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Pharmacology - Renal & Respiratory - Detailed Pharmacogenetic association of the angiotensin-converting enzyme insertion/deletion polymorphism on blood pressure and cardiovascular risk in relation to antihypertensive treatment: the Genetics of Hypertension-Associated Treatment (GenHAT) study.
BACKGROUND: Previous studies have reported that blood pressure response to antihypertensive medications is influenced by genetic variation in the renin-angiotensin-aldosterone system, but no clinical trails have tested whether the ACE insertion/deletion (I/D) polymorphism modifies the association between the type of medication and multiple cardiovascular and renal phenotypes. METHODS AND RESULTS: We used a double-blind, active-controlled randomized trial of antihypertensive treatment that included hypertensives > or =55 years of age with > or =1 risk factor for cardiovascular disease. ACE I/D genotypes were determined in 37 939 participants randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin treatments and followed up for 4 to 8 years. Primary outcomes included fatal coronary heart disease (CHD) and/or nonfatal myocardial infarction. Secondary outcomes included stroke, all-cause mortality, combined CHD, and combined cardiovascular disease. Fatal and nonfatal CHD occurred in 3096 individuals during follow-up. The hazard rates for fatal and nonfatal CHD and the secondary outcomes were similar across antihypertensive treatments. ACE I/D genotype group was not associated with fatal and nonfatal CHD (relative risk of DD versus ID and II, 0.99; 95% CI, 0.91 to 1.07) or any secondary outcome. The 6-year hazard rate for fatal and nonfatal CHD in the DD genotype group was not statistically different from the ID and II genotype group by type of treatment. No secondary outcome measure was statistically different across antihypertensive treatment and ACE I/D genotype strata. CONCLUSIONS: ACE I/D genotype group was not a predictor of CHD, nor did it modify the response to antihypertensive treatment. We conclude that the ACE I/D polymorphism is not a useful marker to predict antihypertensive treatment response. BACKGROUND: Previous studies have reported that blood pressure response to antihypertensive medications is influenced by genetic variation in the renin-angiotensin-aldosterone system, but no clinical trails have tested whether the ACE insertion/deletion (I/D) polymorphism modifies the association between the type of medication and multiple cardiovascular and renal phenotypes. METHODS AND RESULTS: We used a double-blind, active-controlled randomized trial of antihypertensive treatment that included hypertensives > or =55 years of age with > or =1 risk factor for cardiovascular disease. ACE I/D genotypes were determined in 37 939 participants randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin treatments and followed up for 4 to 8 years. Primary outcomes included fatal coronary heart disease (CHD) and/or nonfatal myocardial infarction. Secondary outcomes included stroke, all-cause mortality, combined CHD, and combined cardiovascular disease. Fatal and nonfatal CHD occurred in 3096 individuals during follow-up. The hazard rates for fatal and nonfatal CHD and the secondary outcomes were similar across antihypertensive treatments. ACE I/D genotype group was not associated with fatal and nonfatal CHD (relative risk of DD versus ID and II, 0.99; 95% CI, 0.91 to 1.07) or any secondary outcome. The 6-year hazard rate for fatal and nonfatal CHD in the DD genotype group was not statistically different from the ID and II genotype group by type of treatment. No secondary outcome measure was statistically different across antihypertensive treatment and ACE I/D genotype strata. CONCLUSIONS: ACE I/D genotype group was not a predictor of CHD, nor did it modify the response to antihypertensive treatment. We conclude that the ACE I/D polymorphism is not a useful marker to predict antihypertensive treatment response. ACE inhibitors and congenital anomalies. Friedman JM, 2006. N Engl J Med. 354(23):2498-500.
This is an invited discussion of a paper by Cooper, WO et al. in same issue.
Pharmacogenomics of statin responsiveness. Kajinami K et al. 2005. Am J Cardiol. 96(9A):65K-70K; discussion 34K-35K. Statins are widely prescribed and are established as first-line therapy for the primary and secondary prevention of coronary artery disease. However, the benefit of treatment varies between patients. Genetic variation can contribute to interindividual variations in clinical efficacy of drug therapy, and significant progress has been made in identifying common genetic polymorphisms that influence responsiveness to statin therapy. To date, >30 candidate genes related to pharmacokinetics and pharmacodynamics of statins have been investigated as potential determinants of drug responsiveness in terms of low-density lipoprotein cholesterol lowering. Genetic variation at gene loci that affect intestinal cholesterol absorption include apolipoprotein (apo) E; adenosine triphosphate-binding cassette transporter G5 and G8; cholesterol production, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase; and lipoprotein catabolism, such as apoB and the low-density lipoprotein receptor, all may play a role in modulating responsivesness as well genes involved in metabolism of statins such as cytochrome P450. However, there is considerable variation in results reported, and the data suggest that combined analysis of multiple genetic variants in several genes, all of which have possible functional significance, is more likely to give significant results than single gene studies in small sample populations. In the future, pharmacogenomic studies with a greater number of participants (>2,000 participants) should provide a better picture as to who is most likely and who is least likely to benefit from statin therapy. Using genotyping to predict responses to anti-hypertensive treatment. Kurland L et al., 2005. Trends Pharmacol Sci. 26(9):443-7.
Hypertension is prevalent and affects approximately 1 in every 4 adults in the Western world. Although many drugs are effective in treating hypertension, an individual's response to treatment is unpredictable. Pharmacogenetics holds the promise of becoming a tool to predict this response but obstacles and shortcomings need to be overcome. Significant developments in molecular biology, including the sequencing of the genome, the cataloguing of genetic variation and the development of microarray techniques, enable analysis of many genotypes simultaneously. However, despite these technical advances there are, as yet, no clinical applications of pharmacogenetics in anti-hypertensive treatment. It is therefore necessary to design prospective pharmacogenetic studies that aim to identify a genetic profile that will predict the response to anti-hypertensive treatment. Pharmacogenetics of asthma. Hall IP, 2006. Chest 130(6):1873-78.
Pharmacogenetics offers the potential to optimize treatment for individual patients by using genetic information to improve efficacy or avoid side effects. While there are a number of examples in which the approach is already in routine clinical usage, exploitation of this approach in asthma is still under development. A number of examples of possible pharmacogenetic approaches that may prove of value in the management of asthma are discussed. Genetically mediated interindividual variation in analgesic responses to cyclooxygenase inhibitory drugs. Lee YS et al. 2006. Clin Pharmacol Ther. 79(5):407-18.
Wide inter-individual variation in responses to cyclooxygenase (COX) inhibitory drugs limits their clinical utility and safety. METHODS: To better understand the molecular responses to COX inhibition, we analyzed the gene expression level of the genes encoding enzymes related to prostaglandin production including the COX-1 gene (PTGS1) and the COX-2 gene (PTGS2), as well as their genetic polymorphisms, and the analgesic response to COX inhibitory drugs such as ibuprofen or rofecoxib or to placebo after minor surgery. Notable heterogeneity in global gene expression was evident between subjects. At 2 to 4 hours after surgery, PTGS1 expression was slightly decreased (36%, P < .001) and PTGS2 expression was markedly increased (300%, P < .001) with wide inter-individual variation; at 48 hours after surgery, little detectable change in PTGS1 and PTGS2 expression was found in the control group. However, ibuprofen and rofecoxib treatment significantly increased PTGS2 expression at 48 hours (P = .001 and P = .049, respectively). At 2 to 4 hours after surgery, patients with the G/G allele at the nucleotide position of -765G>C in PTGS2 showed a significantly higher increase in PTGS2 expression (P = .012) compared with G/C and C/C patients, although all of them showed an increase in PTGS2 expression (P < .001 and P = .043, respectively). Among G/G patients, rofecoxib administration resulted in significantly lower pain intensity on a visual analog scale (7.2 +/- 2.5 mm) (P = .008) at 48 hours after surgery, as compared with ibuprofen administration (31.3 +/- 6.7 mm). The finding regarding pain intensity at 48 hours in G/C and C/C patients was opposite (P = .002), being greater in the rofecoxib group (37 +/- 6.8 mm) compared with the ibuprofen group (7 +/- 1.9 mm). These results suggest that wide variability in gene expression and functional polymorphisms in PTGS2 may explain part of the interindividual variations in acute pain and the analgesic efficacy of nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors; this may be useful to define individual responders on the basis of genetic variations to predict patient risk and benefit to drugs. Pharmacogenomics and pharmacogenetics of hypertension: update and perspectives--the adducin paradigm.
There is a growing literature on the potential prospective use of genome information to enhance success in finding new medicines. An example of a prospective efficacy of pharmacogenetic and pharmacogenomics is the detection and impact of adducin polymorphism on hypertension. Adducin is a heterodimeric cytoskeleton protein, the three subunits of which are encoded by genes (ADD1, ADD2, and ADD3) that map to three different chromosomes. A long series of parallel studies in the Milan hypertensive rat strain model of hypertension and humans indicated that an altered adducin function might cause hypertension through an enhanced constitutive tubular sodium reabsorption. In particular, six linkage studies, 18 of 20 association studies, and four of five follow-up studies that measured organ damage in hypertensive patients support the clinical impact of adducing polymorphism. As many modulatory genes and environment affect the adducin activity, the context must be taken into account to measure the clinical effect size of adducins. Pharmacogenomics is giving an important contribution to this end. In particular, the selective advantages of diuretics in preventing myocardial infarction and stroke over other antihypertensive therapies that produce a similar BP reduction in carriers of the mutated adducin may support new strategies that aim to optimize the use of antihypertensive agents for the prevention of hypertension-associated organ damage. Pharmacogenetics of asthma. Palmer LJ, 2002. Am J Respir Crit Care Med. 165(7):861-66.
This is a review article that has no abstract or summary. There is a discussion of treatment based on pharmacogenetics considerations. A table of pharmacogenetic mechanisms with implications for asthma treatment is available. A section describes a consideration of pharmacogenetics of leukotrienes in treatment of asthma. There is also a discussion of the used of statistical analysis of data of different SNPs, effects and treatment. Pharmacogenomics of cholesterol-lowering therapy. Schmitz G & Langmann T, 2006. Vascul Pharmacol. 44(2):75-89.
The prevention of cardiovascular disease is critically dependent on lipid-lowering therapy, including 3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), cholesterol absorption inhibitors, bile acid resins, fibrates, and nicotinic acid. Although these drugs are generally well tolerated, severe adverse effects can occur in a minority of patients. Furthermore, a subset of patients does not respond to cholesterol-lowering therapy with a reduction in coronary heart disease progression. Significant progress has been made in the identification of common DNA sequence variations in genes influencing the pharmacokinetics and pharmacodynamics of statins and in disease-modifying genes relevant for coronary heart disease (CHD). Among the most promising candidate genes for pharmacogenomic analysis of statin therapy are HMG-CoA reductase as a direct target gene and other genes modulating lipid and lipoprotein homeostasis. Based on data from pharmacogenetic trials, a combined analysis of multiple genetic variants in several genes is more likely to give significant results than single gene studies in small cohorts. In the future, pharmacogenomic testing may allow risk stratification of patients to avoid serious side effects and enable clinicians to select lipid-lowering drugs with the highest efficacy resulting in the best response to therapy. How pharmacogenomics will play a role in the management of asthma. Wechsler ME & Israel E, 2005. Am J Respir Crit Care Med. 172(1):12-18.
Pharmacogenomic information may allow us to treat those who can benefit most from particular asthma medications and to avoid oxicity by administering medications to those unlikely to experience toxicity. For example, if pharmacogenomics fulfills its promise, we will be able to administer corticosteroids to those least likely to experience adverse effects. Furthermore, we will be able to introduce and/or develop drugs for asthma that were held back because of potential toxicity in a subset of patients. From a clinician’s point of view, it is expected that pharmacogenomics assays will be readily available in clinical laboratories within the next 5 years. Considering the rapid fall in the cost of genotyping at multiple loci simultaneously, it is unlikely that the technology will limit the introduction of this methodology; rather, the design and execution of clinical trials in multiple populations will be the rate-limiting step. Thus, we advocate obtaining genetic material in all clinical asthma trials and consideration of prospective genotype-stratified clinical trials. Such association studies and biologically informative pharmacogenomics trials over the next decade should allow us not only to “Do no harm” but also to “Do much good.” Overview of the pharmacogenetics of asthma treatment. Weiss ST et al. 2006. Pharmacogenomics J. 6(5):311-26.
Asthma affects approximately 300 million individuals worldwide. Medications comprise a substantial portion of asthma expenditures. Despite the availability of three primary therapeutic classes of medications, there are a significant number of nonresponders to therapy. Available data, as well as previous pharmacogenetic studies, suggest that genetics may contribute as much as 60-80% to the interindividual variability in treatment response. In this methodologic review, after providing a broad overview of the asthma pharmacogenetics literature to date, we describe the application of a novel family-based screening algorithm to the analysis of pharmacogenetic data and highlight our approach to identifying and verifying loci influencing asthma treatment response. This approach seeks to address issues related to multiple comparisons, statistical power, population stratification, and failure to replicate from which previous population-based or case-control pharmacogenetic association studies may suffer. Identification of such replicable loci is the next step towards the goal of 'individualized therapy' for asthma. |
