Dataset Information

ISL1 common variant rs1017 is not associated with susceptibility to congenital heart disease in a Chinese population.

ABSTRACT: ISL1, as a member of the LIM homeodomain transcription factor family, is expressed in a distinct population of undifferentiated cardiac progenitors and plays a pivotal role in cardiogenesis. Lacking ISL1 expression results in growth arrest or displays profound defects in heart development, including atria, ventricle, and the inflow and outflow tracts, which constitute a major form of congenital heart disease (CHD). Recently, an important study by Stevens et al. found that genetic variation in ISL1 is associated with risk of CHD in white and black/African American populations; this observation led us to hypothesize that ISL1 common variants might influence susceptibility to sporadic CHD in our Chinese population.We conducted a case-control study of CHD in Chinese to test our hypothesis by genotyping ISL1 common variant rs1017 in 1003 CHD cases and 1012 non-CHD controls.We found that rs1017 was not associated with the risk of CHD (p=0.213). When we performed stratified analyses according to subjects' age, sex, and CHD classifications, we found no overall heterogeneity of risk in different subgroups.This is the first study which indicates that ISL1 common variant rs1017 may not play a role in sporadic CHD susceptibility in the Chinese population.

SUBMITTER: Xue L

PROVIDER: S-EPMC3396000 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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ISL1 common variant rs1017 is not associated with susceptibility to congenital heart disease in a Chinese population.

Xue Lei L Wang Xiaowei X Xu Jing J Xu Xiaohan X Liu Xiang X Hu Zhibin Z Shen Hongbing H Chen Yijiang Y

Genetic testing and molecular biomarkers 20120405 7

<h4>Background</h4>ISL1, as a member of the LIM homeodomain transcription factor family, is expressed in a distinct population of undifferentiated cardiac progenitors and plays a pivotal role in cardiogenesis. Lacking ISL1 expression results in growth arrest or displays profound defects in heart development, including atria, ventricle, and the inflow and outflow tracts, which constitute a major form of congenital heart disease (CHD). Recently, an important study by Stevens et al. found that gene ...[more]

PMID: 22480195

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Project description:Background: As a key component in the NOTCH signaling pathway, HES1 plays an important role in vertebrate heart development. Variants in the HES1 coding sequence are known to be associated with congenital heart disease (CHD). However, little is known about HES1 non-coding sequence variants and their association with the risk of developing CHD. Method and Results: We initially analyzed the non-coding sequence of the HES1 gene in 12 unrelated CHD families by direct sequencing and identified a previously unreported promoter region variant (NM_005524.4: c.-1279-1278 insAC, rs148941464) in the HES1 gene in four CHD families. The homozygous variant in patients was inherited from carrier parents with normal phenotypes, indicating a likely recessive genetic model. Given that the HES1 gene is predicted to be likely to exhibit haploinsufficiency (%HI: 11.44), we hypothesized that the HES1 homozygous variant is a genetic risk factor underlying CHD. We then carried out sequencing of this HES1 variant in 629 sporadic non-syndromic CHD cases and 696 healthy controls and performed association analysis. Interestingly, we observed a significant association of the homozygous HES1 promoter variant with CHD (18.92% of cases vs. 9.91% of controls; OR: 2.291, 95% CI: 1.637-3.207, p = 9.72 × 10-7). No significant association with CHD was observed for the HES1 promoter heterozygous variant (p > 0.05). However, association analysis tests of the HES1 homozygous variant with each subtype of CHD revealed that this homozygous variant was strongly associated with transposition of the great arteries (TGA) (OR: 3.726, 95% CI: 1.745-7.956, p = 0.0003). Moreover, the prevalence of HES1 homozygous variants in CHD patients with TGA (27.66%) was significantly higher than that in patients with other CHD subtypes or controls. Similar results were observed in a replication group of TGA (n = 64). Functional studies demonstrated that the homozygous variant in the HES1 promoter can disrupt its ability to bind RXRA, an inhibitory transcription factor, which results in abnormally high expression of the HES1 gene, indicating that this variant harbors gain-of-function effects. Conclusions: Our findings reveal that the non-coding homozygous variant in the HES1 promoter has a gain-of-function effect and is associated with an increased risk of CHD development, especially the severe TGA subtype.

Dataset Information

ISL1 common variant rs1017 is not associated with susceptibility to congenital heart disease in a Chinese population.

Publications

ISL1 common variant rs1017 is not associated with susceptibility to congenital heart disease in a Chinese population.

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