Genotype-phenotype association studies have become important tools to explore the pathophysiology of many disease states. They are typically based on single polymorphisms in genes of interest. In some cases multiple polymorphisms within a given gene exist in a fixed combination, i.e. as haplotypes which may exhibit stronger/more consistent associations with phenotypes than single polymorphisms [1, 2].
An expansion of this thought has been based upon studies in the renin-angiotensin-aldosterone (RAAS) system. The RAAS is an important regulator of cardiovascular function and blood pressure [3, 4]. It consists mainly of the angiotensin-converting enzyme (ACE) which metabolizes angiotensinogen (AGT) to form angiotensin II, which can act angiotensin II type 1 receptors (AGTR1) to mediate blood pressure elevations by mechanisms including direct effects on vascular tone and indirect effects via alterations of renal function. Thus, ACE, AGT and AGTR1 act synergistically on the phenotype of blood pressure. Each of the three corresponding genes has several polymorphisms that can be associated with altered expression or function of the corresponding gene product. While each of these polymorphisms may potentially affect the regulation of cardiovascular function by the RAAS, most previous studies have focused on one polymorphism in each of these genes, i.e. the single nucleotide polymorphism (SNP) M235T within exon 2 of the AGT gene, an insertion/deletion (I/D) polymorphism involving 287 bp in intron 16 of the ACE gene and the A1166C SNP in the 3' untranslated part of the AGTR1 gene . The 235T allele of the AGT gene is associated with a stepwise increasing level of circulating angiotensinogen ("gene dose-response") [6, 7]. The ACE I/D polymorphism is strongly associated with the level of circulating enzyme, with mean plasma ACE activities of DD carriers being about twice those of II subjects and heterozygotes having intermediate levels . The direct functional relevance of the 1166C allele of the AGTR1 gene is less clear, but it was shown recently to attenuate the microRNA-155 binding leading to a decreased translation i.e. less receptor density in endothelial and vascular smooth muscle cells  and this is associated with altered serum aldosterone concentrations .
Accordingly, numerous studies have tested whether any of the above three polymorphisms is associated with the presence or severity of arterial hypertension (HT), almost all of them using the categorical variable HT rather than the underlying continuous variables of measured blood pressure. However, the available data remain equivocal as reports of associations have not been consistently confirmed, and even reports on inverse associations have been published [5, 11]. Retrospectively, this is not too surprising as more recent genome wide analyses have not implicated any of these three gene loci in arterial hypertension [12–16]. Therefore, despite being an attractive and pathophysiologically logical concept, the existence of associations between polymorphisms in any of the three main RAAS genes and HT remains unclear. Similarly disappointing results of association studies have been found between polymorphisms of components of the RAAS and some phenotypes other than HT. However, for phenotypes related to renal function a novel concept has been proposed which has yielded stronger genotype-phenotype associations. This concept is based on the idea of synergistic effects of RAAS components and proposes that polymorphisms in each of the RAAS components, which have minor effects in isolation, may have greater effects when they occur concomitantly. Indeed a combined analysis of polymorphisms in the ACE, AGT and AGTR1 genes has shown stronger associations with proximal renal sodium handling  or the development of renal insufficiency  than any of the polymorphisms studied in isolation. While haplotypes represent genetically fixed combinations of polymorphisms within a single gene, this new concept is looking at functionally related polymorphisms (FRPs) . However, the validity of this concept has not been tested against phenotypes other than those directly related to renal function. Against this background, we have explored whether the FRP concept indeed provides stronger/more consistent phenotype associations when applied to a different phenotype, i.e. HT. To increase the robustness of our approach, the high blood pressure phenotype was characterized concomitantly by the presence of HT or by systolic, diastolic or mean arterial pressure.