Previous evidence supports a role of atrial natriuretic peptide (ANP) as a candidate gene for hypertension. We characterized an ANP gene promoter variant, which has been associated with lower peptide levels, in a sample of young male subjects from Southern Italy (n=395, mean age=35.2+/-2 years) followed up for 28 years. In this cohort, the ANP gene variant was associated with early blood pressure increase and predisposition to develop hypertension

BARBA G

BARBATO D

EVANGELISTA A

IACONE R

RUBATTU, Speranza Donatella

STANZIONE R

STRAZZULLO P.

VOLPE, Massimo

English

Archivio della ricerca- Università di Roma La Sapienza

RESEARCH LETTERAtrial natriuretic peptide (ANP) genepromoter variant and increasedsusceptibility to early developmentof hypertension in humansJournal of Human Hypertension (2007) 21, 822–824;doi:10.1038/sj.jhh.1002228; published online 24 May 2007Previous evidence supports a role of atrial natri-uretic peptide (ANP) as a candidate gene forhypertension. We characterized an ANP genepromoter variant, which has been associated withlower peptide levels, in a sample of young malesubjects from Southern Italy (n¼ 395, meanage¼ 35.272 years) followed up for 28 years. Inthis cohort, the ANP gene variant was associatedwith early blood pressure increase and predisposi-tion to develop hypertension.Primary hypertension represents a complex car-diovascular trait determined by both environmentaland genetic factors.1,2 The gene encoding ANP, acardiac hormone with natriuretic diuretic andvasodilatory properties,3 has been shown to favourdevelopment of high BP levels in geneticallymanipulated animal models.4,5 Similar results wereobtained with the manipulation of NPRA (natriure-tic peptide receptor type A) gene.6 Furthermore, theefficacy of a regulatable ANP gene therapy forhypertension has been recently demonstrated.7 Inhumans, the contributory role of ANP gene intopredisposition to develop hypertension has been sofar explored through a few case–control associationstudies with variable results.8,9In this study, we tested the hypothesis that anANP gene promoter polymorphism, which has beenassociated to lower NT-proANP plasma levels,10could represent a valuable tool to investigate thecontributory role of ANP on susceptibility to devel-op hypertension. We used a cohort of young malesubjects (n¼ 395) followed up for 28 years from theOlivetti Heart Study, a survey of cardiovascular riskfactors carried out in Southern Italy.11 At baseline(1975) and subsequent follow-up visits (1987, 1994–1995, and 2002–2004), each participant underwentanthropometry and BP measurements, and a venousblood sample was drawn. Personal and familiarmedical history was collected in the interview.Hypertension was diagnosed when BP was X140and/or 90 mm Hg or in subjects under regularantihypertensive therapy.Genotyping for the ANP gene was performed ongenomic DNA throughout the analysis of a –C664Gpromoter polymorphism by an RsaI restrictionfragment length polymorphism (RFLP) assay, aspreviously reported.8,10,12 The Hardy–Weinbergequilibrium (HWE) was tested by w2 goodness-of-fittest. Differences in quantitative variables accordingto the genotype were tested by Student’s t-test forunpaired data and by analysis of covariance toaccount for possible confounders. The frequen-cies of outcomes (hypertension, antihypertensivetherapy) by exposure factor (genotype) were com-pared by w2 statistics. Results were expressed asmean7s.d. Statistical significance was acceptedat Po0.05. Statistical analysis was performed bySPSS 10.0.The less common ANP promoter allele waspresent in 17 individuals (4.3% of the studypopulation), a proportion similar to that reportedfor other Caucasian populations.10,12 The genotypedistribution followed the HWE (w2¼ 0.191; P¼ 0.66).At the time of enrolment (1975), when the mean ageof the subjects was 3572 years, no between-genotype difference was observed with regard toprevalence of obesity, levels of metabolic parametersand smoking