Giuseppe Bianchi - Academia.edu (original) (raw)

Papers by Giuseppe Bianchi

Journal of Hypertension, 1998

Objective To study whether the SA gene locus (on rat chromosome 1) and the sodium potassium ATPas... more Objective To study whether the SA gene locus (on rat chromosome 1) and the sodium potassium ATPase α1 gene locus (on rat chromosome 2) contribute to the elevated blood pressure in the Milan hypertensive rat. Design Co-segregation analysis using polymorphisms in the SA and Na+/K+-ATPase α1 genes in F2 rats from a cross of Milan hypertensive and Milan normotensive rats. Analysis of SA and N+/K+ATPase α1 gene expression in kidneys of 6 and 25 weeks old Milan hypertensive and normotensive rats. Methods Genotyping of F2 rat DNA by restriction digestion and Southern blotting and comparison of messenger RNA levels by northern blot analysis. Results Renal expression of SA was considerably higher in normotensive than it was in hypertensive rats aged 6 and 25 weeks. Despite this difference the SA genotype did not co-segregate with blood pressure, although the Milan hypertensive rat allele did co-segregate with greater body weight (P = 0.0014) for male F2 rats. Expression of Na+/K−-ATPase α1 was higher in the kidneys of young hypertensive rats than it was in those of normotensive rats and did not decline with age as occurred in the normotensive rats. However, again the Na+/K++ATPase α1 genotype did not co-segregate with blood pressure. Conclusions Despite differences in the patterns of expression of SA and Na+/K+-ATPase α1 genes in the kidneys of Milan hypertensive and normotensive rats, we found no evidence of co-segregation of either gene with blood pressure. Our results suggest that either SA is simply acting as marker for a linked gene in other crosses for which co-segregation with blood pressure has been observed, or at least, the level of its renal expression is not the sole determinant of its effect on blood pressure. The failure of the Na+/K+-ATPase α1 gene to co-segregate with blood pressure suggests that its greater expression in the kidney of the Milan hypertensive rat is either reactive or controlled by other genetic loci.

Journal of Pharmacology and Experimental Therapeutics, 2002

The novel Na ϩ /K ϩ-ATPase inhibitor (E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochl... more The novel Na ϩ /K ϩ-ATPase inhibitor (E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride (PST2744) was characterized for its inotropic and toxic properties. Inhibition potency on dog kidney Na ϩ /K ϩ-ATPase was comparable (0.43 M) to that of digoxin (0.45 M). PST2744 concentration-dependently increased force of contraction in guinea pig atria and twitch amplitude in isolated guinea pig myocytes; in the latter, aftercontractions developed significantly less than with digoxin. Intravenous infusion of 0.2 mg/kg/min PST2744 in anesthetized guinea pigs exerted an immediate and long-lasting inotropic effect (ED 80 of 1.89 Ϯ 0.37 mg/kg) without causing lethal arrhythmias up to a cumulative dose of 18 mg/kg. Conversely, an equieffective infusion of digoxin (0.016 mg/kg/min; ED 80 of 0.32 mg/kg) caused lethal arrhythmias at a cumulative dose of 0.81 mg/kg. At a higher rate (0.4 mg/kg/min), PST2744 induced lethal arrhythmias, with a Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

