| 1. |
- Melander, Olle, et al.
(författare)
-
Association between a variant in the 11 beta-hydroxysteroid dehydrogenase type 2 gene and primary hypertension
- 2000
-
Ingår i: Journal of Human Hypertension. - 1476-5527. ; 14:12, s. 819-823
-
Tidskriftsartikel (refereegranskat)abstract
- The enzyme 11 beta-hydroxysteroid dehydrogenase type 2 (11BHSD2) converts cortisol to cortisone in the kidney, thereby protecting the mineralocorticoid receptor from the mineralocorticoid actions of cortisol. The syndrome of Apparent Mineralocorticoid Excess (AME), a rare monogenic form of early onset hypertension with autosomal recessive inheritance, is caused by homozygous or compound heterozygous loss of function mutations in the 11BHSD2 gene. Association has been reported between a microsatellite marker flanking the 11BHSD2 gene (D16S496) and primary hypertension. The aim of this study was to identify variants in the 11BHSD2 gene and to test if such variants or the D16S496 are associated with primary hypertension, in Swedes. To address this, the coding sequences of the 11BHSD2 gene was screened for mutations in 20 patients with primary hypertension with single strand conformation polymorphism and direct DNA sequencing techniques. A polymorphism was identified in exon 3; G534A (Glu178Glu). This polymorphism and the D16S496 microsatellite were tested for association with primary hypertension in a population consisting of 292 patients with primary hypertension and 263 normotensive control subjects. The frequency of G534G homozygotes was higher in patients with primary hypertension than in normotensive control subjects (92.8% vs 87.8%; P < 0.05). The allele frequencies of the D16S496 microsatellite did not differ between the two groups (chi(2) = 11.0, df = 10; P = 0.36). In conclusion, over-representation of individuals homozygous for the G534 allele in hypertensive patients compared with control subjects suggests that a mutation in linkage disequilibrium with the G534A polymorphism could increase susceptibility to primary hypertension. Journal of Human Hypertension (2000) 14, 819-823
|
|
| 2. |
- Melander, Olle, et al.
(författare)
-
Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension
- 2000
-
Ingår i: Hypertension. - 1524-4563. ; 36:3, s. 389-394
-
Tidskriftsartikel (refereegranskat)abstract
- Gitelman's syndrome is an autosomal recessive disorder characterized by electrolyte disturbances and low blood pressure. The disease is caused by homozygous or compound heterozygous inactivating mutations in the thiazide-sensitive NaCl-cotransporter gene leading to reduced renal sodium reabsorption. We report 4 patients with Gitelman's syndrome from southern Sweden, all in whom we identified compound heterozygous mutations in the thiazide-sensitive NaCl-cotransporter gene (Gly439Ser, Gly731Arg, Gly741Arg, Thr304Pro, and 2745insAGCA), of which the latter 2 have not been described before. We hypothesized that such mutations in their heterozygous form protect against primary hypertension in the general population and that the gene may also harbor activating mutations that increase the risk for primary hypertension. Accordingly, the gene was screened for mutations in 20 patients with primary hypertension and in 20 normotensive subjects by single-strand conformation polymorphism and direct DNA sequencing. The Arg904Gln, Gly264Ala, and C1420T variants, found in the mutation screening of subjects without Gitelman's syndrome, were studied further. Population genotype frequencies were determined in 292 unrelated patients with primary hypertension and 264 unrelated normotensive subjects from southern Sweden. Gln904 homozygotes were overrepresented in hypertensive patients compared with normotensive subjects (5 of 292 versus 0 of 264; P:=0.03). In conclusion, we confirm that Gitelman's syndrome is caused by mutations in the thiazide-sensitive NaCl-cotransporter gene. Our results further suggest that subjects homozygous for the Gln904 variant have an increased risk for development of primary hypertension.
|
|
| 3. |
- Melander, Olle, et al.
(författare)
-
Role of the Gly460Trp polymorphism of the alpha-adducin gene in primary hypertension in Scandinavians
- 2000
-
Ingår i: Journal of Human Hypertension. - 1476-5527. ; 14:1, s. 43-46
-
Tidskriftsartikel (refereegranskat)abstract
- Previous studies have suggested that the Trp460 allele of the Gly460Trp polymorphism in the alpha-adducin gene is associated with salt sensitivity and primary hypertension. The present study was undertaken to evaluate if the Trp460 allele of this polymorphism is associated with primary hypertension in Scandinavians. To address this issue, 294 patients with primary hypertension and 265 normotensive control subjects from Sweden were examined and genotyped for the Gly460Trp polymorphism using polymerase chain reaction and restriction fragment length polymorphism methods. We then used a population of 80 patients with primary hypertension and 154 normotensive control subjects from Finland to replicate the findings. The frequency of the Trp460 allele was lower in hypertensive patients than in normotensive controls in the Swedish population (17.7% vs 23.0%; P = 0.03) and in the Finnish population (14.4% vs 19.5%; NS). Therefore we also performed a pooled analysis in which the frequency of the Trp460 allele was significantly lower in hypertensive patients than in normotensive controls (17.0% vs 21. 7%; P = 0.02). In subjects who did not receive antihypertensive medication (n = 447) there was no difference between carriers of the three different codon 460 genotypes (Trp-Trp; Trp-Gly and Gly-Gly) either for systolic (128 +/- 18; 127 +/- 15 and 129 +/- 17 mm Hg, NS) or for diastolic blood pressure (75.6 +/- 12.1; 74.7 +/- 9.3 and 75.0 +/- 10.4 mm Hg, NS). In conclusion, the lower frequency of the Trp460 allele in hypertensive patients than in normotensive controls strongly argues against a pathogenic role of this allele in primary hypertension. The results rather suggest that another variant in linkage disequilibrium with the Gly460Trp polymorphism increases susceptibility for hypertension.Journal of Human Hypertension (2000) 14, 43-46.
