Susceptibility to Heart Defects in Down Syndrome Is Associated with Single Nucleotide Polymorphisms in HAS 21 Interferon Receptor Cluster and VEGFA Genes

Abstract

Background: Congenital heart defects (CHDs) are present in about 40–60% of newborns with Down syndrome (DS). Patients with DS can also develop acquired cardiac disorders. Mouse models suggest that a critical 3.7 Mb region located on human chromosome 21 (HSA21) could explain the association with CHDs. This region includes a cluster of genes (IFNAR1, IFNAR2, IFNGR2, IL10RB) encoding for interferon receptors (IFN-Rs). Other genes located on different chromosomes, such as the vascular endothelial growth factor A (VEGFA), have been shown to be involved in cardiac defects. So, we investigated the association between single nucleotide polymorphisms (SNPs) in IFNAR2, IFNGR2, IL10RB and VEGFA genes, and the presence of CHDs or acquired cardiac defects in patients with DS. Methods: Individuals (n = 102) with DS, and age- and gender-matched controls (n = 96), were genotyped for four SNPs (rs2229207, rs2834213, rs2834167 and rs3025039) using KASPar assays. Results: We found that the IFNGR2 rs2834213 G homozygous genotype and IL10RB rs2834167G-positive genotypes were more common in patients with DSand significantly associated with heart disorders, while VEGFA rs3025039T-positive genotypes (T/*) were less prevalent in patients with CHDs. Conclusions: We identified some candidate risk SNPs for CHDs and acquired heart defects in DS. Our data suggest that a complex architecture of risk alleles with interplay effects may contribute to the high variability of DS phenotypes.

Interferon receptor gene dosage determines diverse hallmarks of Down syndrome

“…Sample size was determined a priori based on effect sizes of previous studies (e.g., human studies) or by post hoc analyses to ensure >80% power was achieved to reduce type II error (e.g., (HSA21) that may contribute to risk of congenital heart defects (CHDs) in humans with trisomy 21 (T21, yellow), genes with functional evidence whose triplication is necessary or sufficient to 5 increase incidence of CHDs in mouse models of Down syndrome (DS, blue), and genes with supporting evidence in both humans and mouse models of DS (green). Relative cytogenetic locations and number of protein-coding genes (bold) are indicated along ideogram of the q arm for HSA21 colored according to Giemsa banding (3,16,23,24,(56)(57)(58).…”

“…S7 ) ( 3, 16, 23, 24, 56, 57 ). Notably, single nucleotide polymorphisms in IFNGR2 and IL10RB have been associated with risk of CHD in DS ( 58 ). Nevertheless, our results are the first demonstration that normalization of Ifnr copy number is sufficient to rescue this phenotype.…”

MIF rs755622 and IL6 rs1800795 Are Implied in Genetic Susceptibility to End-Stage Renal Disease (ESRD)

“…DNA were extracted using a salting-out protocol and DNA quality was verified by 260/280 nm absorbance ratio and gel electrophoresis as previously reported [ 49 ]. SNP typing was performed using an on-demand assay developed by KBioscience Ltd. (Middlesex, UK) and based on homogeneous FRET (Fluorescence Resonance Energy Transfer) analysis on the products of a specific allele PCR (Kaspar) [ 50 , 51 ]. SNPs are listed in Table 2 .…”

New Molecular and Organelle Alterations Linked to Down Syndrome Heart Disease

“…Finally, as has been proposed, mutations and polymorphisms may contribute to the heterogeneity of DS phenotypes, such as the ones observed in the context of CHD. Balistreri et al studied the relationship between SNPs in four interferon receptors ( IFNAR1 , IFNAR2 , IFNGR2 , IL10RB ) and the VEGFA genes, and CHD in subjects with DS ( Balistreri et al, 2020 ). The interferon receptor genes belong to a cluster located in a 3.7 Mb critical genomic region associated with DS heart defects in the Ts1Cje DS mouse model ( Liu et al, 2014 ).…”

“…Although VEGFA is located in another chromosome, its overexpression in mice embryos triggers severe heart development abnormalities ( Miquerol et al, 2000 ). In this regard, Balisteri et al , found that IFNAR2 and IL10RB SNP were related with heart disorders in subjects with DS, whereas VEGF SNP were less prevalent in subjects with CHD ( Balistreri et al, 2020 ). Similarly, Joziasse et al , identified a SNP in the ALK2 receptor , a member of the TGF-β superfamily, in a patient with DS and CHD, resulting in an H286D substitution.…”