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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 SNP associations with CHD on chromosome 5.a) Analysis of SNP data within and surrounding ISL1 in stage 1 yielded 8 SNPs that were significantly associated with CHD in an ethnically heterogeneous US population. ORs, 95%CIs and P values significant at = 0.05 are depicted in black. Non-significant ORs, 95% CIs and P values are depicted in grey. The yellow highlighted region indicates the location of ISL1 on chromosome 5. Labeled SNPs: (a) rs6867206, (b) rs4865656, (c) rs6869844, (d) rs2115322, (e) rs6449600, (f) rs3762977, (g) IVS1+17C>T, (h) rs1017, (i) rs6449612. b) Analysis of SNP data within and surrounding ISL1 in stage 2 US whites yielded10 SNPs that were significantly associated with CHD in an initial analysis of an ethnically heterogeneous US population. ORs, 95%CIs and P values significant at = 0.05 are depicted in black. Non-significant ORs, 95% CIs and P values are depicted in grey. The yellow highlighted region indicates the location of ISL1 on chromosome 5. Labeled SNPs: a) rs6867206, b) rs4865656, c) rs6869844, d) rs2115322, e) rs6449600, f) rs3762977 †, g) IVS1+17C>T †, h) rs1017 †, i) rs6449612. † SNP genotypes determined by imputation.
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pone-0010855-g001: ISL1 SNP associations with CHD on chromosome 5.a) Analysis of SNP data within and surrounding ISL1 in stage 1 yielded 8 SNPs that were significantly associated with CHD in an ethnically heterogeneous US population. ORs, 95%CIs and P values significant at = 0.05 are depicted in black. Non-significant ORs, 95% CIs and P values are depicted in grey. The yellow highlighted region indicates the location of ISL1 on chromosome 5. Labeled SNPs: (a) rs6867206, (b) rs4865656, (c) rs6869844, (d) rs2115322, (e) rs6449600, (f) rs3762977, (g) IVS1+17C>T, (h) rs1017, (i) rs6449612. b) Analysis of SNP data within and surrounding ISL1 in stage 2 US whites yielded10 SNPs that were significantly associated with CHD in an initial analysis of an ethnically heterogeneous US population. ORs, 95%CIs and P values significant at = 0.05 are depicted in black. Non-significant ORs, 95% CIs and P values are depicted in grey. The yellow highlighted region indicates the location of ISL1 on chromosome 5. Labeled SNPs: a) rs6867206, b) rs4865656, c) rs6869844, d) rs2115322, e) rs6449600, f) rs3762977 †, g) IVS1+17C>T †, h) rs1017 †, i) rs6449612. † SNP genotypes determined by imputation.

Mentions: We analyzed 30 SNPs spanning a 237 kb region around ISL1 on chromosome 5q11.1, selected to capture variation in this region based upon linkage disequilibrium patterns in subjects of European ancestry (http://www.hapmap.org). No genome-wide data were available for this hypothesis-driven, candidate gene study. Eight individual SNPs (rs6867206, rs4865656, rs6869844, rs2115322, rs6449600, IVS1+17C>T, rs1017, rs6449612) were significantly associated with risk of CHD at the α = 0.05 level (Fig. 1A) located within a single LD block. Indeed, HapMap data demonstrate D' = 1 between three of these SNPs (rs6869844, rs6449600, rs6449612) and each of the four Hapmap published SNPs within ISL1 (rs3792733, rs2288468, rs3811911, rs991216). The moderate magnitudes of association seen at these SNPs (OR = 1.32–2.30) were consistent with those expected under the common disease-common variant hypothesis. Furthermore, the closest gene to ISL1 is located in a different LD block more than 540 kb upstream (PARP8), reducing the likelihood that these SNPs are capturing an association between a gene other than ISL1 and risk of CHD. Of the six ISL1-flanking SNPs, rs6869844 remained statistically significant after adjustment for multiple testing (P = 0.039 with Bonferroni correction for 30 SNPs). Located 15.7 kb 5′ of ISL1, rs6869844 was associated with a 50% increase in risk for each additional T allele in a log-additive model (Odds ratio (OR) = 1.51, 95% confidence interval (CI) = 1.18–1.95).


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 SNP associations with CHD on chromosome 5.a) Analysis of SNP data within and surrounding ISL1 in stage 1 yielded 8 SNPs that were significantly associated with CHD in an ethnically heterogeneous US population. ORs, 95%CIs and P values significant at = 0.05 are depicted in black. Non-significant ORs, 95% CIs and P values are depicted in grey. The yellow highlighted region indicates the location of ISL1 on chromosome 5. Labeled SNPs: (a) rs6867206, (b) rs4865656, (c) rs6869844, (d) rs2115322, (e) rs6449600, (f) rs3762977, (g) IVS1+17C>T, (h) rs1017, (i) rs6449612. b) Analysis of SNP data within and surrounding ISL1 in stage 2 US whites yielded10 SNPs that were significantly associated with CHD in an initial analysis of an ethnically heterogeneous US population. ORs, 95%CIs and P values significant at = 0.05 are depicted in black. Non-significant ORs, 95% CIs and P values are depicted in grey. The yellow highlighted region indicates the location of ISL1 on chromosome 5. Labeled SNPs: a) rs6867206, b) rs4865656, c) rs6869844, d) rs2115322, e) rs6449600, f) rs3762977 †, g) IVS1+17C>T †, h) rs1017 †, i) rs6449612. † SNP genotypes determined by imputation.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0010855-g001: ISL1 SNP associations with CHD on chromosome 5.a) Analysis of SNP data within and surrounding ISL1 in stage 1 yielded 8 SNPs that were significantly associated with CHD in an ethnically heterogeneous US population. ORs, 95%CIs and P values significant at = 0.05 are depicted in black. Non-significant ORs, 95% CIs and P values are depicted in grey. The yellow highlighted region indicates the location of ISL1 on chromosome 5. Labeled SNPs: (a) rs6867206, (b) rs4865656, (c) rs6869844, (d) rs2115322, (e) rs6449600, (f) rs3762977, (g) IVS1+17C>T, (h) rs1017, (i) rs6449612. b) Analysis of SNP data within and surrounding ISL1 in stage 2 US whites yielded10 SNPs that were significantly associated with CHD in an initial analysis of an ethnically heterogeneous US population. ORs, 95%CIs and P values significant at = 0.05 are depicted in black. Non-significant ORs, 95% CIs and P values are depicted in grey. The yellow highlighted region indicates the location of ISL1 on chromosome 5. Labeled SNPs: a) rs6867206, b) rs4865656, c) rs6869844, d) rs2115322, e) rs6449600, f) rs3762977 †, g) IVS1+17C>T †, h) rs1017 †, i) rs6449612. † SNP genotypes determined by imputation.
Mentions: We analyzed 30 SNPs spanning a 237 kb region around ISL1 on chromosome 5q11.1, selected to capture variation in this region based upon linkage disequilibrium patterns in subjects of European ancestry (http://www.hapmap.org). No genome-wide data were available for this hypothesis-driven, candidate gene study. Eight individual SNPs (rs6867206, rs4865656, rs6869844, rs2115322, rs6449600, IVS1+17C>T, rs1017, rs6449612) were significantly associated with risk of CHD at the α = 0.05 level (Fig. 1A) located within a single LD block. Indeed, HapMap data demonstrate D' = 1 between three of these SNPs (rs6869844, rs6449600, rs6449612) and each of the four Hapmap published SNPs within ISL1 (rs3792733, rs2288468, rs3811911, rs991216). The moderate magnitudes of association seen at these SNPs (OR = 1.32–2.30) were consistent with those expected under the common disease-common variant hypothesis. Furthermore, the closest gene to ISL1 is located in a different LD block more than 540 kb upstream (PARP8), reducing the likelihood that these SNPs are capturing an association between a gene other than ISL1 and risk of CHD. Of the six ISL1-flanking SNPs, rs6869844 remained statistically significant after adjustment for multiple testing (P = 0.039 with Bonferroni correction for 30 SNPs). Located 15.7 kb 5′ of ISL1, rs6869844 was associated with a 50% increase in risk for each additional T allele in a log-additive model (Odds ratio (OR) = 1.51, 95% confidence interval (CI) = 1.18–1.95).

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