Extended haplotype association study in Crohn's disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3

Genes Immun. Jul-Aug 2013;14(5):310-6. doi: 10.1038/gene.2013.19. Epub 2013 Apr 25.

Abstract

The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn's disease (CD) compared with non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to CD etiology in this population, most notably at NOD2, in which three causal, uncommon and conditionally independent NOD2 variants reside on a shared background haplotype. We present an analysis of extended haplotypes that showed significantly greater association to CD in the Ashkenazi Jewish population compared with a non-Jewish population (145 haplotypes and no haplotypes with P-value <10(-3), respectively). Two haplotype regions, one each on chromosomes 16 and 21, conferred increased disease risk within established CD loci. We performed exome sequencing of 55 Ashkenazi Jewish individuals and follow-up genotyping focused on variants in these two regions. We observed Ashkenazi Jewish-specific nominal association at R755C in TRPM2 on chromosome 21. Within the chromosome 16 region, R642S of HEATR3 and rs9922362 of BRD7 showed genome-wide significance. Expression studies of HEATR3 demonstrated a positive role in NOD2-mediated NF-κB signaling. The BRD7 signal showed conditional dependence with only the downstream rare CD-causal variants in NOD2, but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomes, Human, Pair 16 / genetics
  • Crohn Disease / genetics*
  • Exons / genetics
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study
  • Genotype
  • HEK293 Cells
  • Haplotypes
  • Humans
  • Jews / genetics*
  • Logistic Models
  • Mutation, Missense*
  • NF-kappa B / genetics*
  • Nod2 Signaling Adaptor Protein / genetics
  • Polymorphism, Single Nucleotide
  • Proteins / genetics*
  • RNA Interference
  • Sequence Analysis, DNA
  • Signal Transduction / genetics*

Substances

  • BRD7 protein, human
  • Chromosomal Proteins, Non-Histone
  • HEATR3 protein, human
  • NF-kappa B
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • Proteins