Atherosclerosis 186 (2006) 428–432 Susceptible and protective eNOS haplotypes in hypertensive black and white subjects Valeria Cristina Sandrim a , Eduardo Barbosa Coelho b , Fernando Nobre b , Gustavo Marin Arado b , Vera Lucia Lanchote c , Jose Eduardo Tanus-Santos a,∗ a Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirao Preto, SP, Brazil b Department of Medicine, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirao Preto, SP, Brazil c Department of Clinical Analysis, Faculty of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirao Preto, SP, Brazil Received 5 May 2005; received in revised form 19 July 2005; accepted 1 August 2005 Available online 15 September 2005 Abstract Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene have been inconsistently associated with hypertension. This inconsis- tency may derive from population stratification secondary to ethnic diversity, and consideration limited to only one rather than combinations of polymorphisms. We studied three genetic variations in the eNOS gene: a single nucleotide polymorphism in the promoter region (T -786 C), in exon 7 (Glu298Asp), and a variable number of tandem repeats in intron 4 (b/a) of the eNOS gene in hypertensives (112 whites and 91 blacks) and normotensives (113 whites and 87 blacks). In addition, we also examined the association of eNOS gene haplotypes with hypertension in white and black subjects. No differences were observed in the frequencies of genotypes and alleles of the three polymorphisms when white hypertensives and white normotensives were compared, or when black hypertensives and black normotensives were compared (all P > 0.05). Conversely, the haplotypes “T Asp b” and “C Glu b” were more common among white (16 and 24%, respectively) and black (17 and 16%, respectively) normotensives than in white (7 and 8%, respectively) and black (4 and 6%, respectively) hypertensives, respectively (all P < 0.0039). In addition, the haplotype “C Asp b” was more commonly found in white hypertensives than in white normotensives (P = 0.0007). These results suggest a contribution of eNOS haplotypes to the development of hypertension that is obscured when specific eNOS genotypes alone are considered. In addition, our results suggest two eNOS haplotypes associated with a protective effect against hypertension in both ethnic groups, and one eNOS haplotype conferring susceptibility to hypertension in white subjects. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Endothelial nitric oxide synthase; Ethnicity; Haplotypes; Hypertension; Nitric oxide; Polymorphism 1. Introduction Hypertension is a multifactorial disease with environmen- tal and genetic components. Since nitric oxide (NO) is a major regulator of the cardiovascular system [1], it is con- ceivable that abnormalities in the activity of the enzyme ∗ Corresponding author. Tel.: +55 16 602 3163; fax: +55 16 633 2301. E-mail address: tanus@fmrp.usp.br (J.E. Tanus-Santos). that synthesizes NO in endothelial cells (endothelial nitric oxide synthase; eNOS) may lead to NO deficiency and cause clinical hypertension [2]. Therefore, a number of studies have been carried out to examine whether polymorphisms in the eNOS gene are associated with hypertension [3–9]. While most studies have focused on three clinically relevant polymorphisms including a single nucleotide polymorphism (SNP) in the promoter region (T -786 C), a SNP in exon 7 that results in an amino acid change (Glu298Asp), and a 0021-9150/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2005.08.003