ABSTRACT
AIMS: To investigate whether genetic variation in the renin-angiotensin-aldosterone system (RAAS) and kallikrein-bradykinin pathways is related to hypertension and blood pressure (BP) response to angiotensin-converting enzyme (ACE) inhibitor therapy in stable coronary artery disease (CAD) patients. METHODS AND RESULTS: In 8907 stable CAD patients from the EUROPA trial, 52 haplotype-tagging single-nucleotide polymorphisms (SNPs) in 12 candidate genes within the RAAS and kallikrein-bradykinin pathways were investigated for association with hypertension (defined as BP ≥160/95 mmHg or use of antihypertensives) and BP response to ACE inhibitors, during a 4-week run-in period. All analyses were adjusted for age, sex, body mass index and creatinine clearance and corrected for multiple testing. RESULTS: Hypertension was present in 28.3% of the patients (n = 2526); median BP reduction after perindopril was 10/4 mmHg. Four polymorphisms, located in the ACE (rs4291), angiotensinogen (rs5049) and (pro)renin receptor (rs2968915; rs5981008) genes were significantly associated with hypertension in two vascular disease populations of CAD (EUROPA) and cerebrovascular disease (PROGRESS; n = 3571). A cumulative profile demonstrated a stepwise increase in the prevalence of hypertension, mounting to a 2-3-fold increase (P for trend <0.001). Similar associations on hypertension were observed for angiotensinogen in a healthy population (n = 2197). In addition, genetic polymorphisms were identified that significantly modified the BP reduction by ACE inhibitor therapy; however, the observed BP differences were small and did not remain significant after permutation analysis. CONCLUSION: This large genetic association study identified genetic determinants of hypertension in three cohorts of patients with vascular disease and healthy individuals.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Angiotensinogen/genetics , Blood Pressure/drug effects , Hypertension/genetics , Peptidyl-Dipeptidase A/genetics , Polymorphism, Single Nucleotide , Receptors, Cell Surface/genetics , Aged , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Female , Haplotypes , Humans , Hypertension/drug therapy , Male , Middle Aged , Pharmacogenetics , Prorenin ReceptorABSTRACT
The role of coagulation disorders in the pathogenesis of (recurrent) ischemic stroke is uncertain. Therefore, the clinical utility of screening patients with ischemic stroke for these conditions and the therapeutic implications of a detected coagulation disorder in a patient who experienced ischemic stroke are uncertain. We reviewed the currently available data on the relationship between various inherited and acquired coagulation abnormalities (factor V Leiden and prothrombin G20210A mutations, deficiencies of protein C, protein S and anti-thrombin, hyperhomocysteinemia, the antiphospholipid syndrome and increased levels of fibrinogen) and ischemic stroke. Based on the existing evidence we discuss the usefulness of screening stroke patients for prothrombotic conditions and current recommendations regarding the optimal management of ischemic stroke patients in whom a coagulation disorder is found.
Subject(s)
Blood Coagulation Disorders/complications , Blood Coagulation Disorders/diagnosis , Brain Ischemia/etiology , Mass Screening , Stroke/etiology , Stroke/physiopathology , Adult , Age Factors , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/genetics , Blood Coagulation Disorders/physiopathology , Brain Ischemia/blood , Brain Ischemia/genetics , Brain Ischemia/physiopathology , Child , Factor V/genetics , Female , Humans , Hyperhomocysteinemia/complications , Hyperhomocysteinemia/diagnosis , Protein C Deficiency/complications , Protein C Deficiency/diagnosis , Protein S Deficiency/complications , Protein S Deficiency/diagnosis , Prothrombin/genetics , Risk Factors , Sex Factors , Stroke/blood , Stroke/genetics , Thrombophilia/complications , Thrombophilia/diagnosisABSTRACT
PURPOSE OF REVIEW: C-reactive protein (CRP) is consistently associated with cardiovascular disease in prospective and cross-sectional clinical and epidemiological studies. Inflammation is an important mechanism in cardiovascular disease, and the plasma level of CRP is considered to reflect the inflammatory condition of the patient and/or the vessel wall. In addition, there are also a number of indications for a causal role of CRP in cardiovascular disease. RECENT FINDINGS: A number of new publications show potential causal effects of CRP on cardiovascular disease, and evidence from human-CRP transgenic animals also indicates a causal contribution of CRP to cardiovascular disease. On the other hand, a new large prospective study and an updated meta-analysis indicate that the contribution of CRP to cardiovascular disease is less impressive than reported earlier (odds ratio, 1.58; 95% confidence interval, 1.48-1.68). SUMMARY: We review here the most recent evidence on mechanisms by which CRP is involved as a causal factor in the precipitation of cardiovascular disease. Evidence for such a role is accumulating.
