Genetic analysis of the atrial natriuretic peptide gene in essential hypertension

Atrial natriuretic peptide (ANP) plays an important role in the regulation of blood pressure through sodium-water homoeostasis. Accordingly, several investigators have raised the question of whether the gene encoding ANP is involved in the aetiology of essential hypertension or related phenotypes such as salt sensitivity. Most of the studies have used anonymous polymorphic markers of the gene, and made inconclusive claims about the disease relevance of ANP. Therefore, in order to find sequence variations with potential functional significance and to characterize the pattern of linkage disequilibrium between polymorphisms, we screened a 3368-bp genomic fragment of ANP. Subsequently we tested the association of detected polymorphisms with plasma ANP levels and with hypertension status. Two new polymorphisms were identified, in the 5'-untranslated region and exon 1 respectively, as well as three previously reported polymorphisms in intron 2 and exon 3. When analysed in 102 healthy normotensive subjects, none of the polymorphisms appeared to significantly affect plasma ANP levels. A case-control study in a Japanese population (255 hypertensive and 225 normotensive individuals) revealed a marginally significant association (P=0.026) between an ANP polymorphism located in the 5'-untranslated region (C-664G) and hypertension, but no association for the other polymorphisms. Each of the uncommon variants has an allele frequency of less than 10% in Japanese people, which may have hampered our detection of a significant association between ANP variants and hypertension status (and plasma ANP levels). The pathophysiological relevance of ANP, however, needs to be further defined in relation to hypertension-associated phenotypes, and also should be examined in different ethnic groups.