Genetic Mapping of Blood Pressure Quantitative Trait Loci in Milan Hypertensive Rats (original) (raw)

Role of the adducin family genes in human essential hypertension

Journal of Hypertension, 2005

Objective In both humans and rats, polymorphisms of the alpha adducin (ADD1) gene are involved in renal sodium handling, essential hypertension and some of its organ complications. Adducin functions within cells as a heterodimer composed of various combinations of three subunits that are coded by three genes (ADD1, 2, 3) each located on a different chromosome. Design These characteristics provide the biochemical basis for investigating epistatic interactions among these loci. Methods We examined the three adducin gene polymorphisms and their association with ambulatory blood pressure (ABPM) and with plasma levels of renin activity (PRA), endogenous ouabain (EO), in 512 newly discovered and never-treated hypertensive patients. Results Relative to carriers of the wild type (Gly/Gly) ADD1 gene, patients carrying the mutated Trp ADD1 allele had higher blood pressure (systolic blood pressure (SBP) 143.2 W 1.0 versus 140.6 W 0.6 mmHg P U 0.027 and diastolic blood pressure (DBP) 94.2 W 0.77 versus 92.3 W 0.5 mmHg, P U 0.03), lower PRA and EO, consistent with the hypothesis of the renal sodium retaining effect of the Trp allele. Polymorphisms in the ADD2 and ADD3 genes taken alone were not associated with these variables. However, the differences in SBP and DBP between the two ADD1 genotypes were greatest in carriers of the ADD3 G allele (around + 8 mmHg). The significance of the interaction between ADD1 and ADD3 ranged between P = 0.020 to P = 0.006 according to the genetic model applied. Conclusions The interaction of ADD1 and ADD3 gene variants in humans is statistically associated with variation in blood pressure, suggesting the presence of epistatic effects among these loci.

Association and linkage analysis of the α-adducin gene and blood pressure

In Milan hypertensive rats, a variant in the ␣adducin gene has been shown to account for approximately 50% of the interindividual variation in blood pressure levels between these animals and their normotensive counterparts. Additional studies have suggested that a polymorphism within exon 10 of the human ␣-adducin gene (Gly-460-Trp) may be associated with hypertension and salt sensitivity. On the basis of these observations, we investigated variation within or near the human ␣-adducin gene for linkage and association with a locus influencing blood pressure levels in 281 nuclear families (774 siblings aged 5 to 37 years; 380 parents aged 26 to 57 years), selected from the white population of Rochester, Minnesota, without regard to health. Sib pair linkage analyses (n ‫؍‬ ‫؍‬ 852 sibling pairs) using a dinucleotide repeat marker (D4S43) that maps approximately 660 kb from the ␣-adducin gene provided no evidence of linkage between this marker locus and a locus influencing systolic, diastolic, or mean blood pressure levels. Allele frequencies for the Gly-460-Trp polymorphism were similar to those reported in other white populations (Gly ‫؍‬ ‫؍‬ 0.812, Trp ‫؍‬ ‫؍‬ 0.188); however, this polymorphism was not associated with any measure of blood pressure level in either parents or siblings. Therefore, variation within the ␣adducin gene does not appear to have a major influence on measures of blood pressure in white families from Rochester, Minnesota. Am J Hypertens 2000;13:699 -703

Two Point Mutations within the Adducin Genes are Involved in Blood Pressure Variation

Proceedings of The National Academy of Sciences, 1994

The Milan hypertensive strain of rats (MHS) develops a genetic form of renal hypertension that, when compared to its normotensive control (MNS), shows renal dysfunction similar to that of a subset of human patients with primary hypertension. MHS and MNS were shown to be homozygous by multilocus miisatellite analysis and monolocus microsatellite markers. We show here that one point mutation in each of two genes coding for the membrane skeleton protein adducin is associated with blood pressure in the Milan strain of rats. Adducin is a heterodimer formed by a and 13 subunits that promotes the assembly of actin with spectrin. MHS and

