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    • Keywords

       

      Association; celiac disease; Dutch; energy metabolism; immunochip; meta-analysis; north Indians; replication

    • Abstract

       

      Energy metabolism is a critical factor that influences disease pathogenesis. Recent high-throughput genomicstudies have enabled us to look into disease biology with greater details. Celiac disease (CD) is an inflammatoryautoimmune disease where ~60 non-HLA genes were identified which in conjunction with HLA genes explain

      ~55% of the disease heritability. In this study we aimed to identify susceptibility energy metabolism genes andinvestigate their role in CD. We re-analysed published Immunochip genotyping data, which were originallyanalysed for CD association studies in north Indian and Dutch population. 269 energy metabolism genes weretested. Meta-analysis was done for the identified SNPs. To validate the functional implications of identifiedmarkers and/or genes, in silico functional annotation was performed. Six SNPs were identified in north Indians, ofwhich three markers from two loci were replicated in Dutch. rs2071592 (PMeta=5.01e-75) and rs2251824(PMeta=1.87e-14) from ATP6V1G2-NFKBIL1-DDX39B locus and rs4947331 (PMeta= 9.85e-13) from NEU1locus were found significantly associated. Identified genes are key regulators of cellular energy metabolism andassociated with several immune mediated diseases. In silico functional annotation showed significant biologicalrelevance of these novel markers and genes. FDI approved therapeutics against ATP6V1G2 and NEU1 arecurrently in use to treat chronic and inflammatory diseases. This study identified two pathogenic loci, originallyinvolved in energy metabolism. Extensive investigation showed their synergistic role in CD pathogenesis bypromoting immune mediated enteric inflammation. Proposed CD pathogenesis model in this study needs to betested through tissue-on-chip and in vivo methods to ensure its translational application.

    • Author Affiliations

       

      SANDILYA BHAGAVATULA1 PRATIBHA BANERJEE1 AJIT SOOD2 VANDANA MIDHA3 BK THELMA4 SABYASACHI SENAPATI1

      1. Immunogenomics Laboratory, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, India
      2. Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
      3. Department of Medicine, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
      4. Department of Genetics, University of Delhi South Campus, New Delhi, India
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