Polymorphic haplotypes of CRELD1 differentially predispose Down syndrome and euploids individuals to atrioventricular septal defect

Authors

  • Priyanka Ghosh,

    1. Human Genetics Research Unit, School of Biotechnology and Biological Sciences, West Bengal University of Technology, Kolkata, West Bengal, India
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  • Pranami Bhaumik,

    1. Human Genetics Research Unit, School of Biotechnology and Biological Sciences, West Bengal University of Technology, Kolkata, West Bengal, India
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  • Sujoy Ghosh,

    1. Human Genetics Research Unit, School of Biotechnology and Biological Sciences, West Bengal University of Technology, Kolkata, West Bengal, India
    2. Department of Zoology, Sundarban Hazi Desarat College, Pathankhali, West Bengal, India
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  • Umut Ozbek,

    1. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh. Pennsylvania
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  • Eleanor Feingold,

    1. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh. Pennsylvania
    2. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Cheryl Maslen,

    1. Division of Cardiovascular Medicine and OHSU Heart Research Center, Oregon Health & Science University, Portland, Oregon
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  • Biswanath Sarkar,

    1. DNA laboratory, Anthropological Survey of India, Kolkata, West Bengal, India
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  • Vishmadeb Pramanik,

    1. DNA laboratory, Anthropological Survey of India, Kolkata, West Bengal, India
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  • Priyanka Biswas,

    1. Human Genetics Research Unit, School of Biotechnology and Biological Sciences, West Bengal University of Technology, Kolkata, West Bengal, India
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  • Biswajit Bandyopadhyay,

    1. Rabindranath.Tagore International Institute of Cardiac Sciences, Kolkata, West Bengal, India
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  • Subrata Kumar Dey

    Corresponding author
    1. Human Genetics Research Unit, School of Biotechnology and Biological Sciences, West Bengal University of Technology, Kolkata, West Bengal, India
    • Human Genetics Research Unit, School of Biotechnology and Biological Sciences. West Bengal University of Technology, BF—142, Salt Lake City, Sector I, Kolkata, West Bengal 700064, India.
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  • How to Cite this Article: Ghosh P, Bhaumik P, Ghosh S, Ozbek U, Feingold E, Maslen C, Sarkar B, Pramanik V, Biswas P, Bandyopadhyay B, Dey SK. 2012. Polymorphic haplotypes of CRELD1 differentially predispose Down syndrome and euploids individuals to atrioventricular septal defect. Am J Med Genet Part A 158A: 2843–2848.

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. © 2012 Wiley Periodicals, Inc.

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