ContextGiven the numerous, yet inconsistent, reports of genetic variants being associated with acute coronary syndromes (ACS), there is a need for comprehensive validation of ACS susceptibility genotypes.ObjectiveTo perform an extensive validation of putative genetic risk factors for ACS.Design, Setting, and ParticipantsThrough a systematic literature search of articles published before March 10, 2005, we identified genetic variants previously reported as significant susceptibility factors for atherosclerosis or ACS. Restricting our analysis to white patients to reduce confounding from racial admixture, we identifed 811 patients who presented from March 2001 through June 2003 with ACS at 2 Kansas City, Mo, university-affiliated hospitals. During 2005-2006, we genotyped the 811 patients along with 650 age- and sex-matched controls for 85 variants in 70 genes and attempted to replicate previously reported associations. We further explored possible associations without prior assumption of specific risk models and used the Sign test to search for weak associations.Main Outcome MeasuresCompare each prespecified gene variant associated with ACS risk among cases and controls. A surplus of associations would imply that some are associated with ACS.ResultsOf 85 variants tested, only 1 putative risk genotype (−455 promoter variant in β-fibrinogen) was nominally statistically significant (P = .03). Only 4 additional genes were positive in model-free analysis. Neither number of associations was more frequent than expected by chance, given the number of comparisons. Finally, only 41 of 84 predefined risk variants were even marginally more frequent in cases than in controls (with 1 tie), representing a 48.8% “win rate” (95% confidence interval, 38.1%-59.5%) for the collective risk genotypes (P = .91, Sign test).ConclusionsOur null results provide no support for the hypothesis that any of the 85 genetic variants tested is a susceptibility factor for ACS. These results emphasize the need for robust replication of putative genetic risk factors before their introduction into clinical care.

https://jamanetwork.com/journals/jama/articlepdf/206516/joc70032_1551_1561.pdf

Nonvalidation of Reported Genetic Risk Factors for Acute Coronary Syndrome in a Large-Scale Replication Study

Natriuretic Peptides: An Update on Bioactivity, Potential Therapeutic Use, and Implication in Cardiovascular Diseases

Background and Purpose— Measurement of natriuretic peptides provides prognostic information in various patient populations. The prognostic value of natriuretic peptides among patients with acute stroke is not known, although elevated peptide levels have been observed. Methods— A series of 51 patients (mean age, 68±11years) with first-ever ischemic stroke underwent a comprehensive clinical examination and measurements of plasma atrial natriuretic peptides (N-ANP) and brain natriuretic peptides (N-BNP) in the acute phase of stroke. The patients were followed-up for 44±21 months. Risk factors for all-cause mortality were assessed. Control populations, matched for gender and age, consisted of 51 patients with acute myocardial infarction (AMI) and 25 healthy subjects. Results— Plasma concentrations of N-ANP (mean±SD, 988±993 pmol/L) and N-BNP (751±1608 pmol/L) in the stroke patients were at the same level as those in the AMI patients (NS for both), but significantly higher than those of the healthy subjects (3...

Natriuretic Peptides and Mortality After Stroke

Association of atrial natriuretic peptide and type a natriuretic peptide receptor gene polymorphisms with left ventricular mass in human essential hypertension

Background and Purpose— A precise definition of genetic factors responsible for common forms of stroke is still lacking. The purpose of the present study was to investigate the contributory role of the genes encoding atrial natriuretic peptide (ANP) and type A natriuretic peptide receptor (NPRA) in humans’ susceptibility to develop ischemic stroke. Methods— Allele and genotype frequencies of ANP and NPRA were characterized in an Italian case-control study with patients affected by vascular disease or risk factors. Subjects were recruited from the island of Sardinia (206 cases, 236 controls). Results— A significant association between the ANP/TC2238 polymorphic site and stroke occurrence was found when a recessive model of inheritance was assumed. The risk conferred by this mutant genotype, when estimated by multivariate logistic regression analysis, was 3.8 (95% confidence interval, 1.4 to 10.9). A significantly increased risk of stroke recurrence was observed among cases carrying the ANP/CC2238 genotype ...

Radoslsoław Targoński

Papers

Association of the ScaI atrial natriuretic peptide gene polymorphism with nonfatal myocardial infarction and extent of coronary artery disease.