Anne Blanchard1,2,3, Marion Vallet4, Laurence Dubourg5, Marguerite Hureaux2,6, Julien Allard7,8, Jean-Philippe Haymann9,10,11, Renaud de la Faille12, Armelle Arnoux3,13, Aurelie Dinut3,13, Damien Bergerot1,2,3, Pierre-Hadrien Becker14, Pierre-Yves Courand1,15, Stéphanie Baron2,16, Pascal Houillier2,16, Ivan Tack4, Olivier Devuyst17,18, Xavier Jeunemaitre2,6,19, Michel Azizi1,2,3, Rosa Vargas-Poussou20. 1. Clinical Investigations Center. 2. Faculty of Medicine, Paris Descartes Université, Sorbonne Paris Cité, Paris, France. 3. Clinical Investigations Center-1418, Institut National de la Santé et de la Recherche Médicale, Paris, France. 4. Department of Physiological Functional Investigations, Université Paul Sabatier, CHU de Toulouse, Toulouse, France. 5. Department of Physiological Functional Investigations, Hospital Edouard Herriot, Hospices Civils de Lyon, Lyon, France. 6. Department of Genetics. 7. Department of Nephrology, Hôpital Dupuytren, Centre Hospitalier Universitaire de Limoges, Limoges, France. 8. Clinical Investigations Center-1435, Institut National de la Santé et de la Recherche Médicale, Limoges, France. 9. Department of Physiological Functional Investigations, Hôpital Tenon, Assistance Publique Hôpitaux des Hôpitaux de Paris, Paris, France. 10. Faculty of Medicine, Université Pierre et Marie Curie, Paris, France. 11. Unité Mixte de Recherche_S 1155, Institut National de la Santé et de la Recherche Médicale, Paris, France. 12. Department of Nephrology, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France. 13. Clinical Research Unit, and. 14. Department of Biochemistry, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France. 15. Department of Cardiology, Croix-Rousse and Lyon-Sud Hospital, Hospices Civils de Lyon, Lyon, France. 16. Department of Physiological Functional Investigations, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France. 17. Institute of Physiology, University of Zurich, Zurich, Switzerland. 18. Division of Nephrology, Catholic University of Louvain Medical School, Brussels, Belgium; and. 19. Unité Mixte de Recherche_970, Institut National de la Santé et de la Recherche Médicale, Paris, France. 20. Department of Genetics, Rosa.vargas@aphp.fr.
Abstract
BACKGROUND: Gitelman syndrome is a salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive sodium-chloride cotransporter. Previous studies suggested an intermediate phenotype for heterozygous carriers. METHODS: To evaluate the phenotype of heterozygous carriers of pathogenic SLC12A3 mutations, we performed a cross-sectional study of patients with Gitelman syndrome, heterozygous carriers, and healthy noncarriers. Participants measured their BP at home for three consecutive days before hospital admission for blood and urine sampling and an oral glucose tolerance test. RESULTS: We enrolled 242 participants, aged 18-75 years, including 81 heterozygous carriers, 82 healthy noncarriers, and 79 patients with Gitelman syndrome. The three groups had similar age, sex ratio, and body mass index. Compared with healthy noncarriers, heterozygous carriers showed significantly higher serum calcium concentration (P=0.01) and a trend for higher plasma aldosterone (P=0.06), but measures of home BP, plasma and urine electrolytes, renin, parathyroid hormone, vitamin D, and response to oral glucose tolerance testing were similar. Patients with Gitelman syndrome had lower systolic BP and higher heart rate than noncarriers and heterozygote carriers; they also had significantly higher fasting serum glucose concentration, higher levels of markers of insulin resistance, and a three-fold higher sensitivity to overweight. According to oral glucose tolerance testing, approximately 14% of patients with Gitelman syndrome were prediabetic, compared with 5% of heterozygous carriers and 4% of healthy noncarriers. CONCLUSIONS: Heterozygous carriers had a weak intermediate phenotype, between that of healthy noncarriers and patients with Gitelman syndrome. Moreover, the latter are at risk for development of type 2 diabetes, indicating the heightened importance of body weight control in these patients.
BACKGROUND:Gitelman syndrome is a salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive sodium-chloride cotransporter. Previous studies suggested an intermediate phenotype for heterozygous carriers. METHODS: To evaluate the phenotype of heterozygous carriers of pathogenic SLC12A3 mutations, we performed a cross-sectional study of patients with Gitelman syndrome, heterozygous carriers, and healthy noncarriers. Participants measured their BP at home for three consecutive days before hospital admission for blood and urine sampling and an oral glucose tolerance test. RESULTS: We enrolled 242 participants, aged 18-75 years, including 81 heterozygous carriers, 82 healthy noncarriers, and 79 patients with Gitelman syndrome. The three groups had similar age, sex ratio, and body mass index. Compared with healthy noncarriers, heterozygous carriers showed significantly higher serum calcium concentration (P=0.01) and a trend for higher plasma aldosterone (P=0.06), but measures of home BP, plasma and urine electrolytes, renin, parathyroid hormone, vitamin D, and response to oral glucose tolerance testing were similar. Patients with Gitelman syndrome had lower systolic BP and higher heart rate than noncarriers and heterozygote carriers; they also had significantly higher fasting serum glucose concentration, higher levels of markers of insulin resistance, and a three-fold higher sensitivity to overweight. According to oral glucose tolerance testing, approximately 14% of patients with Gitelman syndrome were prediabetic, compared with 5% of heterozygous carriers and 4% of healthy noncarriers. CONCLUSIONS: Heterozygous carriers had a weak intermediate phenotype, between that of healthy noncarriers and patients with Gitelman syndrome. Moreover, the latter are at risk for development of type 2 diabetes, indicating the heightened importance of body weight control in these patients.
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