Abstract 369: Living In A Box - Three Cosegregating Genes Determine Heart Failure.
Objective: Dilative cardiomyopathy (DCM) exhibits familial aggregation in up to 30% of DCM patients. Marked variabitility of DCM onset and progression, even within a family, suggests the existence of modifiers of penetrance. Previous evidence implicated inflammatory gene polymorphisms as genetic modifiers.
Methods: Linkage disequilibrium (LD) mapping included three independent Caucasian patient cohorts (n=1499 in total) examined by echocardiography and cardiac catheterization. DCM was diagnosed if left ventricular ejection fraction was >50% in the absence of coronary artery stenoses >50%, hypertensive, congenital, valvular, and inflammatory heart disease. Controls (n=3070) were randomly identified and recruited mostly in Northern-Germany (PopGen). Haplotype relationships were detected by median joining network analysis. Morpholino antisense oligonucleotides were injected in zebrafish larvae to study the functional consequences of gene inactivation.
Results: We found replicated association with heart failure of a 600-kb LD block on 5q31.2–3. One hundred and nine haplotype tagging and coding SNPs structured this gene rich LD block in 20 haplotypes which exhibited substantial evolutionary conservation, e.g. in a group of risk haplotypes tagged by rs2569193 (first sample: odds ratio (OR) = 0.73, 95% CI=0.55– 0.96, p=0.024; second sample: OR=0.81, 95% CI=0.66 – 0.99, p=0.039; third sample: OR=0.64, 95% CI=0.45–0.91, p=0.012). The associated gene cluster is conserved in syntenic blocks on mouse and rat chromosomes 18 but not in fish. At least three of the clustered genes were potential candidate genes for DCM: knock-down of HBEGF, IK and SRA1, resulted in contractile dysfunction.
Conclusion: We identified a unique gene cluster contributing to heart failure in cardiomyopathy. Evolutionary conserved clusters of functionally cooperating genes in disease-associated haplotypes may be prime targets to dissect the genetic basis of complex diseases.