Premature Coronary Artery Disease - Clinical and Molecular Genetic Aspects

NCT02146872 | Unknown

• 2 other identifiers: PIHS-KMA13517433
• Study Type: observational
• Target: 400
• Locations: 1 country
• Sites: 1

Brief Summary

Since finishing the sequencing of the human genome in 2003, genetic research in coronary artery disease (CAD) and other complex traits have developed dramatically. Recent genome-wide association studies have identified a considerable number of common genetic variants each associated with the disease. This has led to a new understanding but also to the discovery of new therapeutical targets. However, each of the variants discovered only have minor effects on disease development and even the pooling of the variants only explains a minor percentage of the total heritability. It has been evident that rare or private mutations probably play a great role in the genetic architecture of CAD, especially among young and severely affected patients. These may only be identified by sequencing. Therefore, the investigators hypothesize, that the use of exome sequencing (the read-off of the entire protein-coding regions of the genome) and linkage analysis in families of extreme phenotype cases, will identify disease-causing genetic variants. From the West Denmark Heart Registry the investigators will enroll a minimum of 120 patients with atherosclerosis who have undergone a coronary artery revascularization procedure before the age of 40, to participate in study part 1. A pedigree analysis will be performed and cardiovascular (CVD) risk factors and current preventive treatment will be evaluated. 1. degree relatives aged 30-65 years, who are free of CAD, are invited to participate in study 2. CVD risk factors are evaluated as well as a CT coronary angiogram is performed to quantify the degree of asymptomatic coronary atherosclerosis. Families from study 1 and 2, who are considered severely affected by atherosclerosis, evaluated on a basis of family size, number of affected and severity of disease, will be selected for exome sequencing. Other relevant family members will be included as well as their CVD risk factors will be evaluated. Exome sequencing will be performed and variants found will be filtered on a basis of frequency, linkage analysis, gene position, existing knowledge and in-silico prediction tools. Possible findings will be validated by Sanger-sequencing and causality of new variants will subsequently be sought to be proven by relevant experimental studies.

Conditions

Coronary Artery Disease; Myocardial Infarction; Atherosclerosis

Keywords

Coronary Artery Disease; Myocardial Infarction; Atherosclerosis; High-Throughput Nucleotide Sequencing; Sequence Analysis, DNA; Genetic Testing; Genetic Linkage

Outcome Measures

Primary Outcomes (1)

• Number of patients with very premature coronary artery disease treated according to national guidelines

  Evaluated on the basis of medical history, current medication, BP-TRU-measurement and measurement of blood lipids, and other lab tests.

  At least 6 months after last coronary intervention procedure

Secondary Outcomes (1)

• Coronary artery lesions burden among middle-aged 1st degree relatives of patients with very premature coronary artery disease

  At least 6 months after last coronary intervention procedure

Study Arms (3)

Very Premature CAD

Patients who have received a coronary intervention procedure on the basis of atherosclerosis before the age of 40

Healthy middle-aged 1st degree relatives

Healthy 1st degree relatives aged 30-65 years of patients with very premature CAD.

PCAD families

Families severely affected by premature CAD

Eligibility Criteria

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

Study Population

Patients who has received a coronary intervention procedure at Aarhus University Hospital, Skejby (all interventions are registered in the West Denmark Heart Registry)

You may qualify if:

• Coronary intervention at Aarhus University Hospital, Skejby in the period 2006-2013
• Age \< 40 years at the time of intervention in the above mentioned period
• Intervention on the basis of atherosclerosis
• Residency in Denmark
• \> 6 months since last coronary procedure

You may not qualify if:

• Interventions on transplanted hearts
• Abuse of cocaine/amphetamine in close relation to the intervention
• st degree relatives of patients participating in study part 1.
• Age 30-65 years
• No prior diagnosis of coronary atherosclerosis on the basis of a coronary angiogram
• Obesity (BMI\>30)
• Chronic kidney disease stage 4+5
• Chronic atrial fibrillation
• Former allergic contrast reaction
• Pregnancy
• Families who are considered severely affected by atherosclerosis, evaluated on a basis of family size, number of affected and severity of disease (yet to be defined - depending on the actual cohort (pedigree analysis))
• None

Sponsors & Collaborators

• Aarhus University Hospital Skejby: lead
• University of Aarhus: collaborator
• Kong Christian IX og Dronning Louises Jubilæumslegat: collaborator
• Snedkermester Sophus Jacobsen and hustru Astrid Jacobsens Foundation: collaborator

Study Sites (1)

Aarhus University Hospital, Skejby

Aarhus, 8200, Denmark

RECRUITING

Related Publications (16)

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  BACKGROUND

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Related Links

• Human Genome Project Information Archive
• Danish Guidelines on CVD prevention

Biospecimen

Retention: SAMPLES WITH DNA

2 samples of EDTA blood (4ml glass) and 1 sample of serum (4ml glass) will be retained in a biobank.

MeSH Terms

Conditions

Coronary Artery Disease; Myocardial Infarction; Atherosclerosis

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis

Study Officials

• Morten K Christiansen, MD

  Aarhus University Hospital Skejby

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: FAMILY BASED
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD-student

Study Record Dates

• First Submitted: May 2, 2014
• First Posted: May 26, 2014
• Study Start: February 1, 2014
• Primary Completion: February 1, 2016
• Study Completion: February 1, 2016
• Last Updated: May 26, 2014

Record last verified: 2014-05

Locations

DK (1)