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Abnormalities in the natriuretic peptide system could play a key role in the genesis of hypertension. We evaluated the associations between a family history of hypertension, cardiovascular phenotype and allelic variants of Npr1 and Npr3, two candidate genes that codify for natriuretic peptide receptors.We genotyped 45 young normotensive subjects (19 males, 26.8 ± 3.7 years) with accurately assessed family history of hypertension (FH+) and 52 (26 males, 26.1 ± 3.1 years) without (FH−) for the known variants of Npr1 and Npr3 genes, and for a novel length difference (3C/4C) polymorphism at position 15129 in the 3′-untranslated region of the Npr1 gene. Blood pressure, echocardiography and plasma brain natriuretic peptide were assessed.Both the novel Npr1 3C allele (59 versus 33%, P< 0.001) and the 3C/3C genotype (31 versus 8%; P< 0.001) were significantly more frequent in FH+ than in FH−. The inverse distribution of the 4C/4C genotype suggested that a casual association was very unlikely. Moreover, the 3C/3C homozygous had significantly higher systolic blood pressure (121.1 ± 6.3 versus 115.6 ± 7.8 mmHg in 4C/4C; P< 0.05) and a longer left ventricular isovolumic relaxation time (67 ± 10 versus 61 ± 9 ms; P< 0.05). The Npr3 C(−55) allele variant was also more frequent in FH+ (88 versus 76%, P< 0.05), but was not associated with the cardiovascular phenotype.The novel Npr1 gene 3C variant and the Npr3 gene C(−55) allele are associated with hypertensive family history. Moreover, the functional Npr1 3C variant, when homozygous, is also associated with higher systolic blood pressure and prolonged ventricular relaxation.