title: Polymorphic haplotypes of CRELD1 differentially predispose Down syndrome and euploids individuals to atrioventricular septal defect.
abstract: To explore the role of CRELD1 variants on congenital heart defects, we sequenced the entire reading frame of CRELD1 in the samples from Kolkata and adjoining areas. Nearly, 400 participants were included in the genetic association study and they were stratified as Down syndrome (DS) with atrioventricular septal defect (AVSD), DS without AVSD, euploid with AVSD, and euploid without AVSD. A significant association was found between AVSD and three polymorphisms, namely rs9878047 (c.1049-129T > C), rs3774207 (c.1119C > T), and rs73118372 (c.1136T > C) among the Down syndrome and euploid individuals. The polymorphism rs73118372, involves a transition (c.1136T > C) that leads to change in amino acid methionine to threonine which alters protein secondary structure as confirmed by the bioinformatics software SOPMA. In addition, two haplotypes, C-T-C and C-T-T, in the order of loci rs9878047-rs3774207-rs73118372 were associated with incidence of AVSD among euploid and Down syndrome, with a slightly higher odds ratio in the later group. We hypothesize that these haplotypes increase the risk of AVSD, and the susceptibility is exacerbated in DS, possibly due to the trisomy 21 genetic background. Moreover, we report for the first time on an interaction between the mutant alleles of rs3774207 and rs73118372 which could disrupt the delicate balance between different CRELD1 isoforms.
authors.affiliation: Human Genetics Research Unit, School of Biotechnology and Biological Sciences, West Bengal University of Technology, Kolkata, West Bengal, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Ghosh
authors.forename: Pranami
authors.initials: P
authors.lastname: Bhaumik
authors.forename: Sujoy
authors.initials: S
authors.lastname: Ghosh
authors.forename: Umut
authors.initials: U
authors.lastname: Ozbek
authors.forename: Eleanor
authors.initials: E
authors.lastname: Feingold
authors.forename: Cheryl
authors.initials: C
authors.lastname: Maslen
authors.forename: Biswanath
authors.initials: B
authors.lastname: Sarkar
authors.forename: Vishmadeb
authors.initials: V
authors.lastname: Pramanik
authors.forename: Priyanka
authors.initials: P
authors.lastname: Biswas
authors.forename: Biswajit
authors.initials: B
authors.lastname: Bandyopadhyay
authors.forename: Subrata Kumar
authors.initials: SK
authors.lastname: Dey
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002648:Child; D004314:Down Syndrome / Q000150:complications* / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006343:Heart Septal Defects / Q000235:genetics*; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: C465506:CRELD1 protein, human; D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins