Abstract-We tested the hypothesis that natriuretic peptide precursor A gene polymorphisms are significantly associated with blood pressure progression and incident hypertension among healthy, middle-aged women. We performed a prospective cohort study among 18 437 white women participating in the Women's Health Study who were free of hypertension at baseline. Two previously characterized single nucleotide polymorphisms within the natriuretic peptide precursor A gene (rs5063 GϾA and rs5065 TϾC) were genotyped. Blood pressure progression at 48 months and incident hypertension during the entire follow-up according to the different genotypes and inferred haplotypes were assessed by logistic regression and Cox proportional hazards models, respectively. n a Western population, the cumulative lifetime risk of developing hypertension approaches 90%. 1 Although obesity and other environmental factors 2 substantially contribute to the high incidence of hypertension, twin studies suggest that, in human beings, up to one third of the interindividual variability of blood pressure is heritable. 3 Thus, it is important to understand genetic influences on blood pressure and hypertension. However, genetic studies of multifactorial disorders such as hypertension have proven difficult because of the multiplicity of genes underlying complex phenotypes and the modest effect of an individual polymorphism or gene.Atrial natriuretic peptide plays a significant role in the regulation of vascular tone and sodium homeostasis. 4 Experimental studies showed that underexpression of the natriuretic peptide precursor A gene (NPPA; gene ID 4878, chromosome location 1p36.21) is associated with elevated blood pressure in transgenic mice, 5 whereas overexpression of NPPA leads to decreased blood pressure levels. 6 In humans, few studies revealing controversial findings are available on the association between hypertension and polymorphisms within the NPPA gene. [7][8][9][10] The large sample size and long follow-up of the Women's Health Study provide a unique opportunity to prospectively analyze genetic influences on multifactorial disorders. We, therefore, tested the hypothesis that NPPA gene polymorphisms are significantly associated with blood pressure progression and incident hypertension in initially healthy, middle-aged women.
Methods
ParticipantsAll of the study subjects were participants of the Women's Health Study, a completed randomized trial evaluating the risks and benefits of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer among female health professionals. Details of the study design have been described previously. [11][12][13] Briefly, information on baseline variables was collected using mailed questionnaires. Follow-up questionnaires asking participants about study outcomes and other information were sent every 6