Abstract
Receptors are essential mediators of cellular physiology, which facilitate molecular and cellular cross-talk with the environment. Nearly 20% of the all known celiac disease (CD) genes are receptors by function. We hypothesized that novel biologically relevant susceptibility receptor genes act in synergy in CD pathogenesis. We attempted to identify novel receptor genes in CD by re-analyzing published Illumina Immunochip dense genotype data for a north Indian and a European (Dutch) cohort. North Indian dataset was screened for 269 known receptor genes. Association statistics for SNPs were considered with minor allele frequency >15% and association P ≤ 0.005 to attend desired study power. Identified markers were tested for cross-ethnic replication in a European CD dataset. Markers were analyzed in-silico to explain their functional significance in CD. Six novel SNPs from MOG (rs29231, p = 1.21e-11), GABBR1 (rs3025643, p = 1.60e-7), OR2H2 (rs1233388, p = 0.0002), ABCF1 (rs9262119, p = 0.0005), ADRA1A (rs10102024, p = 0.003), and ACVR2A (rs7560426, p = 0.004) were identified in north Indians, of which three genes namely, GABBR1 (rs3025643, p = 5.38e-8), OR2H2 (rs1233388, p = 3.29e-5) and ABCF1 (rs9262119, p = 0.0002) were replicated in Dutch. Tissue specific functional annotation, potential epigenetic regulation, co-expression, protein-protein interaction and pathway enrichment analyses indicated differential expression and synergistic function of key genes that could alter cellular homeostasis, ubiquitination mediated phagosome pathway and cellular protein processing to contribute for CD. At present multiple therapeutic compounds/drugs are available targeting GABBR1 and ADRA1A, which could be tested for their effectiveness against CD in controlled drug trials.
Highlights
To know more about the importance of identified genes in human diseases biology, cross-disease association was checked by scanning all the GWAS reports till date
Other four SNPs from OR2H2, ABCF1, ADRA1A, and activin receptor type-2A (ACVR2A) were identified with suggestive p values
Top four SNPs from Myelin oligodendrocyte glycoprotein (MOG), gamma-aminobutyric acid type B receptor subunit 1 (GABBR1), OR2H2 and ABCF1 are localized within extended MHC locus
Summary
KEGG and Gene Ontology (GO) pathway databases were used to curate a list of known receptor genes for his study[10,11]. Published association summary statistics of north Indian celiac disease study (using Illumina Immunochip platform) was available in-house This dataset was used to identify novel receptor genes associated with CD. Molecular functions of each of these genes were obtained from UniProtKB/Swiss-Prot database[12] Regulatory significance of these SNPs was checked on RegulomeDB and ENCODE database[15,16,17]. Biological relevance of identified genes was estimated by evaluating protein-protein interaction (PPI) and molecular networks. NetworkAnalyst 3.0 online tool was used for network enrichment analysis, generic PPI, and tissue specific co-expression to investigate the cumulative functional implication of the identified genes[20]. This database presently has a total of 12,110 drug entries (including 2,554 approved small molecule drugs, 1,280 approved proteins/peptide drugs, 130 nutraceuticals and over 5,842 experimental compounds) and 5156 non-redundant proteins against query target(s)
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