Current Opinion in Nephrology and Hypertension, Mar 1, 1997

Lancet, 1997

Abnormalities in renal sodium transport may be involved in hypertension. Adducin, an α/β heterodi... more Abnormalities in renal sodium transport may be involved in hypertension. Adducin, an α/β heterodimeric protein found in the renal tubule is thought to regulate ion transport through changes in the actin cytoskeleton. We investigated whether an α-adducin polymorphism (Gly 460 Trp) is involved in essential hypertension in two separate populations.Linkage analysis of three DNA markers at different distances from the α-adducin locus (20-2500 kb) was done in 137 hypertensive sibling-pairs. 477 hypertensive and 322 normotensive individuals were genotyped for the α-adducin polymorphism. The blood-pressure response to acute and chronic changes in sodium balance was studied in hypertensive individuals with and without the 460 Trp α-adducin allele.Significant linkage was found for all three markers in the sibling-pair study. The extra shared alleles (9·1%, 6·5%, and 4·7%) and the significance level for linkage (p=0·0006, p=0·0119, and p=0·0211) both decreased with increasing distance from the α-adducin locus. There was a significant association between the 460 Trp mutation and hypertension (p=0·0003). In the salt-sensitivity test, to assess the acute blood-pressure response to changes in body sodium in 86 hypertensive patients, the decrease in mean arterial pressure was greater in 65 patients who were heterozygous for the mutant allele (Gly/Trp) than in 21 wild-type homozygotes (Gly/Gly) (mean decrease 15·9 [SE 2·0] vs 7·4 [1·3] mm Hg; p=0·001). Similarly, 21 heterozygous hypertensive patients showed a greater fall in mean arterial pressure in response to 2 months' treatment with hydrochlorothiazide than did 37 wild-type homozygous hypertensive patients (mean decrease 14·7 [2·2] vs 6·8 [1·4] mm Hg; p=0·002).Our findings of significant linkage of the α-adducin locus to essential hypertension and greater sensitivity to changes in sodium balance among patients with the mutant allele suggest that α-adducin is associated with a salt-sensitive form of essential hypertension. We suggest the α-adducin polymorphism may identify hypertensive patients who will benefit from diuretic treatment or manoeuvres to reduce total body sodium.

The Lancet, 1997

Abnormalities in renal sodium transport may be involved in hypertension. Adducin, an alpha/beta h... more Abnormalities in renal sodium transport may be involved in hypertension. Adducin, an alpha/beta heterodimeric protein found in the renal tubule is thought to regulate ion transport through changes in the actin cytoskeleton. We investigated whether an alpha-adducin polymorphism (Gly 460 Trp) is involved in essential hypertension in two separate populations. Linkage analysis of three DNA markers at different distances from the alpha-adducin locus (20-2500 kb) was done in 137 hypertensive sibling-pairs. 477 hypertensive and 322 normotensive individuals were genotyped for the alpha-adducin polymorphism. The blood-pressure response to acute and chronic changes in sodium balance was studied in hypertensive individuals with and without the 460 Trp alpha-adducin allele. Significant linkage was found for all three markers in the sibling-pair study. The extra shared alleles (9.1%, 6.5%, and 4.7%) and the significance level for linkage (p = 0.0006, p = 0.0119, and p = 0.0211) both decreased with increasing distance from the alpha-adducin locus. There was a significant association between the 460 Trp mutation and hypertension (p = 0.0003). In the salt-sensitivity test, to assess the acute blood-pressure response to changes in body sodium in 86 hypertensive patients, the decrease in mean arterial pressure was greater in 65 patients who were heterozygous for the mutant allele (Gly/Trp) than in 21 wild-type homozygotes (Gly/Gly) (mean decrease 15.9 [SE 2.0] vs 7.4 [1.3] mm Hg; p = 0.001). Similarly, 21 heterozygous hypertensive patients showed a greater fall in mean arterial pressure in response to 2 months&amp;#39; treatment with hydrochlorothiazide than did 37 wild-type homozygous hypertensive patients (mean decrease 14.7 [2.2] vs 6.8 [1.4] mm Hg; p = 0.002). Our findings of significant linkage of the alpha-adducin locus to essential hypertension and greater sensitivity to changes in sodium balance among patients with the mutant allele suggest that alpha-adducin is associated with a salt-sensitive form of essential hypertension. We suggest the alpha-adducin polymorphism may identify hypertensive patients who will benefit from diuretic treatment or manoeuvres to reduce total body sodium.

