NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe?

Genes Immun. 2004 Aug;5(5):417-25. doi: 10.1038/sj.gene.6364111.

Abstract

NOD2/caspase recruitment domain (CARD)15 variants are identified in up to 50% of Crohn's disease (CD) patients. Functional variants of toll-like receptor-4 (TLR4) and CD14 genes may also be relevant to disease pathophysiology. We aimed to assess the contribution of NOD2/CARD15, TLR4 and CD14 variants in Scottish and Irish CD patients. In all, 612 patients with well-characterised inflammatory bowel disease (252 Scottish CD, 247 Scottish UC, 113 Irish CD) and 304 controls were genotyped for variants of NOD2/CARD15 (1007fsinsC, G908R, R702W, P268S), TLR4 (A299G) and CD14 (T-159C). Genotype-phenotype analyses were performed. Variant 1007fsinsC (P=0.003) and G908R (P=0.008) but not R702W (P=0.269) alleles were more prevalent in Scottish CD (4.7, 1.8 and 7.1%, respectively) than Scottish control (2.3, 0.3 and 5.4%). CD allelic frequencies were lower than the series from Europe (P<0.00001) and North America (P<0.00001) but not Scandinavia (P<0.7). Associations were identified with age at diagnosis (P=0.002), ileal disease (P<0.02), penetrating disease (P=0.04) and inflammatory joint disease (P<0.02). TLR4 and CD14 variants did not differ between CD and controls. In conclusion, we present compelling evidence for genetic heterogeneity within Europe. These NOD2/CARD15 variants have a minor contribution in Scottish and Irish CD patients, consistent with an emerging pattern from Northern Europe.

MeSH terms

  • Adult
  • Crohn Disease / ethnology
  • Crohn Disease / genetics*
  • European Continental Ancestry Group / genetics
  • Female
  • Gene Frequency
  • Genetic Heterogeneity*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Ireland
  • Lipopolysaccharide Receptors / genetics*
  • Male
  • Membrane Glycoproteins / genetics*
  • Mutation
  • Nod2 Signaling Adaptor Protein
  • Receptors, Cell Surface / genetics*
  • Scotland
  • Toll-Like Receptor 4
  • Toll-Like Receptors

Substances

  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharide Receptors
  • Membrane Glycoproteins
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • Receptors, Cell Surface
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Toll-Like Receptors