habits. In contrast, systolic bloodpressure (BP) was significantly higher in theheterozygous (131.8723.5 mm Hg) as compared tothe wild-type genotype (123.6714.2 mm Hg),P¼ 0.02. Diastolic BP tended also to be higher inheterozygous than in wild type (86715.7 vs81.579.9 mm Hg, P¼ 0.07), also accounting forage and body mass index. At the last follow-upvisit (2002–2004) no significant differences betweenheterozygous and wild-type participants weredetected.As shown in Figure 1 (upper panel), prevalence ofhypertension was significantly higher among het-erozygous at baseline (w2¼ 4.376, Po0.05), while thedifference was no longer significant at subsequentfollow-up visits. The use of antihypertensive treat-ment was significantly higher among heterozygousat the earlier 1987 examination (w2¼ 7.902, P¼ 0.02)but not at the following examinations (Figure 1,bottom panel). At the 2002–2004 visit (28-yearfollow-up), the heterozygous group reported a high-er occurrence of transitory cerebrovascular ischemicevents (5.9 vs 0.5% in wild type, Po0.05), and,among their first-degree relatives, a greater numberJournal of Human Hypertension (2007) 21, 822–824& 2007 Nature Publishing Group All rights reserved 0950-9240/07 $30.00www.nature.com/jhhof strokes along with a trend for a higher prevalenceof hypertension.We show that subjects harbouring the ANPpromoter gene allelic variant are more susceptibleto develop hypertension at a younger age, and showin an early phase of life higher BP levels ascompared to subjects carrying the wild-type ANPgene variant. The same individuals required moreoften and at an earlier age the prescription of anantihypertensive treatment. The influence of ANPgene appeared to be independent of age, obesity,smoking and diabetes status. This result providesthe first evidence of a direct contributory role ofANP gene to hypertension development in humans.The ANP promoter polymorphism investigated inthe present analysis has been associated with lowerplasma NT-proANP levels.10 Therefore, it seemsreasonable that lower ANP levels determine higherBP levels and favour development of sustainedhypertension at a younger age.It is well known that genetic studies performed inyoung subjects are expected to be more powerfulon identifying genes causing diseases. In fact, theeffects of exposure to risk factors related to environ-ment and lifestyles have less of an impact in youngindividuals. In addition, the 28 years longitudinalobservation has allowed us to recognize the pre-cocious need for antihypertensive therapy amongcarriers of the promoter allelic variant. Of interest, agreater incidence of transient ischemic cerebrovas-cular events and a certain degree of familialaggregation for cardiovascular diseases were ob-served among heterozygous compared with wild-type homozygous individuals for the ANP genevariant.S Rubattu1,2, A Evangelista2, D Barbato2, G Barba3, RStanzione2, R Iacone4, M Volpe1,2 and P Strazzullo4,on behalf of the Olivetti Heart Study Research Group1Department of Cardiology, IInd School of Medicine,University La Sapienza, Ospedale S. Andrea, Rome,Italy;2IRCCS Neuromed, Cardiology Department, PoloMolisano University, La Sapienza, Pozzilli, Isernia,Italy;3Epidemiology and Population Genetics, Institute ofFood Sciences, CNR, Avellino, Italy and4Department of Clinical & Experimental Medicine,Federico II University of Naples Medical School,Naples, ItalyE-mail: speranza.rubattu@neuromed.itPublished online 24 May 2007References1 Ward R. Familial aggregation and genetic epidemiol-ogy of blood pressure. In: Laragh JH, Brenner BM (eds).Hypertension: Pathphysiology, Diagnosis and Manage-ment. Raven Press : New York, 1990, pp 81–100.1975 1987 1994 2002-04Antihypertensive Rx (%)P<0.050204060801000204060801001975 1987 1994 2002-04Wild typeWild typeHeterozygousHeterozygousPrevalence of hypertension (%)P<0.05Figure 1 Over time prevalence of hypertension (upper panel)and of antihypertensive therapy (bottom panel) by –C664G ANPgene promoter