American Journal of Hypertension, 2009

nature publishing group Endogenous ouabain (EO), a mammalian counterpart to the plant-derived car... more nature publishing group Endogenous ouabain (EO), a mammalian counterpart to the plant-derived cardiac glycoside ouabain, is synthesized and released from the adrenal glands and possibly from the hypothalamus. EO is a versatile modulator of the ubiquitously expressed Na + pump and has been linked to human essential hypertension and cardiac hypertrophy. 1-6 Also in genetically hypertensive Milan rats (MHS), Na/K-ATPase activity and blood pressure levels are associated (M. Ferrandi, personal communication) to elevated hypothalamic and plasma levels of EO compared to control rats (MNS). 7,8 The molecular basis for the elevated EO in MHS was probed in the hypothalamus and adrenal using bioinformatics and genomic techniques. Elevated transcripts for cholesterol side-chain cleavage (also known as cytochrome P450scc, CYP11A1) and β-hydroxysteroid dehydrogenase/δ5-4 isomerase genes (HSD3B) were detected in hypothalamus but not in the adrenal. 9 Other studies have suggested that, as with aldosterone (Aldo), the biosynthesis of cardiac glycosides by the adrenal gland likely involves cholesterol side-chain cleavage to form pregnenolone with further metabolism of progesterone. 10-12 Recently, we observed marked increases in circulating EO in uremic patients. 13 These data imply that, in addition to secretion, renal clearance is one of the major determinants of plasma EO. The recovery of the cardiac glycosides digoxin and ouabain at the basolateral membrane of the proximal tubular cell is mediated by an organic anion transporting polypeptide (SLCO4C1). 14 In addition, the secretion

American Journal of Hypertension, 2005

Preliminary evidence suggested that in hypertensive patients the ␣-adducin 460Trp allele might be... more Preliminary evidence suggested that in hypertensive patients the ␣-adducin 460Trp allele might be associated with a twofold higher risk of coronary heart disease. In a prospective population study, we investigated whether the ␣-adducin Gly460Trp polymorphism, alone or in combination with other risk factors, predicted outcome. From August 1985 until July 2003, we randomly recruited 2235 Belgian residents. We obtained information on vital status (until July 1, 2004) and the incidence of events via registries and repeat (median, 3) examinations. For the main analyses, we used multiple Cox regression. After adjustment for other risk factors, we found strong interaction between systolic blood pressure at baseline, analyzed as a continuous variable, and the ␣-adducin polymorphism in relation to total (Pϭ0.01) and cardiovascular mortality (Pϭ0.008), all cardiovascular (Pϭ0.003) complications, and cardiac (Pϭ0.0009) and coronary events (Pϭ0.03). The hazard ratios for total mortality associated with the Trp allele relative to GlyGly homozygosity were 2.30 (95 percent confidence interval, 1.09 to 4.83) in patients with stage-2 systolic hypertension (Ն160 mm Hg) and 0.88 (0.62 to 1.25) in the other participants. For all cardiovascular complications, these estimates were 2.94 (1.24 to 6.95) and 0.83 (0.58 to 1.19), respectively. For all cardiovascular events in stage-2 systolic hypertension, the positive predictive value and the attributable risk associated with the Trp allele were 76.9 percent and 44.3 percent, respectively. In combination with systolic blood pressure, the ␣-adducin Gly460Trp polymorphism is a strong predictor of cardiovascular mortality and morbidity.

