Prevalence and Significance of Mutations in Genes Encoding NaPi-co-transporters in the Development of CAVD
Study Details
Study Description
Brief Summary
Mutations in the SLC34A2 gene, that encodes the sodium phosphate co-transporter (NaPi-IIb), cause defect cell-uptake of phosphate, which leads to formation of calcium-phosphate concretions in the lungs as seen in Pulmonary Alveolar Microlithiasis (PAM). Extra pulmonary calcifications, including heart valve calcification, have previously been reported in patients with PAM.
Calcific Aortic Valve Disease (CAVD) is a common disease in the elderly and is characterised by thickening and calcification of the aortic valve leaflets in the absence of rheumatic heart disease. CAVD is present in more than 25% of patients older than age 65 years and is associated with an increased risk of cardiovascular events. Currently, there is no effective therapy for the disease other than surgical aortic valve replacement. Both calcium and phosphate are the major components of calcific deposits in PAM and CAVD. Based on these preliminary findings, the investigators hypothesize that mutations in sodium phosphate co-transporters may play a role in both pulmonary and extra pulmonary calcifications.
Two studies will be performed: 1. A retrospective cross-sectional study including patients with an age ≤ 65 years with CAVD from Denmark and Örebro, will be carried out. Genetic association analysis will be performed to investigate the incidence of common variants in five genes representing sodium phosphate co-transporters (SLC34A1, SLC34A2, SLC34A3, SLC20A1, SLC20A2) compared to healthy controls. Associated genes will subsequently be sequenced to identify possible causal mutations. 2. In a prospective study, aortic valve tissue will be collected from patients with AS undergoing surgical valve replacement. Molecular characterisation of the transporters will be conducted by determining the level of specific mRNA and protein by RT-PCR/qPCR, and Western Blotting, respectively. The localisation and visualisation will be investigated by immunostaining and confocal laser microscopy. Fibroblasts and endothelial cells will be isolated and grown in cultures with subsequent functional studies of the phosphate uptake.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Aortic valve calcification Patients with calcific aortic valve disease, age = 65 years or below |
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| Control group Matched control group |
Outcome Measures
Primary Outcome Measures
- Frequencies of single-nucleotide polymorphisms in genes encoding NaPi co-transporters [Association analyses will be performed after 3 years]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Aortic valve calcification
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Informed consent before study participation
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Age: ≥ 18 years ≤ 65 years
Exclusion Criteria:
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Lacking ability to give informed consent
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Radiotherapy towards the thorax
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Severe kidney disease (in dialysis)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Department of Biomedicine, Aarhus University | Aarhus | Denmark | 8000 |
Sponsors and Collaborators
- University of Aarhus
Investigators
- Study Chair: Ulf Simonsen, Professor, Department of Biomedicine, Aarhus University
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- AV-SLC-2014-01