NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe?
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.
Arnott
I D R
ID
Gastrointestinal Unit, University Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh, UK. ian.arnott@doctors.org.uk
Nimmo
E R
ER
Drummond
H E
HE
Fennell
J
J
Smith
B R K
BR
MacKinlay
E
E
Morecroft
J
J
Anderson
N
N
Kelleher
D
D
O'Sullivan
M
M
McManus
R
R
Satsangi
J
J
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
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