Brief Title
Prevalence and Significance of Mutations in Genes Encoding NaPi-co-transporters in the Development of CAVD
Official Title
Prevalence and Significance of Mutations in Genes Encoding NaPi-co-transporters in the Development of CAVD
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.
Study Type
Observational
Primary Outcome
Frequencies of single-nucleotide polymorphisms in genes encoding NaPi co-transporters
Condition
Aortic Valve Calcification
Study Arms / Comparison Groups
Aortic valve calcification
Description: Patients with calcific aortic valve disease, age = 65 years or below
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Estimated Enrollment
600
Start Date
May 2014
Completion Date
April 2019
Primary Completion Date
April 2018
Eligibility Criteria
Inclusion Criteria: - Aortic valve calcification - Informed consent before study participation - Age: ≥ 18 years ≤ 65 years Exclusion Criteria: - Lacking ability to give informed consent - Radiotherapy towards the thorax - Severe kidney disease (in dialysis)
Gender
All
Ages
N/A - 65 Years
Accepts Healthy Volunteers
No
Contacts
Ulf Simonsen, Professor, +45 40513516, [email protected]
Location Countries
Denmark
Location Countries
Denmark
Administrative Informations
NCT ID
NCT02516800
Organization ID
AV-SLC-2014-01
Responsible Party
Sponsor
Study Sponsor
University of Aarhus
Study Sponsor
Ulf Simonsen, Professor, Study Chair, Department of Biomedicine, Aarhus University
Verification Date
May 2017