HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy

• Published in: Genome Research 2009-03, Vol.19 (3), p.395-403
• Main Authors: Friedrichs, Frauke, Zugck, Christian, Rauch, Gerd-Jörg, Ivandic, Boris, Weichenhan, Dieter, Müller-Bardorff, Margit, Meder, Benjamin, El Mokhtari, Nour Eddine, Regitz-Zagrosek, Vera, Hetzer, Roland, Schäfer, Arne, Schreiber, Stefan, Chen, Jian, Neuhaus, Isaac, Ji, Ruiru, Siemers, Nathan O, Frey, Norbert, Rottbauer, Wolfgang, Katus, Hugo A, Stoll, Monika
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Cardiomyopathies - genetics; Case-Control Studies; Cell Line; Chromosome Mapping; Chromosome Segregation - physiology; Chromosomes, Human, Pair 5; Cluster Analysis; Cytokines - genetics; Cytokines - physiology; Embryo, Nonmammalian; Genetic Markers - physiology; Heparin-binding EGF-like Growth Factor; Humans; Inflammation - genetics; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - physiology; Letter; Linkage Disequilibrium; Polymorphism, Single Nucleotide; RNA, Long Noncoding; RNA, Untranslated - genetics; RNA, Untranslated - physiology; Ventricular Function, Left - genetics; Zebrafish - embryology; Zebrafish - genetics
• ISSN: 1088-9051; 1549-5477
• DOI: 10.1101/gr.076653.108

Human dilated cardiomyopathy (DCM), a disorder of the cardiac muscle, causes considerable morbidity and mortality and is one of the major causes of sudden cardiac death. Genetic factors play a role in the etiology and pathogenesis of DCM. Disease-associated genetic variations identified to date have been identified in single families or single sporadic patients and explain a minority of the etiology of DCM. We show that a 600-kb region of linkage disequilibrium (LD) on 5q31.2-3, harboring multiple genes, is associated with cardiomyopathy in three independent Caucasian populations (combined P-value = 0.00087). Functional assessment in zebrafish demonstrates that at least three genes, orthologous to loci in this LD block, HBEGF, IK, and SRA1, result independently in a phenotype of myocardial contractile dysfunction when their expression is reduced with morpholino antisense reagents. Evolutionary analysis across multiple vertebrate genomes suggests that this heart failure-associated LD block emerged by a series of genomic rearrangements across amphibian, avian, and mammalian genomes and is maintained as a cluster in mammals. Taken together, these observations challenge the simple notion that disease phenotypes can be traced to altered function of a single locus within a haplotype and suggest that a more detailed assessment of causality can be necessary.