Risk Of Tetralogy Of Fallot Research Articles

LINE-1 methylation status and its association with tetralogy of fallot in infants

BackgroundMethylation levels of long interspersed nucleotide elements (LINE-1) are representative of genome-wide methylation status and play an important role in maintaining genomic stability and gene expression. To derive insight into the association between genome-wide methylation status and tetralogy of fallot (TOF), we compared the methylation status of LINE-1 element between TOF patients and controls. The methylation of the NKX 2–5, HAND 1, and TBX 20 promoter regions was also evaluated.MethodsGenomic DNA from right ventricular tissue samples was obtained from 32 patients with TOF and 15 control subjects. Sequenom MassARRAY platform was performed to examine the methylation levels of LINE-1, NKX2-5, HAND1 and TBX20. Mann–Whitney U test was used to compare differences in methylation levels between two groups.ResultsThe methylation level of LINE-1 was significantly lower in patients with TOF, with a median of 57.95% (interquartile range [IQR]: 56.10%–60.04%), as opposed to 59.70% in controls (IQR: 59.00%–61.30%; P = 0.0021). The highest LINE-1 methylation level was 61.3%. The risk of TOF increased in subjects with the lowest methylation levels (less than or equal to 59.0%; OR = 14.7, 95% CI: 1.8–117.7, P = 0.014) and in those with medium methylation levels (59.0%–61.3%; OR = 2.0, 95% CI: 0.3–14.2, P = 0.65). An ROC curve analysis showed a relatively high accuracy of using the LINE-1 methylation level in predicting the presence of TOF (AUC = 0.78, 95% CI: 0.65–0.91; P = 0.002). The association of the LINE-1 methylation level with TOF was only observed in males (P = 0.006) and not in females (P = 0.25). Neither age nor gender was found to be associated with the LINE-1 methylation level in patients or controls. Higher methylation levels of NKX2-5 and HAND1 and lower methylation levels of TBX20 were also observed in patients with TOF than in controls. No association was found between the methylation levels of NKX2-5, HAND1 and TBX 20 with the LINE-1 methylation level.ConclusionsLower LINE-1 methylation levels are associated with increased risk of TOF and may provide important clues for the development of TOF.

A common variant in the PTPN11 gene contributes to the risk of tetralogy of Fallot.

Tetralogy of Fallot (TOF) is the commonest cyanotic form of congenital heart disease. In 80% of cases, TOF behaves as a complex genetic condition exhibiting significant heritability. As yet, no common genetic variants influencing TOF risk have been robustly identified. Two hundred and seven haplotype-tagging single nucleotide polymorphisms in 22 candidate genes were genotyped in a test cohort comprising 362 nonsyndromic British white patients with TOF together with 717 unaffected parents of patients and 183 unrelated healthy controls. Single nucleotide polymorphisms with suggestive evidence of association in the test cohort (P<0.01) were taken forward for genotyping in an independent replication cohort comprising 392 cases of TOF, 218 unaffected parents of patients, and 1319 controls. Significant association was observed for 1 single nucleotide polymorphism, rs11066320 in the PTPN11 gene, in both the test and the replication cohort. Genotype at rs11066320 was associated with a per-allele odds ratio of 1.34 (95% confidence interval [CI], 1.19 to 1.52; P=2.9 × 10(-6)) in the total cohort of TOF cases and controls; this remained highly significant after Bonferroni correction for 207 analyses (corrected P=0.00061). Genotype at rs11066320 was responsible for a population-attributable risk of TOF of approximately 10%. Common variation in the linkage disequilibrium block including the PTPN11 gene contributes to the risk of nonsyndromic TOF. Rare mutations in PTPN11 are known to cause the autosomal dominant condition Noonan syndrome, which includes congenital heart disease, by upregulating Ras/mitogen-activated protein kinase (MAPK) signaling. Our results suggest a role for milder perturbations in PTPN11 function in sporadic, nonsyndromic congenital heart disease.

Abstract 17706: A Common Variant in the PTPN11 Gene Contributes to the Risk of Tetralogy of Fallot

Background: Tetralogy of Fallot (TOF) is the commonest form of cyanotic congenital heart disease. In 80% of cases, TOF behaves as a complex disease exhibiting significant heritability. We investigated whether common genetic variation in 23 candidate genes, selected either because of their expression in the second heart field or their involvement in syndromic congenital heart disease, predisposes to risk of “sporadic”, non-syndromic TOF. Methods and Results: 207 haplotype-tagging single nucleotide polymorphisms (SNPs) in the candidate genes with minor allele frequencies ≥0.05 were genotyped in a test cohort comprising 362 non-syndromic British Caucasian cases of TOF, and 900 controls (717 unaffected parents of cases, and 183 unrelated healthy people). Six SNPs with suggestive evidence of association (p&lt;0.01) were taken forward for genotyping in a replication cohort comprising 392 cases of TOF, 218 unaffected parents of cases, and 1319 controls. Significant association at p&lt;0.01 was confirmed for one SNP, rs11066320 in the PTPN11 gene, in the replication cohort. Genotype at rs11066320 was associated with a per-allele odds ratio of 1.35 (95% CI 1.20-1.52; p=2.94x10-6) in the total cohort of TOF cases and controls. Genotype at rs11066320 was responsible for a population attributable risk of TOF of approximately 5%. Association between rs11066320 genotype and TOF remained significant after Bonferroni correction for 207 analyses (corrected p=0.00061) Conclusions: Common variation in the PTPN11 gene contributes to the risk of non-syndromic TOF.