Natriuretic Peptide Precursor A Gene Polymorphisms and Risk of Blood Pressure Progression and Incident Hypertension

Abstract

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

Association of CVD Candidate Gene Polymorphisms with Ischemic Stroke and Cerebral Hemorrhage in Chinese Individuals

“…The strategy was initially designed to increase the chance of finding genes predisposing to ischemic stroke and cerebral hemorrhage independent of blood pressure. In addition, it has been noted that in a large-scale prospective study, the A allele of NPPA rs5063 has provided a protective effect for blood pressure progression in 48 months and incident hypertension for the entire follow-up[41]. Qian ea al, reported that in a meta-analysis that MTHFR rs1801133 was significantly associated with hypertension among both the European and East Asian adult population [42].…”

Blood pressure and urinary sodium excretion in relation to 16 genetic polymorphisms in the natriuretic peptide system in Chinese

“…Of these genetic variants, two known missense variants (rs5063 and rs5065) in the NPPA gene have been shown to be associated with hypertension [15,16], coronary heart disease [30], stroke [31,32], and response to diuretic therapy [17]. In addition, several other SNPs at the NPPA-NPPB locus (rs198388, rs198389, rs6668352) [33] and the NPPC (rs5268) [34], NPRA (rs28730726) [35] and NPRC genes (rs700923) [33] were reported to be associated with the risk of left ventricular dysfunction after primary coronary artery bypass grafting and with the risk of hypertension.…”

“…Extension products were purified by a 15-min incubation with 1 U of shrimp alkaline phosphatase (Promega, Madison, Wisconsin, USA) at 37 °C and a subsequent 15-min incubation at 80 °C to inactivate the enzyme. The purified products (0.5 μL) were mixed with 9 μL of formamide and 0.5 μL of GeneScan-120 LIZ Size Standard (Applied Biosystems) and separated 15,16], and response to diuretic therapy [17]. In addition, the minor alleles of two highly linked polymorphisms (T555I/Q568P) in the Corin gene were reported to be associated with increased risk of hypertension and enhanced cardiac hypertrophic response to pressure overload in African Americans [18,19].…”

A Contemporary Review on the Genetic Basis of Atrial Fibrillation

“…notably, two common genetic variants that create nonsynonymous amino acid changes within nPPa, rs5063, and rs5065 had previously been implicated in conditions associated with af. 55, 56 a small Chinese study had suggested that the presence of rs5063 resulted in an increased risk of af. 57 however, our study involving 620 af cases and 2,446 controls found no association between either single nucleotide polymorphism (snp) and the risk of af.…”