethnicity (2,14).
The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure, fluid balance, vascular tone, and sympathetic nervous system activity. Renin is a proteolytic enzyme synthesized in the kidneys, and is released following changes in renal perfusion pressure. This triggers a cascade in which angiotensinogen is cleaved to form angiotensin I, which is then cleaved by angiotensin converting enzyme (ACE) to form angiotensin II, a powerful vasoconstrictor. Angiotensin II further increases blood pressure by inducing aldosterone secretion, leading to sodium and fluid retention and the release of norepinephrine from the sympathetic nervous system (16).
Many polymorphisms in RAAS genes have been associated with cardiovascular disease and, more specifically, hypertension. Some of these include angiotensin converting enzyme, angiotensin II receptor-specific, angiotensinogen and renin genes, all of which have biologically plausible mechanisms for influencing hypertension and LVH, and could help explain differences in the pharmacotherapeutic effects of antihypertensive drugs between individuals with similar phenotypes (15).
The RAAS is a major target of antihypertensive therapies such as atenolol, a beta adrenergic receptor blocker, or beta blocker. Atenolol selectively binds to cardio-specific adrenoreceptors, preventing norepinephrine from binding, and thereby inhibiting the activity of the sympathetic nervous system in that area. Atenolol also suppresses the beta 1 receptor-mediated release of renin and subsequent formation of angiotensin II, thereby reducing blood pressure. Irbesartan, another antihypertensive drug, is an angiotensin II subtype 1-specific receptor antagonist. Irbesartan inhibits the negative feedback of angiotensin II on renin secretion, effectively blocking the RAAS, even thought plasma renin and angiotensin II levels are elevated. As a result, angiotensin II is unable to bind to its receptor and aldosterone is not released (1,3,4,15).
Previous studies have shown that polymorphisms of the angiotensinogen gene (AGT)—specifically those involving changes at the 235T position—are associated with hypertension, as well as with circulating levels of angiotensinogen. Linkage disequilibrium between the 1198C allele that codes for the 235T position and the AGT -6A allele is a possible explanation for this association as it is thought that the AGT -6A allele is located in the promoter region of the gene, thereby regulating transcription, and ultimately influencing production of the protein angiotensinogen. Angiotensinogen leads to increased blood pressure by causing vasoconstriction and fluid retention (5,10).
The Finding
The data come from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) clinical trial of hypertensive patients with LVH. The goal of the trial is to compare the effects of irbesartan, an angiotensin II type 1 receptor antagonist, with those of atenolol, a beta-1 adrenoreceptor-blocker, on the change in LVH in hypertensive patients.
In this study, 115 patients with mild to moderate primary hypertension were randomized in a double-blind manner into two treatment groups following a 4-6 week placebo lead-in period, one group receiving 150 mg irbesartan and the other receiving 50 mg atenolol, the doses of which would be adjusted based on individual response to treatment over a 12 week period. Fourteen people dropped out of the study following randomization, and a random sample of 97 were genotyped and analyzed. Subjects were men and women greater than 18 years of age (mean age=54 years) with confirmed LVH of defined left ventricular mass. The investigators chose 30 single nucleotide polymorphisms (SNPs) from the li tera ture and several databases, and genotyped them using a minisequencing reaction validated in a previous study. Data were analyzed using a factorial one-way ANOVA; a two-tailed p-value less than 0.01 was considered significant. This more conservative significance threshold was chosen to help compensate for multiple comparisons.
Overall reduction in both systolic and diastolic blood pressure was similar in both groups following 12 weeks of treatment. There were no significant differences in the two groups based on gender, age or baseline characteristics. No SNPs were significantly associated with reduction in bp following treatment with irbesartan. Two SNPs of the AGT gene were significantly associated with a reduction in the systolic bp of patients treated with atenolol. The T1198C SNP is a substitution of cytosine for thymidine resulting in a substitution of methionine for threonine, and in the significant reduction in systolic bp, even after adjusting for age and gender, with a p-value of 0.008 when comparing 1198CC and CT with 1198TT. The AGT -6A allele was associated with the most statistically significant reduction in systolic bp, with a p-value of 0.001 when AGT -6AA and AG was compared with GG. The AGT 1198C allele and the AGT -6A allele may be considered a haplotype as they are in linkage disequilibrium. The greatest absolute reduction in systolic bp was among patients with the AGT -20C SNP, and although it was not significant, it is also linked to the 1198C allele.