Otology & Neurotology, 2008

Ménière&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;a... more Ménière&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (MD) is an inner ear disorder characterized by recurrent episodic vertigo, hearing loss that is fluctuating in the first stages, aural fullness, and tinnitus. Raised endolymphatic pressure (hydrops) is commonly accepted as a causal condition. Approximately 90% of cases of MD are sporadic, whereas the remaining 10% of cases are linked to genetic factors. The ionic composition of endolymph may also depend on the activity of Na, K-ATPase. Adducin is a heterodimeric cytoskeleton protein consisting of 3 subunits (alpha, beta, and gamma) coded by 3 different genes (ADD1, ADD2, and ADD3). ADD1 Gly460Trp polymorphism is associated with salt-sensitive hypertension and increased Na-K pump activity in transfected cells. This study aims to verify the role of adducin in the development of MD. We genotyped 28 patients affected by definite MD according to American Academy of Otolaryngology-Head and Neck Surgery Foundation criteria. Results were compared with those from 2 different control populations (normotensive control group from San Raffaele Hospital and general population group). We have not found any significant difference in the distribution of ADD2 C1797T and ADD3 IVS11+386A/G polymorphism genotypes. On the other hand, the frequency of ADD1 Trp allele is significantly increased in patients with MD compared with controls. We present data supporting the possibility that increased Na, K-ATPase activity may be one of the pathologic mechanisms inducing hyperosmolarity in endolymph which, in turn, may lead to hydrops.

Kidney International, 2002

all women, 2.92 (P ϭ 0.03) in post-menopausal subjects, and Association between hypertension and ... more 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],

Journal of the renin-angiotensin-aldosterone system : JRAAS, 2006

Introduction. The pathogenesis of essential hypertension (EH) has a major genetic component and i... more Introduction. The pathogenesis of essential hypertension (EH) has a major genetic component and is associated with renal abnormalities. Normotensive offspring of hypertensive parents are likely to develop EH and are a suitable population for identifying possible relations between genetic and renal abnormalities.Methods. We investigated if renin-angiotensin-aldosterone system associated genotypes (angiotensinogen [M235T] and ACE [I/D]) are related to blood pressure (BP), renal haemodynamics and sodium excretion in sex and age-matched (18—35 years) healthy Caucasian offspring of either two parents with EH (n=101, EH-offspring) or two normotensive parents (n=50, controls). The alpha-adducin polymorphism (G460W) was also investigated.Results. Compared to controls, BP, heart rate, renal vascular resistance (RVR) and urinary sodium excretion were, respectively, 5%, 7%, 15% and 20% higher in EH-offspring. In controls, the TT-genotype of the M235T angiotensinogen polymorphism was associated...

Journal of the American College of Cardiology, 2006

The goal of our study was to investigate the relationships between atrial natriuretic peptide (AN... more The goal of our study was to investigate the relationships between atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and type A natriuretic peptide receptor (NPRA) gene polymorphisms and left ventricular structure in human essential hypertension. BACKGROUND Experimental evidence supports a key role for natriuretic peptides in the modulation of cardiac mass. This relationship has not yet been described in human disease. METHODS A total of 203 hypertensive patients were studied by mono-bidimensional echocardiography. Three markers of the ANP gene (ϪC664G, G1837A, and T2238C polymorphisms) and a microsatellite marker of both NPRA and BNP genes were characterized. RESULTS Patients carrying the ANP gene promoter allelic variant had increased left ventricular mass index (117.4 Ϯ 1.7 g vs. 95.7 Ϯ 1.7 g, p ϭ 0.005), left ventricular posterior wall thickness (1.14 Ϯ 0.07 cm vs. 0.96 Ϯ 0.01 cm, p Ͻ 0.0001), left ventricular septal thickness (1.12 Ϯ 0.10 cm vs. 1.04 Ϯ 0.01 cm, p ϭ 0.01), and relative wall thickening (47.5 Ϯ 4.1% vs. 39.4 Ϯ 5.3%, p ϭ 0.001) as compared with the wild-type genotype. These associations were independent from anthropometric factors and major clinical features and were confirmed in a large subgroup of never-treated hypertensive patients (n ϭ 148). Carrier status of the ANP gene promoter allelic variant was associated with significantly lower plasma proANP levels: 1,395 Ϯ 104 fmol/ml versus 3,110 Ϯ 141 fmol/ml in hypertensive patients carrying the wild-type genotype (p Ͻ 0.05). A significant association for NPRA gene variants with left ventricular mass index and left ventricular septal thickness was found. The analysis of BNP did not reveal any effect on cardiac phenotypes. CONCLUSIONS Our findings show that the ANP/NPRA system significantly contributes to ventricular remodeling in human essential hypertension.