Genetics of primary hypertension: The clinical impact of adducin polymorphisms

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2010

The usefulness of the results so far published on genetics of primary hypertension for establishing the clinical impact of candidate gene polymorphisms is weakened by the scanty information regarding: a) the functional effect of the gene variants of interest in humans; b) the regulatory genetic network (RGN) where the gene is operating with all the interacting environmental-biological factors and the respective hierarchical organization; c) the consistency between the natural history of the established pathophysiological mechanisms underlying hypertension and the new molecular mechanism detected with genetics; d) the limitations regarding the translation of animal data to human due to the differences among species of the genetic molecular mechanisms underlying similar organ function changes in the different species. Of course, not all these information are available for adducin polymorphisms. In this review, being aware of their importance, the evaluation of the clinical impact of adducin has been focused on data obtained together with the interacting genetic-environmental or biological factors. Adducin polymorphisms and endogenous ouabain (EO) were detected by a top-down approach in rodents after having demonstrated, at cellular and kidney level, that an increase in tubular Na reabsorption could underlies the transition from normotension to hypertension both in rodents and humans. Therefore, we hypothesized that adducin polymorphisms and EO may operate within the triggering RGN that initiates the increase in blood pressure in both species. The distinction between triggering RGN and the secondary RGN is important both to limit the level of genetic complexity arising from secondary changes, and to detect the molecular target to develop tailored therapeutic approach. The pharmacogenomic approach, both in rodents or humans, with newly discovered and never treated hypertension, may be useful to strengthen the "causation" of genetic mechanism. Mutant adducin increases tubular reabsorption: diuretics, because of their effect on overall tubular reabsorption, or rostafuroxin, because of its selective inhibition of the adducin and ouabain effects, may be used for this purpose. Indeed the pharmacogenomic approach with both drugs have provided data consistent with the role of adducin and EO. Taken together, all these findings indicate a clear impact of adducin polymorphism and EO in a subset of patients when the appropriate environmental, biological or genetic context is taken into account. The size of this impact is variable and affected by the context.

Adducin Polymorphism: Detection and Impact on Hypertension and Related Disorders

Hypertension, 2005

Adducin is a heterodymeric cytoskeleton protein, the 3 subunits of which are encoded by genes (ADD1, ADD2, ADD3) mapping to 3 different chromosomes. A long series of parallel studies in the Milan hypertensive rat strain model of hypertension and humans indicated that an altered adducin function may cause hypertension through an enhanced constitutive tubular sodium reabsorption. Six human linkage studies showed positive results when a DNA marker mapping to 30 kb from the ADD1 locus or single-nucleotide polymorphisms (SNPs) of 1 of the 3 adducin genes were considered either alone or in combination with each other or angiotensin-converting enzyme (ACE) D allele or salt intake. When DNA markers mapping at much larger distance from the ADD1 locus were used, negative results were found by 4 studies. Positive results were also obtained in 18 of 20 association studies that, in addition to blood pressure, investigated variables reflecting body sodium or the renin-angiotensin system. Mixed results regarded case-control studies or studies in predominantly normotensive populations that did not consider the above-mentioned variables. Four of 5 studies showed a selective beneficial effect of diuretics in carriers of the mutated ADD1. Twelve of 16 studies found that ADD1 polymorphism alone or in combination with that of ACE positively associates with stroke or coronary heart disease or renal or vascular dysfunctions. In conclusion, when context is taken into account, the impact of adducin in hypertension and its related disorders is clear. (Hypertension. 2005;45:331-340.)