The authors conclude that these two polymorphisms in the AGT gene are associated with treatment-specific reduction in systolic bp in hypertensive patients with LVH. Although an association with treatment with an angiotensin II type 1 receptor antagonist like irbesartan might be expected given the gene, it is hypothesized that the association with atenolol treatment is due to the timing of its influence on RAAS activity. In fact, the findings were the opposite of a priori expectations of the authors, based on the known action of irbesartan on angiotensin II type 1 receptors. If patients with SNPs thought to regulate/increase transcription of the angiotensinogen gene (thereby increasing RAAS activity) benefit most from treatment with atenolol, it seems logical that this increase could be due to the reduction in RAAS activity by atenolol’s suppression of renin release, upstream from angiotensin receptor blockage, thereby halting the pathway to hypertension earlier. These results indicate the potential for a tool that would allow more efficient prescription of antihypertensive therapies in the form of individualized treatments based on the patient’s genotype.
Public Health Implications
The findings of this study demonstrate how difficult it is to use genotype to predict reaction to pharmacotherapy, even in a relatively well-understood system such as the RAAS. If the relationship between specific pharmacotherapies and specific gene polymorphisms can be consistently established, this could lead to earlier, more efficient treatment of hypertension by identifying particularly high risk individuals or individuals for whom specific treatments would or would not be effective. Potential benefits of patient-specific antihypertensive therapy are minimizing the time and money wasted on ineffective treatment regimens and their consequences, such as side effects, which in turn could prevent the development of severe complications of hypertension, such as LVH, if patients are being treated earlier in their disease course. This would significantly reduce the morbidity, mortality, and public health burden of hypertension.
Genotyping for individualized treatment for hypertension could have a significant impact as this is a common, treatable disease, especially if patients at higher risk for the more severe consequences of high blood pressure could be identified, and if knowing a patient’s genotype would significantly impact their disease outcome. Unfortunately, the tests are very expensive, and developing a test with high sensitivity and specificity might be difficult given such a complex system of genes. In addition, the authors of this study found that blood pressure was lower in both groups, regardless of genotype or treatment received, so genotyping would have to predict more than simply reduction in blood pressure in response to antihypertensive pharmacotherapy.
More data is needed to confirm the associations of the various RAAS gene polymorphisms with antihypertensive therapies before there can be a useful clinical application of this relationship. The biological mechanisms of the genes and their products need to be further investigated as well in order to explain/support the variability in individual response to treatment in relation to genotype. Specifically, the role of the AGT -6A allele in the transcription of angiotensinogen should be evaluated further. Gene-gene and gene-environment interactions may be investigated to aid in this process, although this will be difficult as hypertension is so complex, and response to antihypertensive drugs is likely due to the interaction of many polymorphisms. As noted by the authors, a larger study that permitted gender-specific analyses would be very useful as some of the polymorphisms, such as the AGT -20A SNP, may lead to a different response to treatment in men than in women.
References
- http://www.harcourt-international.com/e-books/pdf/146.pdf
- http://www.musc.edu/bmt737/Spr_1999/russell/
- http://www.sunderland.ac.uk/~hs0dad/profile/atenolol/atenhmpg.htm
- Blumenfeld J, et al. Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects. Am J Hypertens 1999 May; 12(5): 451–459.
- Danser AH, et al. Renin-angiotensin system gene polymorphisms: potential mechanisms for their association with cardiovascular diseases. Eur J Pharmacol 2000 Dec; 410 (2-3):303-316.
- Inoue I, et al. A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro. J Clin Invest 1997 Apr; 99(7): 1786–1797.
- Jeunemaitre X, et al. Haplotypes of angiotensinogen in essential hypertension. Am J Hum Genet 1997 June; 60(6): 1448–1460.
- Jeunemaitre X, et al. Molecular basis of human hypertension: role of angiotensinogen. Cell 1992 Oct; 71(1): 169–180.
- Kim H, et al. Genetic control of blood pressure and the angiotensinogen locus. Proc Natl Acad Sci USA 1995 Mar; 92(7): 2735–2739.
- Kunz R, et al. Association between the angiotensinogen 235T-variant and essential hypertension in whites: a systematic review and methodological appraisal. Hypertension 1997 Dec; 30(6): 1331–1337.
- Kurland L, et al. Aldosterone synthase (CYP11B2) -344 C/T is related to antihypertensive response. Am J Hypertens 2002 May; 15(5): 387–393.
- Kurland L, et al. Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type I antagonist treatment in hypertensive patients. J Hypertension 2001 Oct; 19(10): 1783–1787.
- Liljedahl U, et al. A microarray minisequencing system for pharmacogeentic profiling of antihypertensive drug response. Pharmacogenetics. 2003 Jan; 13(1): 7–17.
- Malmqvist K, et al. Long-term effects of irbesartan and atenolol on the renin-angiotensin-aldosterone system in human primary hypertension. J Cardiovasc Pharmacol 2003; 42:719–726.
- Malmqvist K, et al. Regression of left ventricular hypertrophy in human hypertension with irbesartan. J Hypertens 2001 June; 19(6): 1167–1176.
- Wang J, et al. Genetic polymorphisms in the renin-angiotensin system: relevance for susceptibility to cardiovascular disease. Eur J Pharmacol 2000 Dec; 410(2-3):289–302.