|
|
| 4. |
|
|
| 5. |
- Berglund, A Scott, et al.
(författare)
-
Metaiodobenzylguanidine (MIBG) scintigraphy and computed tomography (CT) in clinical practice. Primary and secondary evaluation for localization of phaeochromocytomas
- 2001
-
Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 249:3, s. 247-251
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine the diagnostic value of metaiodobenzylguanidine (MIBG) scintigraphy compared with computed tomography (CT) for the localization of phaeochromocytomas in clinical practice. DESIGN: Retrospective comparison between MIBG scintigrams and CT for localization of phaeochromocytomas in all patients successively examined with MIBG scintigraphy in Malmo from 1984 until January 1997. SETTING: Malmo University Hospital, Sweden. SUBJECTS: Sixty-four patients with clinically suspected phaeochromocytomas. MAIN OUTCOME MEASURES: MIBG scintigrams and CTs classified as positive or negative based on original interpretations (primary evaluation) and in a secondary evaluation by one blinded examiner are assessed through histological confirmation or clinical rule out of phaeochromocytomas. RESULTS: Twenty-five patients had surgically removed phaeochromocytomas. The remaining 39 patients had no proof of phaeochromocytomas. In the secondary evaluation, sensitivity for MIBG scintigraphy was 88% (22/25) and for CT was 100% (25/25). The specificity for MIBG scintigraphy was 89% (35/39) but only 50% for CT (18/36). Two out of a total of six extra-adrenal tumours were amongst the false-negative MIBG scintigrams. CONCLUSIONS: MIBG scintigraphy for the localization of phaeochromocytomas is superior to CT as far as specificity, whereas CT has a higher sensitivity. After biochemical diagnosis, CT will detect most phaeochromocytomas. MIBG scintigraphy can be of value in patients who show inconclusive results with biochemical testing and CT.
|
|
| 6. |
- Fava, Cristiano, et al.
(författare)
-
Determinants of kidney function in Swedish families: role of heritable factors.
- 2008
-
Ingår i: Journal of Hypertension. - 1473-5598. ; 26:9, s. 1773-1779
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate the determinants of kidney function and the role of heritable factors in a sample of 249 siblings free from known cardiovascular disease and without antihypertensive drugs belonging to 110 families. Four different measures and estimates of kidney function were considered. Blood pressure was recorded during 24 h by ambulatory blood pressure monitoring. Heritability was estimated with and without adjustment for significant covariates.In multivariate analysis, in addition to age, sex, BMI, HDL-cholesterol, 24-h systolic and mean blood pressure, systolic nocturnal blood pressure dipping resulted independently related to serum creatinine, estimated Cockcroft-Gault-creatinine clearance and estimated by the modification of diet in renal disease-glomerular filtration rate. After full adjustment, the heritability values were 51% for the measured creatinine clearance (P < 0.01), 58% for the estimated Cockcroft-Gault-creatinine clearance (P < 0.001), 40% for the estimated by the modification of diet in renal disease-glomerular filtration rate (P < 0.001), but 8% (P = 0.34) for serum creatinine.Our data confirm that kidney function is partially under genetic control and that genetic variants of importance for this trait could be mapped. The association of the circadian rhythm of blood pressure with kidney function in this sample deserves further investigation.
|
|
| 7. |
- Fava, Cristiano, et al.
(författare)
-
Dipping and variability of blood pressure and heart rate at night are heritable traits.
