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      Influence of the Alpha-Adducin and ACE Gene Polymorphism on the Progression of Autosomal-Dominant Polycystic Kidney Disease

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          Background: A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). The variability can not be fully explained by the genetic heterogenity of the disease. We examined the influence of the ACE I/D polymorphism, adducin Trp460Gly polymorphism and the association of both polymorphisms on the progression of ADPKD towards end-stage renal failure (ESRF). Methods: 320 ADPKD patients (pts) were analyzed, 220 pts (113 males, 107 females) with ESRF before 63 years of age, with a subgroup (rapid progressors) of 20 pts (12 males, 8 females) with ESRF before 40 years of age, 52 pts (23 males, 29 females) with ESRF later than 63 years of age (slow progressors), 48 ADPKD pts (18 males, 30 females) with mean age ±50 years with serum creatinine <110 µmol/l (slow progressors) and 200 genetically unrelated healthy Czech subjects. DNA samples from collected blood were genotyped for the ACE I/D polymorphism and the Trp460Gly of α-adducin gene polymorphism. Results: The α-adducin genotypes showed no differences among the groups of slow progressors (74% Gly/Gly, 22.9% Gly/Trp and 3.1% Trp/Trp), pts with ESRF before 63 years of age (67.7% Gly/Gly, 30.5% Gly/Trp and 1.8% Trp/Trp) and rapid progressors (75% Gly/Gly, 25% Gly/Trp). The ACE genotypes did not differ among the groups of slow progressors (27.1% I/I, 44.8% I/D and 28.1% D/D), pts with ESRF before 63 years of age (23.6% I/I, 51.4% I/D and 25% D/D) and rapid progressors (20% I/I, 55% I/D and 25% D/D). The distribution did not differ from the control group. The ages of ESRF according to different genotypes did not significantly differ. We observed a significant tendency to better prognosis in Trp allele carriers for I/I genotype in comparison with Gly/Gly homozygous subjects. Conclusion: The ACE and α-adducin polymorphisms do not play a significant role in the progression of ADPKD to ESRF.

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          Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension.

          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' 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.
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            Comparison of phenotypes of polycystic kidney disease types 1 and 2

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              Mutation detection of PKD1 identifies a novel mutation common to three families with aneurysms and/or very-early-onset disease.

              It is known that several of the most severe complications of autosomal-dominant polycystic kidney disease, such as intracranial aneurysms, cluster in families. There have been no studies reported to date, however, that have attempted to correlate severely affected pedigrees with a particular genotype. Until recently, in fact, mutation detection for most of the PKD1 gene was virtually impossible because of the presence of several highly homologous loci also located on chromosome 16. In this report we describe a cluster of 4 bp in exon 15 that are unique to PKD1. Forward and reverse PKD1-specific primers were designed in this location to amplify regions of the gene from exons 11-21 by use of long-range PCR. The two templates described were used to analyze 35 pedigrees selected for study because they included individuals with either intracranial aneurysms and/or very-early-onset disease. We identified eight novel truncating mutations, two missense mutations not found in a panel of controls, and several informative polymorphisms. Many of the polymorphisms were also present in the homologous loci, supporting the idea that they may serve as a reservoir for genetic variability in the PKD1 gene. Surprisingly, we found that three independently ascertained pedigrees had an identical 2-bp deletion in exon 15. This raises the possibility that particular genotypes may be associated with more-severe disease.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                24 April 2003
                : 26
                : 1
                : 42-49
                a1st Internal Department and bDepartment of Biology and Human Genetics, 1st Medical Faculty, Charles University, Prague, and cInstitute of Clinical and Experimental Medicine, Prague, Czech Republic
                69768 Kidney Blood Press Res 2003;26:42–49
                © 2003 S. Karger AG, Basel

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                Figures: 3, Tables: 2, References: 56, Pages: 8
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