polymorphism. The prevalence of hypertension atthe 1975 examination was significantly higher in the hetero-zygous individuals than in the wild-type carriers (w2¼4.376,Po0.05) as well as the use of antihypertensive treatment at the1987 examination (w2¼ 7.902, P¼ 0.02).What is known about this topic:K Hypertension represents a complex cardiovascular trait due toboth genetic and environmental factors.1K The atrial natriuretic peptide (ANP) plays a pivotal role in themaintenance of blood pressure homeostasis through itsdiuretic, natriuretic and vasodilatory effects.3K The gene encoding ANP is a plausible contributor toincreased susceptibility to develop hypertension. In fact,ablation of ANP gene leads to a form of salt-sensitivehypertension,4 whereas overexpression of ANP causeshypotension.5What this study adds:K A molecular variant of ANP gene, which falls within thepromoter region and has been previously associated toreduced NT-proANP plasma levels,10 is associated withsignificantly higher blood pressure levels and with anincreased prevalence of hypertension in young male subjects.K Carriers of the ANP gene promoter allelic variant show anincreased predisposition to develop hypertension along withan increased occurrence of transitory cerebrovascularischemic events over a 28-year follow-up period.K This study provides the first epidemiological evidence inhumans of the effect of an ANP gene variant on susceptibilityto early development of hypertension, thanks to a combinedcross-sectional and longitudinal approach.Research Letter823Journal of Human Hypertension2 Lifton RP, Gharavi AG, Geller DS. Molecular mechan-isms of human hypertension. Cell 2001; 104: 545–556.3 Levin ER, Gardner DG, Samson WK. Natriureticpeptides. N Engl J Med 1998; 339: 321–328.4 John SW, Krege JH, Oliver PM, Hagaman JR, Hodgin JB,Pang SC et al. Genetic decreases in atrial natriureticpeptide and salt sensitive hypertension. Science 1995;267: 679–683.5 Steinhelper ME, Cochrane KL, Field IJ. Hypotension intransgenic mice expressing atrial natriuretic factorfusion genes. Hypertension 1990; 16: 301–307.6 Oliver PM, Fox JE, Kim R, Rockman HA, Kim HS,Reddick RL et al. Hypertension, cardiac hypertrophy, andsudden death in mice lacking natriuretic peptide receptorA. Proc Natl Acad Sci USA 1997; 94: 14730–14735.7 Schillinger KJ, Tsai SY, Taffet GE, Reddy AK, MarianAJ, Entman ML et al. Regulatable atrial natriureticpeptide gene therapy for hypertension. Proc Natl AcadSci USA 2005; 102: 13789–13794.8 Kato N, Sugiyama T, Murita H, Nabika T, Kurihara H,Yamori T et al. Genetic analysis of the atrial natriureticpeptide gene in essential hypertension. Clin Sci 2000;98: 251–258.9 Beige J, Ringel J, Hohenbleicher H, Rubattu S, KreutzR, Sharma AM. HpaII polymorphism of the atrialnatriuretic peptide gene and essential hypertension inwhites. Am J Hypertens 1997; 10: 1316–1318.10 Rubattu S, Bigatti G, Evangelista A, Lanzani C,Stanzione R, Zagato L et al. Association of atrialnatriuretic peptide and type-A natriuretic peptidereceptor gene polimorphisms with left ventricularmass in human essential hypertension. J Am CollCardiol 2006; 48: 499–505.11 Strazzullo P, Iacone R, Iacoviello L, Russo O, Barba G,Russo P et al. Genetic variation in the renin-angioten-sin system and the development of obesity in men: theOlivetti Prospective Heart Study. Ann Int Med 2003;138: 17–23.12 Rubattu S, Stanzione R, Di Angelantonio E, Zanda B,Evangelista A, Tarasi D et al. Atrial natriuretic peptidegene polymorphisms and risk of ischemic stroke inhumans. Stroke 2004; 35: 814–818.Research Letter824Journal of Human Hypertension

Atrial natriuretic peptide (ANP) gene promoter variant and increased susceptibility to early development of hypertension in humans.

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Atrial natriuretic peptide (ANP) gene promoter variant and increased susceptibility to early development of hypertension in humans.

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