Common variation in ISL1 confers genetic susceptibility for human congenital heart disease.
Congenital heart disease (CHD) is the most common birth abnormality and the etiology is unknown in the overwhelming majority of cases. ISLET1 (ISL1) is a transcription factor that marks cardiac progenitor cells and generates diverse multipotent cardiovascular cell lineages. The fundamental role of ISL1 in cardiac morphogenesis makes this an exceptional candidate gene to consider as a cause of complex congenital heart disease. We evaluated whether genetic variation in ISL1 fits the common variant-common disease hypothesis. A 2-stage case-control study examined 27 polymorphisms mapping to the ISL1 locus in 300 patients with complex congenital heart disease and 2,201 healthy pediatric controls. Eight genic and flanking ISL1 SNPs were significantly associated with complex congenital heart disease. A replication study analyzed these candidate SNPs in 1,044 new cases and 3,934 independent controls and confirmed that genetic variation in ISL1 is associated with risk of non-syndromic congenital heart disease. Our results demonstrate that two different ISL1 haplotypes contribute to risk of CHD in white and black/African American populations.
Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA.
Kristen N
KN
Stevens
Hakon
H
Hakonarson
Cecilia E
CE
Kim
Pieter A
PA
Doevendans
Bobby P C
BP
Koeleman
Seema
S
Mital
Jennifer
J
Raue
Joseph T
JT
Glessner
John G
JG
Coles
Victor
V
Moreno
Anne
A
Granger
Stephen B
SB
Gruber
Peter J
PJ
Gruber
D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006330:Heart Defects, Congenital / Q000208:ethnology / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D060850:LIM-Homeodomain Proteins; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014157:Transcription Factors; D014481:United States; D044465:White People / Q000235:genetics
D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1