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Common variation in ISL1 confers genetic susceptibility for human congenital heart disease.

Stevens KN, Hakonarson H, Kim CE, Doevendans PA, Koeleman BP, Mital S, Raue J, Glessner JT, Coles JG, Moreno V, Granger A, Gruber SB, Gruber PJ - PLoS ONE (2010)

Bottom Line: ISLET1 (ISL1) is a transcription factor that marks cardiac progenitor cells and generates diverse multipotent cardiovascular cell lineages.We evaluated whether genetic variation in ISL1 fits the common variant-common disease hypothesis.Our results demonstrate that two different ISL1 haplotypes contribute to risk of CHD in white and black/African American populations.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA.

ABSTRACT
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.

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Related in: MedlinePlus

ISL1 haplotypes and risk of congenital heart disease by race/ethnicity.a) The A-C-T risk haplotype in white stage 1 (US) and stage 2 (US, Canada, Netherlands) populations. Odds ratios (95% CIs) for each stage are denoted by black boxes (gray lines). Summary OR estimates are represented by black diamonds, where diamond width corresponds to 95% CI bounds. Box and diamond heights are inversely proportional to precision of the OR estimate. b) The G-C-T risk haplotype in black/African American stage 1 (US) and stage 2 (US) populations. Odds ratios (95% CIs) are denoted as in 2a.
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pone-0010855-g002: ISL1 haplotypes and risk of congenital heart disease by race/ethnicity.a) The A-C-T risk haplotype in white stage 1 (US) and stage 2 (US, Canada, Netherlands) populations. Odds ratios (95% CIs) for each stage are denoted by black boxes (gray lines). Summary OR estimates are represented by black diamonds, where diamond width corresponds to 95% CI bounds. Box and diamond heights are inversely proportional to precision of the OR estimate. b) The G-C-T risk haplotype in black/African American stage 1 (US) and stage 2 (US) populations. Odds ratios (95% CIs) are denoted as in 2a.

Mentions: Haplotype analysis in the stage 2 white population confirmed that the A-C-T haplotype is significantly associated with risk among whites (Global P = 0.00003). Each copy of the A-C-T haplotype conferred an 18% increase in risk (OR = 1.18, 95% CI 1.00–1.39, P = 0.0485) compared to the A-C-A haplotype. Combined analysis of both stage 1 and stage 2 for the A-C-T haplotype in whites was highly significant (Tables 2, S4, S5; Fig. 2), with a 27% increase in risk of CHD (95% CI 1.09–1.48, P = 0.0018).


Common variation in ISL1 confers genetic susceptibility for human congenital heart disease.

Stevens KN, Hakonarson H, Kim CE, Doevendans PA, Koeleman BP, Mital S, Raue J, Glessner JT, Coles JG, Moreno V, Granger A, Gruber SB, Gruber PJ - PLoS ONE (2010)

ISL1 haplotypes and risk of congenital heart disease by race/ethnicity.a) The A-C-T risk haplotype in white stage 1 (US) and stage 2 (US, Canada, Netherlands) populations. Odds ratios (95% CIs) for each stage are denoted by black boxes (gray lines). Summary OR estimates are represented by black diamonds, where diamond width corresponds to 95% CI bounds. Box and diamond heights are inversely proportional to precision of the OR estimate. b) The G-C-T risk haplotype in black/African American stage 1 (US) and stage 2 (US) populations. Odds ratios (95% CIs) are denoted as in 2a.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2877111&req=5

pone-0010855-g002: ISL1 haplotypes and risk of congenital heart disease by race/ethnicity.a) The A-C-T risk haplotype in white stage 1 (US) and stage 2 (US, Canada, Netherlands) populations. Odds ratios (95% CIs) for each stage are denoted by black boxes (gray lines). Summary OR estimates are represented by black diamonds, where diamond width corresponds to 95% CI bounds. Box and diamond heights are inversely proportional to precision of the OR estimate. b) The G-C-T risk haplotype in black/African American stage 1 (US) and stage 2 (US) populations. Odds ratios (95% CIs) are denoted as in 2a.
Mentions: Haplotype analysis in the stage 2 white population confirmed that the A-C-T haplotype is significantly associated with risk among whites (Global P = 0.00003). Each copy of the A-C-T haplotype conferred an 18% increase in risk (OR = 1.18, 95% CI 1.00–1.39, P = 0.0485) compared to the A-C-A haplotype. Combined analysis of both stage 1 and stage 2 for the A-C-T haplotype in whites was highly significant (Tables 2, S4, S5; Fig. 2), with a 27% increase in risk of CHD (95% CI 1.09–1.48, P = 0.0018).

Bottom Line: ISLET1 (ISL1) is a transcription factor that marks cardiac progenitor cells and generates diverse multipotent cardiovascular cell lineages.We evaluated whether genetic variation in ISL1 fits the common variant-common disease hypothesis.Our results demonstrate that two different ISL1 haplotypes contribute to risk of CHD in white and black/African American populations.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus