title: Clinical effect of naturally random allocation to lower systolic blood pressure beginning before the development of hypertension.
abstract: Systolic blood pressure (SBP) rises approximately linearly with age in most societies. The cause of this rise is unclear. We tested the hypothesis that SBP is causally associated with the rate of rise in SBP with age by evaluating the effect of 12 polymorphisms associated with lower SBP on the age-related rate of rise in SBP in a series of meta-regression analyses involving ≤199 477 participants in 63 studies. We then evaluated the effect of these polymorphisms on the odds of coronary heart disease in 22,223 case and 64,762 control subjects and compared it with the effect of lower SBP observed in both prospective cohort studies and blood pressure-lowering randomized trials. All 12 polymorphisms were associated with both lower SBP and a slower age-related rise in SBP. The weighted mean effect of these 12 polymorphisms was associated with a 0.32-mm Hg lower SBP (P=1.79×10(-7)) and a 0.093-mm Hg/decade slower age-related rise in SBP (P=3.05×10(-5)). The effect of long-term exposure to lower SBP on coronary heart disease mediated by these polymorphisms was 2-fold greater than that observed in prospective cohort studies (P=0.006) and 3-fold greater than that observed in short-term blood pressure treatment trials (P=0.001). We conclude therefore that SBP seems to be causally associated with the rate of rise in SBP with age and has a cumulative effect on the risk of coronary heart disease.
authors.affiliation: Division of Translational Research and Clinical Epidemiology, Division of Cardiovascular Medicine, Wayne State University School of Medicine, UHC 2E2, Detroit, MI 48202. bference@med.wayne.edu.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Ference
authors.forename: Stevo
authors.initials: S
authors.lastname: Julius
authors.forename: Nitin
authors.initials: N
authors.lastname: Mahajan
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Levy
authors.forename: Kim Allan
authors.initials: KA
authors.lastname: Williams
authors.forename: John M
authors.initials: JM
authors.lastname: Flack
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects* / Q000235:genetics*; D002648:Child; D003327:Coronary Disease / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D017063:Outcome Assessment, Health Care / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D018570:Risk Assessment / Q000706:statistics & numerical data; D012307:Risk Factors; D013997:Time Factors; D055815:Young Adult
chemical_list: D000959:Antihypertensive Agents
keywords: Mendelian randomization analysis; hypertension; prevention & control