Abstract 20888: A Common Variant in the T-Cadherin Gene is Associated with Exercise-Induced Myocardial Ischemia in Asymptomatic Siblings of Probands with Premature Coronary Artery Disease
Background: T-cadherin is a member of a large family of calcium dependent adhesion molecules that promote vascular cell proliferation, vascular wall remodeling and angiogenesis, and atherogenesis. Although variants in the cadherin gene, CDH13, have been associated with higher blood pressure in genome-wide association studies (GWAS), no studies have shown associations with coronary artery disease (CAD) phenotypes. We thus examined whether variants in CDH13 were associated with inducible ischemia as a marker for occult CAD in asymptomatic siblings of persons with CAD <60 years of age.
Methods: The sample was comprised of 792 white siblings (mean age 50±7 years; 45% female) in the GeneSTAR Study (Genetic Study of Atherosclerosis Risk). All siblings were screened for traditional CAD risk factors and inducible ischemia on exercise stress perfusion imaging. We selected 929 single nucleotide polymorphisms (SNPs) for coverage across the CDH13 gene (Illumina 1M) and analyzed associations with the presence or absence of inducible ischemia, using an additive model logistic regression, adjusted for age, sex, and family relatedness (GEE).
Results: Inducible ischemia was observed in 17% of subjects. Multiple intronic SNPs across a 37 kb region in a large single linkage disequilibrium (LD) block were associated with inducible ischemia, with p-values <0.001. A strong protective association was observed with the minor allele of rs4238691 (allelic OR 0.56, 95% CI 0.42-0.76, p=0.0001), a highly common SNP with a minor allele frequency of 46.5%. No other SNPs were significant after adjusting for rs4238691. After full adjustment in the model for age, sex, systolic BP, smoking, glucose, HDL cholesterol, LDL cholesterol, BMI, and triglycerides, the protective association of rs4238691 with inducible ischemia remained significant (p= 0.0003).
Conclusion: These results show that a common polymorphism in the T-cadherin gene may contribute to early preclinical CAD in apparently healthy siblings of probands with premature CAD and suggest that this region is involved in vascular disease mechanisms independent from elevated blood pressure or other CAD risk factors.
- Coronary artery disease
- Ischemic heart disease
- Myocardial perfusion
- Subclinical atherosclerosis
- © 2010 by American Heart Association, Inc.