Association between hypertension and variation in the α- and β-adducin genes in a white population

Kidney International, 2002

all women, 2.92 (P ϭ 0.03) in post-menopausal subjects, and Association between hypertension and variation in the ␣and 3.79 (P ϭ 0.09) in users of oral contraceptives. ␤-adducin genes in a white population. Conclusions. The 1797T allele of the ␤-adducin gene is asso-Background. The substitution of tryptophan for glycine at ciated with increased risk of hypertension in post-menopausal amino acid 460 (Gly460Trp polymorphism) of the ␣-subunit women and in users of oral contraceptives, particularly in the of the heterodimeric cytoskeleton protein adducin increases presence of the mutated ␣-adducin Trp allele. We hypothesize renal sodium reabsorption and may be involved in the pathothat inhibition of the renin-aldosterone system in men and physiology of essential hypertension. In the present study, we absence of such a compensatory mechanism in women may investigated in multivariate analyses whether the risk of hyperexplain, at least to some extent, the sexual dimorphism of the tension was associated with the C1797T polymorphism of the blood pressure phenotype in relation to the C1797T ␤-adducin ␤-adducin gene. polymorphism. Methods. A total of 1848 subjects randomly selected from a white population were genotyped. Study nurses measured blood pressure at the participants' homes. Results. The frequencies of the ␣-adducin Trp and ␤-adducin Adducin is a ubiquitously expressed membrane-skele-T alleles were 0.23 and 0.11, respectively. In men (N ϭ 904), ton protein, which is composed of either ␣ and ␤ or ␣ the ␤-adducin T allele was not associated with hypertension and ␥ subunits that to a large extent are similar in amino [adjusted relative risk (RR) vs. CC homozygotes 0.94, P ϭ 0.77], but T allele carriers had lower plasma renin activity acid sequence and domain organization [1]. Adducin (PRA) and 24-hour urinary aldosterone excretion (P Ͻ 0.04). plays an important role in the determination of cellular In all women (N ϭ 944), ␤-adducin T allele carriers had a morphology and motility and in the regulation of memhigher risk of hypertension than CC homozygotes (RR 1.81, brane ion transport [1-3]. Point mutations of the ␣and CI 1.18-2.77, P ϭ 0.007), but similar PRA and 24-hour urinary ␤-adducin account for up to 50% of the blood pressure aldosterone excretion (P Ͼ 0.29). In 345 post-menopausal women and 190 users of oral contraceptives, the RRs of hyperdifference between Milan normotensive and hypertentension were 2.47 (CI 1.34-4.64, P ϭ 0.003) and 2.56 (CI sive rat strains [4], probably via the modulation of the 0.83-7.86, P ϭ 0.10), respectively. For systolic pressure in Na ϩ-K ϩ ATPase activity [2, 3]. The Gly460Trp polymorwomen, there was a significant interaction (P ϭ 0.02) between phism of the human ␣-adducin gene is associated with sothe ␣and ␤-adducin polymorphisms. Only in female carriers dium sensitivity [5-8]. Hypertensive carriers of the 460Trp of the mutated ␣-adducin Trp allele was the systolic pressure significantly higher in ␤-adducin T allele carriers compared allele of the ␣-adducin gene, compared with GlyGly howith CC homozygotes (ϩ3.8 mm Hg, P ϭ 0.02). Furthermore, mozygotes, show an enhanced membrane sodium transin the presence of the mutated ␣-adducin Trp allele, the RRs port rate in erythrocytes [8], higher proximal tubular associated with the ␤-adducin T allele were 2.35 (P ϭ 0.01) in renal reabsorption of sodium [6, 7], and larger blood pressure changes in response to sodium loading or diuretic treatment [5]. Several [5, 9, 10], though not all [11, 12],

Genetics of hypertension: From experimental animals to humans

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2010

Essential hypertension affects 20 to 30% of the population worldwide and contributes significantly to cardiovascular mortality and morbidity. Heridability of blood pressure is around 15 to 40% but there are also substantial environmental factors affecting blood pressure variability. It is assumed that blood pressure is under the control of a large number of genes each of which has only relatively mild effects. It has therefore been difficult to discover the genes that contribute to blood pressure variation using traditional approaches including candidate gene studies and linkage studies. Animal models of hypertension, particularly in the rat, have led to the discovery of quantitative trait loci harbouring one or several hypertension related genes, but translation of these findings into human essential hypertension remains challenging. Recent development of genotyping technology made large scale genome-wide association studies possible. This approach and the study of monogenic forms of hypertension has led to the discovery of novel and robust candidate genes for human essential hypertension, many of which require functional analysis in experimental models.