**1. Introduction**

The atrial natriuretic peptide (ANP) belongs to the natriuretic peptide family along with brain (BNP) and C-type (CNP) natriuretic peptides [1]. It is mainly secreted by the atrial cardiomyocytes and exerts important regulatory functions for the maintenance of cardio-renal homeostasis. The latter is achieved through the activation of guanylyl cyclase (GC)-coupled receptor, mainly GC-A, and an increase of cyclic guanylate monophosphate (cGMP) levels [2]. ANP plays natriuretic, diuretic, and vasorelaxant effects [1,2]. In addition, it exerts antiproliferative, antifibrotic, antiangiogenetic functions and, consequently, it contributes to the cardiovascular remodeling process [3]. An extra-atrial expression of ANP has been reported [4].

The gene encoding ANP (*NPPA*) is located in the distal arm of chromosome 1 (1p36.2), in tandem with the gene encoding brain natriuretic peptide (BNP). It includes three exons and two introns [5]. The signal sequence is located on exon 1, whereas the coding sequence is located on exon 2; exon3 encodes the terminal tyrosine and the 3 untranslated region.

Human ANP is synthetized as a pre-prohormone of 151 amino acids and it is subsequently cleaved to obtain a biologically active α-carboxy-terminal peptide along with the amino-terminal end. After removal of the signal peptide, the proANP1–126 is released and stored into granules within the atrial cardiomyocytes. Before secretion, proANP1–126 is processed by corin, a type II transmembrane serine protease [2], into the circulating forms of ANP(1–98) and ANP(99–126). Of note, the active corin protease is obtained through the cleavage of procorin by PCSK6 [6,7]. The major form of biological active ANP is the 28-amino acid carboxy-terminal peptide, ANP(99–126). On the other hand, further cleavage of the ANP(1–98) generates LANP (long-acting natriuretic peptide), the vessel dilator, and the kaliuretic hormone [8]. The primary structure of αANP is conserved across species, apart from few variations. In particular, an isoleucine is present at position 10 in rats, mice, and rabbits, whereas humans, dogs, and bovines have a methionine at this position.

Both the high degree of homology and the persistence in the phylogenetic scale support the key role of the ANP primary structure in order to perform its functions.

The relevance of the ANP primary structure to allow the regular biological activities of the peptide has also been underscored by the discovery of few gene variants that change the amino acid sequence and, consequently, the physiological properties of ANP [9].

The first evidence in this regard was obtained in an animal model of spontaneous hypertension and increased predisposition to cerebrovascular disease, the stroke-prone spontaneously hypertensive rat (SHRSP). In this model, the ANP gene was found to map at the peak of linkage of a stroke quantitative trait locus (QTL) [10] and to carry both a variant within the promoter sequence and a variant within the exon 2 sequence, with consequent alterations of peptide regulation, expression, and function [11–13]. The latter were associated with the higher stroke susceptibility of the strain [10–14].

The subsequent translation of the rat data to the human disease led to very interesting findings. In fact, with regard to the human gene, several variants were reported to fall within the promoter region, the coding, and the intronic parts, as well as within the 3 end of the gene [9]. These gene variants were associated either with alterations in gene expression and peptide levels (rs5068, G664C) or with an abnormal peptide structure (rs5065). Their contribution to hypertension, coronary artery disease, atrial fibrillation, cardiac hypertrophy, heart failure, and the metabolic syndrome was explored in distinct studies with several remarkable results [9].

The present review article will discuss the role of the rs5065 (T2238C) ANP gene variant since it has revealed important biological and pathological effects and has emerged as a relevant risk factor for the development of cardiovascular diseases.