Journal of Hypertension, 2005

Objective In both humans and rats, polymorphisms of the alpha adducin (ADD1) gene are involved in... more 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.

Hypertension, 2013

cGMP-dependent protein kinase type I is a major mediator of cGMP signaling in the cardiovascular ... more cGMP-dependent protein kinase type I is a major mediator of cGMP signaling in the cardiovascular system. Recent studies on cardiac-specific PRKG1 knockout mice demonstrated that cGMP-dependent protein kinase type I mediates the negative inotropic effect of cGMP in the myocardium. We therefore investigated the association between left ventricular (LV) function and common polymorphisms in the PRKG1 gene in a general population. In 609 randomly selected participants (51.2% women; mean age, 48.8 years; 36.6% hypertensive) who were free from overt cardiac disease, we performed echocardiography and genotyped intronic tag single-nucleotide polymorphisms (SNPs) rs1904694, rs7897633, and rs7905063 in PRKG1. On the basis of color Doppler myocardial motion data, we calculated end-systolic longitudinal and radial deformation (strain) of the LV inferolateral wall. In multivariable-adjusted analyses accounting for confounders and relatedness, systolic radial strain was significantly ( P ≤0.005) h...

Hypertension, 2005

Preliminary evidence from 1 case-control study suggested that in hypertensive patients, the α-add... more Preliminary evidence from 1 case-control study suggested that in hypertensive patients, the α-adducin 460Trp allele might be associated with a 2-fold higher risk of coronary heart disease. In a prospective population study, we investigated whether the α-adducin Gly460Trp polymorphism predicted mortality and morbidity. From August 1985 until July 2003, we randomly recruited 2235 Belgian residents. We obtained information on vital status (until July 1, 2004) and the incidence of events via registries and repeat examinations (median 3). In Cox regression, before and after adjustment for other risk factors, we found strong interaction between systolic blood pressure at baseline, analyzed as a continuous variable, and the α-adducin polymorphism in relation to total ( P =0.01) and cardiovascular mortality ( P =0.007) and all cardiovascular ( P =0.003), cardiac ( P =0.001), and coronary events ( P =0.03). The hazard ratio for total mortality associated with the Trp allele relative to GlyGl...

Hypertension, 1995

Previous studies on genetic rat hypertension have shown that polymorphism within the α-adducin ge... more Previous studies on genetic rat hypertension have shown that polymorphism within the α-adducin gene may regulate blood pressure. Adducin is a cytoskeletal protein that may be involved in cellular signal transduction and interacts with other membrane-skeleton proteins that affect ion transport across the cell membrane. There is a high homology between rat and human adducin and pathophysiological similarities between the Milan hypertensive rat strain and a subgroup of patients with essential hypertension. Thus, we designed a case-control study to test the possible association between the α-adducin locus and hypertension. One hundred ninety primary hypertensive patients were compared with 126 control subjects. All subjects were white and unrelated. Four multiallelic markers surrounding the α-adducin locus located in 4p16.3 were selected: D4S125 and D4S95 mapping at 680 and 20 kb centromeric, and D4S43 and D4S228/E24 mapping at 660 and 2500 kb telomeric. Alleles for each marker were poo...

Hypertension, 2000

In a previous study, by using a candidate gene approach, we detected in both Milan hypertensive r... more 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.

