HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy.
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.
Friedrichs
Frauke
F
Division of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, Heidelberg 69120, Germany.
Zugck
Christian
C
Rauch
Gerd-Jörg
GJ
Ivandic
Boris
B
Weichenhan
Dieter
D
Müller-Bardorff
Margit
M
Meder
Benjamin
B
El Mokhtari
Nour Eddine
NE
Regitz-Zagrosek
Vera
V
Hetzer
Roland
R
Schäfer
Arne
A
Schreiber
Stefan
S
Chen
Jian
J
Neuhaus
Isaac
I
Ji
Ruiru
R
Siemers
Nathan O
NO
Frey
Norbert
N
Rottbauer
Wolfgang
W
Katus
Hugo A
HA
Stoll
Monika
M
D000818:Animals; D030801:Animals, Genetically Modified; D009202:Cardiomyopathies / Q000235:genetics*; D016022:Case-Control Studies; D002460:Cell Line; D002874:Chromosome Mapping; D020090:Chromosome Segregation / Q000502:physiology*; D002895:Chromosomes, Human, Pair 5; D016000:Cluster Analysis; D016207:Cytokines / Q000235:genetics* / Q000502:physiology; D004625:Embryo, Nonmammalian; D005819:Genetic Markers / Q000502:physiology; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D007249:Inflammation / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics* / Q000502:physiology; D016277:Ventricular Function, Left / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
D016207:Cytokines; D005819:Genetic Markers; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; C090444:IK protein, human; D036341:Intercellular Signaling Peptides and Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C405423:steroid receptor RNA activator