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

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 Overview

• Status: Unknown
• Conditions: Aortic Stenosis; Aortic Valve Calcification

• Study Type: Observational
• Enrollment (Anticipated): 600

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark, 8000
    • Recruiting
    • Department of Biomedicine, Aarhus University
    • Contact: Åsa Lina Alle Madsen, MD; Phone Number: +45 40513516; Email: jonsson@biomed.au.dk
    • Principal Investigator: Åsa Lina Alle Madsen, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with premature aortic valve stenosis in Denmark and Sweden.

Description

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)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Aortic valve calcification; Patients with calcific aortic valve disease, age = 65 years or below
Control group; Matched control group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Frequencies of single-nucleotide polymorphisms in genes encoding NaPi co-transporters	Association analyses will be performed after 3 years

Collaborators and Investigators

• Sponsor: University of Aarhus
• Investigators: Study Chair: Ulf Simonsen, Professor, Department of Biomedicine, Aarhus University

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Anticipated): April 1, 2018
• Study Completion (Anticipated): April 1, 2019

Study Registration Dates

• First Submitted: February 2, 2015
• First Submitted That Met QC Criteria: August 3, 2015
• First Posted (Estimate): August 6, 2015

Study Record Updates

• Last Update Posted (Actual): May 9, 2017
• Last Update Submitted That Met QC Criteria: May 8, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Aortic Valve Stenosis
• Other Study ID Numbers: AV-SLC-2014-01