Genetic Mapping of Blood Pressure Quantitative Trait Loci in Milan Hypertensive Rats

Abstract

Abstract-In a previous study, by using a candidate gene approach, we detected in both Milan hypertensive rats and humans a polymorphism in the ␣-adducin gene (ADD1) that was associated with blood pressure and renal sodium handling. In the present study, a genomewide search with 264 informative markers was undertaken in 251 (Milan hypertensive strain ϫ Milan normotensive strain) F2 rats to further investigate the contribution of the adducin gene family (Add1, Add2, and Add3) and to identify novel quantitative trait loci (QTLs) that affect blood pressure. The influence of 2 different methods of blood pressure measurement, the intracarotid catheter and the tail-cuff method, was also evaluated. We found evidence that QTLs affected systolic blood pressure (SBP) measured at the carotid (direct SBP) on rat chromosome 1 with a logarithm of the odds (LOD) score peak of 3.3 on D1Rat121 and on rat chromosome 14 on Add1 locus (LODϭ3.2). A QTL for SBP measured at the tail (indirect SBP) was found on rat chromosome 10 around D10Rat33 (LODϭ5.0). All of these QTLs identified chromosomal regions not detected in other rat studies and harbor genes (Na ϩ /H ϩ exchanger A3; ␣-adducin; ␣ 1B -adrenergic receptor) that may be involved in blood pressure regulation. Therefore, these findings may be relevant to human hypertension, also in consideration of the biochemical and pathophysiological similarities between MHS and a subgroup of patients of primary hypertension, which led to the identification of ␣-adducin as a candidate gene in both species. (Hypertension. 2000;36:734-739.) Key Words: genes Ⅲ rats, inbred strains Ⅲ hypertension, essential A variety of strategies can be applied to demonstrate the molecular genetic determinants of human essential hypertension. Our approach was to study, in parallel, hypertensive patients and an animal model of genetic hypertension, the Milan hypertensive strain (MHS) rat with its normotensive control (Milan normotensive strain [MNS]). 1 In this way, it may be possible to reduce the enormous complexity that arises from the polygenic nature of hypertension, the environmental and genetic context dependency of each gene effect, and all of the consequences that these 2 confounding characteristics may have at the different levels of biological organization. The main drawbacks of this strategy are that (1) only the genes at work in a particular strain of rats can be detected, and other genes, with their interactions, that may be involved in human hypertension are ignored, and (2) the small degree of polymorphism between 2 strains of rats derived from common ancestors may hamper the detection of a number of polymorphic markers suitable to carry out a total genome search and the congenic strain selection. This last limitation considerably delayed the whole genome screening in the MHSϫMNS cross. The continuous improvements and the recent availability of new rat markers 2-4 allowed us to provide a systematic genome scan for blood pressure (BP) quantitative trait loci (QTLs) in an (MHSϫMNS) F2 population.Bioche...

Genomewide Linkage Scan of Resting Blood Pressure

“…Two plausible candidates in this region include the transforming growth factor ␣ (TGFA) and adducin 2 (␤, ADD2) genes. ADD2 was found to be a modulator of a missense mutation in ADD1 (␣-adducin) in Milan hypertensive rats (see, for example, Zagato et al 20 ), and in humans ADD1 was associated with hypertension (see, for example, Cusi et al 21 ). TGFA, among other functions, is involved in development of the vascular supply as a regulator of angiogenesis (see, for example, Ferrara 22 ).…”

γ-Adducin Stimulates the Thiazide-sensitive NaCl Cotransporter

“…26 ␥-Adducin was selected as an interesting candidate on the basis of the previous involvement of this protein family in primary hypertension in both humans and rats. [27][28][29] Here, we delineated the molecular basis by which ␥-adducin stimulates the activity of NCC.…”

Hunting for genes for hypertension: the Millennium Genome Project for Hypertension

“…Point mutations on the Add1 and Add2 genes account for the 50% BP difference between Milan hypertensive and normotensive strains via the modulation of Na þ -K þ activity. 8,9 In humans, association of the ADD1 G460W polymorphism (rs4961) with hypertension has been widely investigated in various populations 7 under the hypothesis that the ADD1 W allele accelerates Na þ -K þ co-transport, 10 which in turn results in increased renal sodium reabsorption. As for the ADD2 gene, several articles have reported that this may confer susceptibility in association analyses.…”