Clinical Science, 2003

β-Adducin plays a role in maintaining the structural integrity of the red blood cell (erythrocyte... more β-Adducin plays a role in maintaining the structural integrity of the red blood cell (erythrocyte) membrane. Moreover, β-adducin-deficient knockout mice show a phenotype characterized by mild anaemia and compensated haemolysis. We therefore investigated whether, in humans, common haematological phenotypes of red blood cells were associated with a polymorphism in exon 15 of the human β-adducin gene (C1797T). We studied 802 unrelated individuals and 294 families (459 parents and 609 offspring) randomly selected from a Caucasian population. We employed generalized estimating equations to allow for the non-independence of the observations within families, while controlling for co-variables. In 917 men, with adjustments applied for age, body mass index, serum total cholesterol, smoking and alcohol intake, CC homozygotes had significantly (P U 0.02) lower values for red blood cell count (4.93W10 12 /l compared with 4.86W10 12 /l), haemoglobin level (9.30 compared with 9.18 mmol/l) and haematocrit (45.0 % compared with 44.4 %) than T allele carriers. In the 329 men who consumed alcohol, the differences between CC homozygotes and T allele carriers were 0.13W10 12 /l (P U 0.02) for red blood cell count, 0.23 mmol/l (P U 0.005) for haemoglobin and 1.08 % (P U 0.02) for haematocrit. In 953 women, none of these associations was significant (P 0.06), regardless of alcohol intake [13.3 % of women (n U 127) consmued alcohol]. In conclusion, in men consuming alcohol, the β-adducin CC genotype was associated with lower red blood cell count, haemoglobin level and haematocrit. We hypothesize that, in CC homozygotes, alcohol consumption may unveil the greater fragility of the red blood cell membrane. This genotype may slightly potentiate the structural and functional haematological disturbances associated with alcohol intake.

Clinical and Experimental Pharmacology and Physiology, 1995

ABSTRACT Summary1. Previous studies on the pathogenetic mechanisms of hypertension in the Milan h... more ABSTRACT Summary1. Previous studies on the pathogenetic mechanisms of hypertension in the Milan hypertensive strain of rat (MHS) showed that a polymorphism within the α-adducin gene is responsible for up to 50% of the blood pressure difference between MHS and their MNS normotensive control strain. A case-control study has shown also in humans an association between α-adducin locus and hypertension using 4 multiallelic markers surrounding the α-adducin locus.2. With a multiple regression approach we provide an estimate of the contribution of the genotype for each marker to the blood pressure variability in comparison to that provided by sex, body mass index and age.3. While sex, body mass index and age contributed by about 40–45% to the overall blood pressure variability, the inclusion of the genotype for the marker closer to the α-adducin locus provided a further increase of the variability explained of about 5%.4. The contribution independently provided by the other markers decreased exponentially with the increase of distance from α-adducin locus.

Hypertension, 2007

The angiotensin-converting enzyme ( ACE ) I/D and the α-adducin ( ADD1 ) Gly460Trp polymorphisms ... more The angiotensin-converting enzyme ( ACE ) I/D and the α-adducin ( ADD1 ) Gly460Trp polymorphisms are associated with cardiovascular risk factors. In a prospective population study and in cell models, we investigated the combined effects of these 2 polymorphisms. We randomly recruited 1287 white subjects (women: 50.0%; mean age: 55.9 years). We obtained outcomes from registries and repeat examinations (median 3). Over 9.0 years (median), 178 fatal or nonfatal cardiovascular events occurred. In ADD1 Trp allele carriers, the multivariate-adjusted hazard ratios associated with ACE DD versus I were 1.72 ( P =0.007) for total mortality, 2.35 ( P =0.02) for cardiovascular mortality, 2.02 ( P =0.005) for all cardiovascular events, and 2.59 ( P =0.03) for heart failure. In contrast, these hazard ratios did not reach significance in ADD1 GlyGly homozygotes (0.08≤ P ≤0.90). The positive predictive value and attributable risk associated with ACE DD homozygosity combined with mutated ADD1 were 3...

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American journal of …, 2003

The associations of the β-adducin C1797T polymorphism with blood pressure (BP) and various indexe... more The associations of the β-adducin C1797T polymorphism with blood pressure (BP) and various indexes of sodium homeostasis were investigated in 388 men and 456 women, aged 18 to 60 years, recruited from three European populations (Cracow, Poland, n= 300; ...