Lack of Association of the 3′-UTR Polymorphism (rs1017) in the ISL1 Gene and Risk of Congenital Heart Disease in the White Population

Cresci, Monica; Vecoli, Cecilia; Foffa, Ilenia; Pulignani, Silvia; Ait-Alì, Lamia; Andreassi, Maria Grazia

doi:10.1007/s00246-012-0578-z

Cited by 8 publications

(4 citation statements)

References 18 publications

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“…On the other hand, VEGF : rs36208048 showed no significant MAF differences in cases and controls, a result that contradicts a previous study [ 24 ]. For variation in the gene ISL1 , findings were in contrast to published data [ 25 , 26 ]. The VEGF variant was also studied in the 1000 genome project in 53 different populations.…”

Section: Discussioncontrasting

confidence: 99%

Genetic studies in the Pakistani population reveal novel associations with ventricular septal defects (VSDs)

et al. 2023

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Background With prevalence up to 4%, Ventricular Septal Defect (VSD) is one of the leading causes of neonatal deaths. VSD is a common complex genetic disorder that has been associated with many genetic determinants. Variants from genes for the transcription factors including T-Box TBX5 and NFATc1 (nuclear factor of activated T cells, cytoplasmic 1), Vascular endothelial growth factor (VEGF), ISLET1 (encoded by the ISL1 gene) and enzyme MTHFR, a methylene tetrahydrofolate reductase were selected. Genetic risk score (GRS) is a widely accepted approach used to convert the genetic data into prediction and assessment tool for disease susceptibility. Methods A total of 200 participants were recruited for the current study, 100 VSD patients and 100 controls. Genotyping of the ISL1: rs1017, NFATc1: rs7240256, VEGF: rs36208048, TBX5: rs11067075, and MTHFR: rs1801133 variants was performed using tetra primer ARMS PCR and PCR-RFLP. For the statistical analysis, the software SPSS version 23 was used. Genotypic frequencies of cases and controls were calculated using chi-square (χ²) whereas allelic frequencies were calculated by using the SNPStats tool. The association of GRS quartiles with VSD was examined using binary logistic regression. Adjusted p-value 0.01 was used as significance threshold for all analyses. Results The ISL1 (OD: 0.242, CI: 0.158–0.37, p-value: 2.15 × 10− 4 :), NFATc1 (OD: 2.53, CI: 1.64–3.89, p-value: 2.11 × 10− 5), TBX5 (OD: 2.24, CI: 1.47–3.41, p-value:1.6 × 10− 4) and MTHFR (OD: 10.46, CI: 5.68–19.26, p-value: 2.09 × 10− 9:) variants were found to be in association with VSD. In contrast, the VEGF (OD: 0.952, CI: 0.56–1.62, p-value: 0.8921) variant did not show significance association with the VSD. For cases, the mean GRS score was 3.78 ± 1.285 while in controls it was 2.95 ± 1.290 (p-value: 0.479, CI: 0.474–1.190). Comparison of GRS between cases and control showed that mean GRS of cases was 1.90 ± 0.480 while in controls it was 1.68 ± 0.490 (p-value: 0.001, CI: 0.086–0.354). Higher quartiles were more prevalent in cases whereas lower quartiles were more prevalent in controls. Conclusion GRS of these five loci was strongly associated with VSD. Moreover, genetic risk score can provide better information for the association between variants and disease as compared to a single SNP. We also illustrated that the cumulative power of GRS is greater over the single SNP effect. This is a pilot scale study with a relatively small sample size whose findings should be replicated in a larger sample size for the unique local Pakistani population.

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Section: Discussioncontrasting

confidence: 99%

Genetic studies in the Pakistani population reveal novel associations with ventricular septal defects (VSDs)

et al. 2023

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“…Following identification of two disease-associated haplotypes in large Caucasian and African American cohorts 35 , the SHF marker / Lim-homeodomain transcription factor, ISL1, has emerged as a possible susceptibility candidate. Although the pathogenicity of at least one of the reported variants remains uncertain 36,37 , these studies highlight a growing recognition of the potential for common alleles to contribute to CHD pathogenesis.…”

Section: Complex Signaling and Transcriptional Network Regulate Hearmentioning

confidence: 99%

Genetics and Genetic Testing in Congenital Heart Disease

Cowan

Ware

2015

Clinics in Perinatology

110

122

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“…A study of meta-analysis suggested this polymorphism as a risk factor for heart disease [ 5 ]. In contrast to the Chinese population, no association was detected in a White population [ 28 ]. Surprisingly, in the current study, results showed the minor allele as the protective allele for VSDs in the Pakistani population.…”

Section: Discussionmentioning

confidence: 99%

Study of variants associated with ventricular septal defects (VSDs) highlights the unique genetic structure of the Pakistani population

et al. 2022

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Background Ventricular septal defects (VSDs) are one of the leading causes of death due to cardiac anomalies during the first months of life. The prevalence of VSD in neonates is reported up to 4%. Despite the remarkable progress in medication, treatment and surgical procedure for VSDs, the genetic etiology of VSDs is still in infancy because of the complex genetic and environmental interactions. Methods Three hundred fifty subjects (200 VSD children and 150 healthy controls) were recruited from different pediatric cardiac units. Pediatric clinical and demographic data were collected. A total of six variants, rs1017 (ISL1), rs7240256 (NFATc1), rs36208048 (VEGF), variant of HEY2, rs11067075 (TBX5) and rs1801133 (MTHFR) genes were genotyped by tetra-ARMS PCR and PCR–RFLP methods. Results The results showed that in cases, the rs1017 (g.16138A > T) variant in the ISL1 gene has an allele frequency of 0.42 and 0.58 respectively for the T and A alleles, and 0.75 and 0.25 respectively in the controls. The frequencies of the AA, TA and TT genotypes were, 52%, 11% and 37% in cases versus 21%, 8% and 71% respectively in the controls. For the NFATc1 variant rs7240256, minor allele frequency (MAF) was 0.43 in cases while 0.23 in controls. For the variant in the VEGF gene, genotype frequencies were 0% (A), 32% (CA) and 68% (CC) in cases and 0.0%, 33% and 67% respectively in controls. The allele frequency of C and A were 0.84 and 0.16 in cases and 0.83 and 0.17 respectively in controls. The TBX5 polymorphism rs11067075 (g.51682G > T) had an allelic frequency of 0.44 and 0.56 respectively for T and G alleles in cases, versus 0.26 and 0.74 in the controls. We did not detect the presence of the HEY2 gene variant (g.126117350A > C) in our pediatric cohort. For the rs1801133 (g.14783C > T) variant in the MTHFR gene, the genotype frequencies were 25% (CC), 62% (CT) and 13% (TT) in cases, versus 88%, 10% and 2% in controls. The ISL1, NFATc1, TBX5 and MTHFR variants were found to be in association with VSD in the Pakistani pediatric cohort whilst the VEGF and HEY2 variants were completely absent in our cohort. Conclusion We propose that a wider programme of genetic screening of the Pakistani population for genetic markers in heart development genes would be helpful in reducing the risk of VSDs.

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Lack of Association of the 3′-UTR Polymorphism (rs1017) in the ISL1 Gene and Risk of Congenital Heart Disease in the White Population

Cited by 8 publications

References 18 publications

Genetic studies in the Pakistani population reveal novel associations with ventricular septal defects (VSDs)

Genetic studies in the Pakistani population reveal novel associations with ventricular septal defects (VSDs)

Genetics and Genetic Testing in Congenital Heart Disease

Study of variants associated with ventricular septal defects (VSDs) highlights the unique genetic structure of the Pakistani population

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