Clinical significance of circulating microRNAs as markers in detecting and predicting congenital heart defects in children.

BACKGROUND: Circulating microRNAs (miRNAs) are emerging as novel biomarkers for detecting cardiovascular diseases. In this study, we aimed to investigate the usefulness of miRNAs as biomarkers in diagnosing and predicting children with congenital heart defects (CHD), particularly in the context of multiple subtypes of CHD. METHODS: We recruited 26 families, each having a child with CHD and parents who do not have any cardiovascular disorder. 27 families unaffected by cardiovascular disease were also included as controls. Firstly, we screened 84 circulating miRNAs relating to cardiovascular development in 6 children with atrial septal defects (ASD) and 5 healthy children. We validated the selected miRNAs with differential expression in a larger sample size (n = 27 for controls, n = 26 for cases), and evaluated their signal in different types of septal defects. Finally, we examined the identified miRNAs signatures in the parent population and assessed their diagnostic values for predicting CHD. RESULTS: The three miRNAs hsa-let-7a, hsa-let-7b and hsa-miR-486 were significantly upregulated in children with ASD. A further validation study showed that overexpression of hsa-let-7a and hsa-let-7b was specifically present in ASD children, but not in children with other subtypes of septal defects. A similar expression profile of hsa-let-7a and hsa-let-7b was discovered in mothers of ASD children. Receiver-operating characteristic curve analyses indicated that hsa-let-7a and hsa-let-7b had significant diagnostic values for detecting ASD and in maternal samples predicting the occurrence of ASD in offspring. CONCLUSIONS: Circulating miRNAs are important markers not only for diagnosing CHD, but also for predicting CHD risk in offspring. The distinct miRNA signatures are likely to present in various subtypes of CHD, and the phenotypic heterogeneity of CHD should be considered to develop such miRNA-based assays.

No simple answers for the Finnish and Russian Karelia allergy contrast: Methylation of CD14 gene.

BACKGROUND: Finnish and Russian Karelian children have a highly contrasting occurrence of asthma and allergy. In these two environments, we studied associations between total serum immunoglobulin E (IgE) with methylation levels in cluster of differentiation 14 (CD14). METHODS: Five hundred Finnish and Russian Karelian children were included in four groups: Finnish children with high IgE (n = 126) and low IgE (n = 124) as well as Russian children with high IgE (n = 125) and low IgE (n = 125). DNA was extracted from whole blood cells and pyrosequenced. Three CpG sites were selected in the promoter region of CD14. RESULTS: Methylation levels in two of the three CpG sites were higher in the Finnish compared to Russian Karelian children. In the promoter area of CD14, the Finnish compared to Russian children with low IgE had a significant (p < 0.0001) increase in methylation levels at the Amp5Site 2. Likewise, the Finnish compared to Russian children with high IgE had a significant (p = 0.003) increase in methylation levels at the Amp5Site 3. In Russian children with low vs. high IgE, there were significant differences in methylation levels, but this was not the case on the Finnish side. In the regression analysis, adding the methylation variation of CD14 to the model did not explain the higher asthma and allergy risk in the Finnish children. CONCLUSIONS: The methylation levels in the promoter region of CD14 gene were higher in the Finnish compared to Russian Karelian children. However, the methylation variation of this candidate gene did not explain the asthma and allergy contrast between these two areas.

Interleukin-10 (IL-10) polymorphisms are associated with IL-10 production and clinical malaria in young children.

The role of interleukin-10 (IL-10) in malaria remains poorly characterized. The aims of this study were to investigate (i) whether genetic variants of the IL-10 gene influence IL-10 production and (ii) whether IL-10 production as well as the genotypes and haplotypes of the IL-10 gene in young children and their mothers are associated with the incidence of clinical malaria in young children. We genotyped three IL-10 single nucleotide polymorphisms in 240 children and their mothers from a longitudinal prospective cohort and assessed the IL-10 production by maternal peripheral blood mononuclear cells (PBMCs) and cord blood mononuclear cells (CBMCs). Clinical episodes of Plasmodium falciparum malaria in the children were documented until the second year of life. The polymorphism IL-10 A-1082G (GCC haplotype of three SNPs in IL-10) in children was associated with IL-10 production levels by CBMC cultured with P. falciparum-infected erythrocytes (P = 0.043), with the G allele linked to low IL-10 production capacity. The G allele in children was also significantly associated with a decreased risk for clinical malaria infection in their second year of life (P = 0.016). Furthermore, IL-10 levels measured in maternal PBMCs cultured with infected erythrocytes were associated with increased risk of malaria infection in young children (P < 0.001). In conclusion, IL-10 polymorphisms and IL-10 production capacity were associated with clinical malaria infections in young children. High IL-10 production capacity inherited from parents may diminish immunological protection against P. falciparum infection, thereby being a risk for increased malaria morbidity.

The role of GSTP1 polymorphisms and tobacco smoke exposure in children with acute asthma.

BACKGROUND: The glutathione S-transferase enzymes (GSTs) play an important role in the detoxification of environmental tobacco smoke (ETS), which contributes to airway inflammation, a key component of asthma. Genetic variation in GST genes may influence individuals' ability to detoxify environmental pollutants. OBJECTIVE: To examine the role of polymorphisms in GSTP1 (Ile105Val and Ala114Val), alone and in combination with ETS exposure, on atopy and asthma severity. METHODS: GSTP1 Ile105Val and Ala114Val were genotyped and ETS exposure was assessed by parental questionnaire, which was validated by urinary cotinine measurements. Associations between ETS exposure, GSTP1 polymorphisms, and their interaction on atopy and asthma severity were investigated. RESULTS: For the functional GSTP1 105 SNP, those with the Ile/Ile genotype had odds for atopy of 2.77 (p = .054) when assessed by genotype alone, which increased to 9.02 (p = .050) when ETS was included, relative to individuals with other genotypes. Likewise, compared to children with other GSTP1 114 genotypes, those with Ala/Ala genotype had a 5.47-fold (p = .002) increased risk of atopy (p = .020) when assessed by genotype alone, increasing to 9.17-fold when ETS was included. The 105 Ile/Ile individuals all had the AA (105 Ile/Ile and 114 Ala/Ala) haplotype group; therefore, the odds for atopy were the same. Individuals without any *C haplotype (105 Val and 114 Val allele) who were exposed to ETS had a 9.17-fold increased risk of atopy when compared with individuals with at least one *C haplotype and not exposed to ETS (p = .020). CONCLUSION: There were significant interactions between GSTP1 SNPs, atopy, and ETS exposure in this cohort.