Immunochip meta-analysis in European and Argentinian populations identifies two novel genetic loci associated with celiac disease

Eur J Hum Genet. 2020 Mar;28(3):313-323. doi: 10.1038/s41431-019-0520-4. Epub 2019 Oct 7.

Abstract

Celiac disease (CeD) is a common immune-mediated disease of the small intestine that is triggered by exposure to dietary gluten. While the HLA locus plays a major role in disease susceptibility, 39 non-HLA loci were also identified in a study of 24,269 individuals. We now build on this earlier study by adding 4125 additional Caucasian samples including an Argentinian cohort. In doing so, we not only confirm the previous associations, we also identify two novel independent genome-wide significant associations at loci: 12p13.31 and 22q13.1. By applying a genomics approach and differential expression analysis in CeD intestinal biopsies, we prioritize potential causal genes at these novel loci, including LTBR, CYTH4, and RAC2. Nineteen prioritized causal genes are overlapping known drug targets. Pathway enrichment analysis and expression of these genes in CeD biopsies suggest that they have roles in regulating multiple pathways such as the tumor necrosis factor (TNF) mediated signaling pathway and positive regulation of I-κB kinase/NF-κB signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Argentina
  • Celiac Disease / genetics*
  • Celiac Disease / pathology
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Chromosomes, Human, Pair 12 / genetics
  • Chromosomes, Human, Pair 22 / genetics
  • Europe
  • Genetic Loci*
  • Genome-Wide Association Study
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Intestinal Mucosa / metabolism
  • Lymphotoxin beta Receptor / genetics
  • Lymphotoxin beta Receptor / metabolism
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • NF-kappa B / metabolism
  • Polymorphism, Single Nucleotide*
  • RAC2 GTP-Binding Protein
  • Tumor Necrosis Factor-alpha / metabolism
  • rac GTP-Binding Proteins / genetics
  • rac GTP-Binding Proteins / metabolism

Substances

  • CYTH4 protein, human
  • Cell Adhesion Molecules
  • Guanine Nucleotide Exchange Factors
  • LTBR protein, human
  • Lymphotoxin beta Receptor
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • NADPH Oxidases
  • NCF2 protein, human
  • rac GTP-Binding Proteins