title: NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe?
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.
authors.affiliation: Gastrointestinal Unit, University Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh, UK. ian.arnott@doctors.org.uk
authors.forename: I D R
authors.initials: ID
authors.lastname: Arnott
authors.forename: E R
authors.initials: ER
authors.lastname: Nimmo
authors.forename: H E
authors.initials: HE
authors.lastname: Drummond
authors.forename: J
authors.initials: J
authors.lastname: Fennell
authors.forename: B R K
authors.initials: BR
authors.lastname: Smith
authors.forename: E
authors.initials: E
authors.lastname: MacKinlay
authors.forename: J
authors.initials: J
authors.lastname: Morecroft
authors.forename: N
authors.initials: N
authors.lastname: Anderson
authors.forename: D
authors.initials: D
authors.lastname: Kelleher
authors.forename: M
authors.initials: M
authors.lastname: O'Sullivan
authors.forename: R
authors.initials: R
authors.lastname: McManus
authors.forename: J
authors.initials: J
authors.lastname: Satsangi
mesh_terms: D000328:Adult; D003424:Crohn Disease / Q000208:ethnology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007494:Ireland; D018950:Lipopolysaccharide Receptors / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D011956:Receptors, Cell Surface / Q000235:genetics*; D012606:Scotland; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D044465:White People / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors