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Current Hypertension Reports Oct 2011The concept of "pharmacogenomics" or "pharmacogenetics" promises to offer the ultimate in personalized medicine, and the renin-angiotensin system (RAS) is one of the... (Review)
Review
Do genetic variants of the Renin-Angiotensin system predict blood pressure response to Renin-Angiotensin system-blocking drugs?: a systematic review of pharmacogenomics in the Renin-Angiotensin system.
The concept of "pharmacogenomics" or "pharmacogenetics" promises to offer the ultimate in personalized medicine, and the renin-angiotensin system (RAS) is one of the most plausible candidates for the application of this approach in the area of hypertension. For the past two decades, genetic variants of the RAS have been tested for association with blood pressure response, but the results have been inconsistent. The problems have been attributed to many issues, but the most fundamental concern is thought to be the statistical power of the studies. Therefore, we have tried to put together a new systematic review using a database search including only recent reports with adequate numbers of subjects, and 11 reports were identified. From the results, we were able to draw conclusions with nearly consistent findings that the conventional genetic variants of the system (i.e., the ACE I/D, AGT M235T, AT1 A1166C, and AT2 variant) are not associated with antihypertensive effects by RAS blockade, at least by one individual SNP. By contrast, significant associations have been reported (by one report each) for AGT rs7079, AT1 haplotype, REN, and ACE2. For these variants, further evaluations and confirmation are anticipated.
Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Genetic Variation; Humans; Hypertension; Peptidyl-Dipeptidase A; Pharmacogenetics; Polymorphism, Genetic; Renin-Angiotensin System
PubMed: 21562941
DOI: 10.1007/s11906-011-0212-0 -
Circulation. Cardiovascular Genetics Feb 2010Carotid intima-media thickness (CIMT) is highly heritable and associated with stroke and myocardial infarction, making it a promising quantitative intermediate phenotype... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Carotid intima-media thickness (CIMT) is highly heritable and associated with stroke and myocardial infarction, making it a promising quantitative intermediate phenotype for genetic studies of vascular disease. There have been many CIMT candidate gene association studies, but no systematic review to identify consistent, reliable findings.
METHODS AND RESULTS
We comprehensively sought all published studies of association between CIMT and any genetic polymorphism. We obtained additional unpublished data and performed meta-analyses for the 5 most commonly studied genes (studied in at least 2 studies in a total of >5000 subjects). We used a 3-step meta-analysis method: meta-analysis of variance; genetic model selection; and random effects meta-analysis of the mean CIMT difference between genotypes. We performed subgroup analyses to investigate effects of ethnicity, vascular risk status, and study size. We accounted for potential reporting bias by assessing qualitatively the possible effects of including unavailable data. Polymorphisms in 3 of the 5 genes (apolipoprotein E, angiotensin I converting enzyme, and 5,10-methylenetetrahydrofolate reductase) had an apparent association with CIMT, but for all these, we found evidence of small study bias. Apolipoprotein E epsilon2/epsilon3/epsilon4 was the only polymorphism with a persistent, statistically significant but modest association when we restricted analysis to larger studies (>1000 subjects).
CONCLUSIONS
Of the most extensively studied polymorphisms, apolipoprotein E epsilon2/epsilon3/epsilon4 is the only one so far with a convincing association with CIMT. Larger studies than have generally been performed so far may be needed to confirm the associations identified in future genome-wide association studies, and to investigate modification of effect according to characteristics such as ethnicity and vascular risk status.
Topics: 5,10-Methylenetetrahydrofolate Reductase (FADH2); Analysis of Variance; Apolipoproteins E; Carotid Arteries; Carotid Artery Diseases; Genotype; Humans; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors; Sterol Regulatory Element Binding Protein 1; Tunica Intima; Tunica Media; Vascular Diseases
PubMed: 20160191
DOI: 10.1161/CIRCGENETICS.108.834366 -
PLoS Medicine Apr 2007Ischaemic stroke in persons of European descent has a genetic basis, but whether the stroke-susceptibility alleles, the strength of any association, and the extent of... (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
Ischaemic stroke in persons of European descent has a genetic basis, but whether the stroke-susceptibility alleles, the strength of any association, and the extent of their attributable risks are the same in persons of non-European descent remains unanswered. Whether ethnicity itself has a relevant or substantial contribution on those effect estimates is controversial. Comparative analyses between the ethnic groups may allow general conclusions to be drawn about polygenic disorders.
METHODS AND FINDINGS
We performed a literature-based systematic review of genetic association studies in stroke in persons of non-European descent. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined for each gene-disease association using fixed and random effect models. We further performed a comparative genetic analysis across the different ethnic groups (including persons of European descent derived from our previous meta-analysis) to determine if genetic risks varied by ethnicity. Following a review of 500 manuscripts, eight candidate gene variants were analysed among 32,431 individuals (12,883 cases and 19,548 controls), comprising mainly Chinese, Japanese, and Korean individuals. Of the eight candidate genes studied, three were associated with ischaemic stroke: the angiotensin I converting enzyme (ACE) insertion/deletion (I/D) polymorphism with a mean OR of 1.90 (95% CI 1.23-2.93) in the Chinese and 1.74 (95% CI 0.88-3.42) in the Japanese; the summary OR for the C677T variant of 5,10-methylenetetrahydrofolate reductase (MTHFR) was 1.18 (95% CI 0.90-1.56) in Chinese and 1.34 (95% CI 0.87-2.06) in Koreans; and the pooled OR for the apolipoprotein E (APOE) gene was 2.18 (95% CI 1.52-3.13) in Chinese and 1.51 (95% CI 0.93-2.45) in Japanese. Comparing the commonly investigated stroke genes among the Asian groups against studies in persons of European descent, we found an absence of any substantial qualitative or quantitative interaction for ORs by ethnicity. However, the number of individuals recruited per study in the studies of persons of non-European descent was significantly smaller compared to studies of persons of European descent, despite a similar number of studies conducted per gene.
CONCLUSIONS
These data suggest that genetic associations studied to date for ischaemic stroke among persons of non-European descent are similar to those for persons of European descent. Claims of differences in genetic effects among different ethnic populations for complex disorders such as stroke may be overstated. However, due to the limited number of gene variants evaluated, the relatively smaller number of individuals included in the meta-analyses of persons of non-European descent in stroke, and the possibility of publication bias, the existence of allele variants with differential effects by ethnicity cannot be excluded.
Topics: Asian People; Brain Ischemia; Ethnicity; Europe; Genetic Linkage; Genetic Variation; Humans; Korea; Polymorphism, Genetic; Stroke
PubMed: 17455988
DOI: 10.1371/journal.pmed.0040131