- 2005
-
Ingår i: American Journal of Hypertension. - : Oxford University Press (OUP). - 1941-7225 .- 0895-7061. ; 18:11, s. 1402-1407
-
Konferensbidrag (refereegranskat)abstract
- Background: Blunted nocturnal blood pressure dipping (NBPD) as well as high variability in blood pressure (BPV) and low variability in heart rate (HRV), are associated with increased cardiovascular morbidity and mortality. The aim of this study was to determine whether these traits are heritable. Methods: We studied 260 healthy siblings without antihypertensive drugs from 118 Swedish families. The BPV and HRV were defined as the standard deviation of BP and heart rate values recorded during 24 h, daytime (6 AM to 10 Pm), and night-time (10 Pm to 6 AM). The NBPD was defined as the ratio between night-time and daytime BP. Heritability was estimated with a maximal likelihood method implemented in the Solar software package with and without adjustment for significant covariates. Results: At night, significant heritability was found for systolic (33%, P <.05), diastolic (36%, P <.05), and mean (42%, P <.01) BPV. After covariate adjustment the corresponding heritability values were 23% (P =.08), 29% (P <.05), and 37% (P <.05). Daytime BPV was not heritable. The heritability of NBPD was 38% (P <.05) for systolic, 9% (P =.29) for diastolic, and 36% (P <.05) for mean BP, but after adjustment only systolic NBPD was significant (29%, P <.05). Heart rate was highly heritable both during daytime (57%, P <.001) and night-time (58%, P <.001), but the variability of heart rate, after adjustment, was only significant at night (37%, P <.05). Conclusions: Our data suggest that BPV and HRV are partially under genetic control and that genetic loci of importance for these traits could be mapped by linkage analysis. Am J Hypertens 2005;18:1402-1407 0 2005 American Journal of Hypertension, Ltd.
|
|
| 8. |
|
|
| 9. |
- Fava, Cristiano, et al.
(författare)
-
Novel mutations in the SLC12A3 gene causing Gitelman's syndrome in Swedes
- 2007
-
Ingår i: DNA Sequence. - : Informa UK Limited. - 1029-2365 .- 1042-5179. ; 18:5, s. 395-399
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Gitelman's syndrome (GS) is an inherited autosomal recessive disorder due to loss of function mutations in the SLC12A3 gene encoding the Na-Cl co-transporter (NCCT), the target of thiazide diuretics. The defective function of the NCCT, which normally is expressed in the apical membrane of the distal convolute tubule in the kidney, leads to mild hypotension, hypokalemia, hyperreninemic hyperaldosteronism, mild metabolic alkalosis, hypomagnesemia and hypocalciuria. Up to now, more than 100 mutations of the SLC12A3 gene have been described in GS patients. METHODS: We have collected 30 patients from Sweden with a clinical diagnosis of GS and undertaken a mutation screening by SSCP and successive sequencing of the 26 exons and intronic boundaries. Both mutations were identified in most (n = 28, 93%) and at least one mutation was identified in all patients. RESULTS: We found 22 different mutations evenly distributed throughout the gene, 11 of which have not been described previously. The new variants include 8 missense mutations (Glu68Lys, His69Asn, Argl45His, Vall53Met, Gly230Asp, Gly342Ala, Val677Leu and Gly867Ser), 1 insertion (c.834_835insG on exon 6) and 2 splice-site mutations (c.2667 + lT>G substitution in splicing donor site after exon 22, c.1569-1G>A substitution in the splicing acceptor site before exon 13). CONCLUSION: In Swedish patients with the clinical features of GS, disease-causing mutations in the SLC12A3 gene were identified in most patients. The spectrum of GS mutations is wide making full mutation screening of the SLC12A3 gene necessary to confirm the diagnosis.
|
|
| 10. |
- Fava, Cristiano, et al.
(författare)
-
Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure
- 2008
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 17:3, s. 413-418
-
Tidskriftsartikel (refereegranskat)abstract
- Gitelmans syndrome (GS) is an inherited recessive disorder caused by homozygous or compound heterozygous loss of function mutations of the NaCl cotransporter (NCCT) gene encoding the kidney-expressed NCCT, the pharmacological target of thiazide diuretics. An observational study estimated the prevalence of GS to 19/1 000 000, in Sweden, suggesting that similar to 1% of the population carries one mutant NCCT allele. As the phenotype of GS patients, who always carry two mutant alleles, is indistinguishable from that seen in patients treated with high-dose thiazide diuretics, we aimed at investigating whether subjects carrying one mutated NCCT allele have a phenotype resembling that of treatment with low-dose thiazide diuretics. We screened first-degree relatives of 18 of our patients with an established clinical end genetic diagnosis of GS for NCCT loss of function mutations and identified 35 healthy subjects carrying one mutant allele (GS-heterozygotes). Each GS-heterozygote was assigned a healthy control subject matched for age, BMI and sex. GS-heterozygotes had markedly lower blood pressure (systolic 103.3 +/- 16.4 versus 123.2 +/- 19.4 mmHg; diastolic 62.5 +/- 10.5 versus 73.1 +/- 9.4 mmHg; P < 0.001) than controls. There was no significant difference between the groups either in plasma concentration or urinary excretion rate of electrolytes, however, GS-heterozygotes had higher fasting plasma glucose concentration. Similar to patients being treated with low-dose thiazide diuretics, GS-heterozygotes have markedly lower blood pressure and slightly higher fasting plasma glucose compared with control subjects. Our findings suggest that GS-heterozygotes, the prevalence of which can be estimated to 1%, are partially protected from hypertension through partial genetic loss of function of the NCCT. However, as our study had a case-control design, it is important to underline that any potential effects on population blood pressure and risk of future cardiovascular disease need to be examined in prospective and population-based studies.
|
|
