Prevalence and Significance of Mutations in Genes Encoding NaPi-co-transporters in the Development of CAVD

NCT02516800 | Unknown DMC

• 1 other identifier: AV-SLC-2014-01
• Study Type: observational
• Target: 600
• Locations: 1 country
• Sites: 1

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.

Conditions

Aortic Valve Calcification; Aortic Stenosis

Outcome Measures

Primary Outcomes (1)

• Frequencies of single-nucleotide polymorphisms in genes encoding NaPi co-transporters

  Association analyses will be performed after 3 years

Study Arms (2)

Aortic valve calcification

Patients with calcific aortic valve disease, age = 65 years or below

Control group

Matched control group

Eligibility Criteria

• Age: Up to 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with premature aortic valve stenosis in Denmark and Sweden.

You may qualify if:

• Aortic valve calcification
• Informed consent before study participation
• Age: ≥ 18 years ≤ 65 years

You may not qualify if:

• Lacking ability to give informed consent
• Radiotherapy towards the thorax
• Severe kidney disease (in dialysis)

Sponsors & Collaborators

• University of Aarhus: lead

Study Sites (1)

Department of Biomedicine, Aarhus University

Aarhus, 8000, Denmark

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

Full blood Aortic Valve

MeSH Terms

Conditions

Aortic Valve, Calcification of; Aortic Valve Stenosis

Condition Hierarchy (Ancestors)

Aortic Valve Disease; Heart Valve Diseases; Heart Diseases; Cardiovascular Diseases; Ventricular Outflow Obstruction

Study Officials

• Ulf Simonsen, Professor

  Department of Biomedicine, Aarhus University

  STUDY CHAIR

Central Study Contacts

Åsa Lina Alle Madsen, MD

CONTACT

+45 40513516; jonsson@biomed.au.dk

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 2, 2015
• First Posted: August 6, 2015
• Study Start: May 1, 2014
• Primary Completion: April 1, 2018
• Study Completion: April 1, 2019
• Last Updated: May 9, 2017

Record last verified: 2017-05

Locations

DK (1)