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

被引:170
作者
Arnott, IDR
Nimmo, ER
Drummond, HE
Fennell, J
Smith, BRK
MacKinlay, E
Morecroft, J
Anderson, N
Kelleher, D
O'Sullivan, M
McManus, R
Satsangi, J
机构
[1] Univ Edinburgh, Western Gen Hosp, Univ Dept Med Sci, Gastrointestinal Unit, Edinburgh EH4 2XU, Midlothian, Scotland
[2] St James Hosp, Dublin Mol Med Ctr, Dublin, Ireland
[3] St James Hosp, Trinity Ctr Hlth Sci, Dept Clin Med, Dublin, Ireland
[4] Adelaide & Meath Incorporating Natl Childrens Hos, Dept Clin Med, Dublin, Ireland
关键词
Crohn's disease; NOD2/CARD1; 5; toll-like receptor 4; CD14;
D O I
10.1038/sj.gene.6364111
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:417 / 425
页数:9
相关论文
共 50 条
[1]   Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease [J].
Abreu, MT ;
Taylor, KD ;
Lin, YC ;
Hang, T ;
Gaiennie, J ;
Landers, CJ ;
Vasiliauskas, EA ;
Kam, LY ;
Rojany, M ;
Papadakis, KA ;
Rotter, JI ;
Targan, SR ;
Yang, HY .
GASTROENTEROLOGY, 2002, 123 (03) :679-688
[2]   The molecular classification of the clinical manifestations of Crohn's disease [J].
Ahmad, T ;
Armuzzi, A ;
Bunce, M ;
Mulcahy-Hawes, K ;
Marshall, SE ;
Orchard, TR ;
Crawshaw, J ;
Large, O ;
De Silva, A ;
Cook, JT ;
Barnardo, M ;
Cullen, S ;
Welsh, KI ;
Jewell, DP .
GASTROENTEROLOGY, 2002, 122 (04) :854-866
[3]  
[Anonymous], 1982, CASE CONTROL STUDIES
[4]   TLR4 mutations are associated with endotoxin hyporesponsiveness in humans [J].
Arbour, NC ;
Lorenz, E ;
Schutte, BC ;
Zabner, J ;
Kline, JN ;
Jones, M ;
Frees, K ;
Watt, JL ;
Schwartz, DA .
NATURE GENETICS, 2000, 25 (02) :187-+
[5]   Incidence of juvenile-onset Crohn's disease in Scotland [J].
Armitage, E ;
Drummond, H ;
Ghosh, S ;
Ferguson, A .
LANCET, 1999, 353 (9163) :1496-1497
[6]   Crohn's disease or Crohn's diseases? [J].
Arnott, IDR ;
Satsangi, J .
GUT, 2003, 52 (04) :460-461
[7]   Association of NOD2 with Crohn's disease in a homogenous Irish population [J].
Bairead, E ;
Harmon, DL ;
Curtis, AM ;
Kelly, Y ;
O'Leary, C ;
Gardner, M ;
Leahy, DT ;
Vaughan, P ;
Keegan, D ;
O'Morain, C ;
O'Donoghue, D ;
Shanahan, F ;
Parfrey, NA ;
Quane, KA .
EUROPEAN JOURNAL OF HUMAN GENETICS, 2003, 11 (03) :237-244
[8]   Toll-like receptor signaling pathways [J].
Barton, GM ;
Medzhitov, R .
SCIENCE, 2003, 300 (5625) :1524-1525
[9]   Crohn's disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan [J].
Bonen, DK ;
Ogura, Y ;
Nicolae, DL ;
Inohara, N ;
Saab, L ;
Tanabe, T ;
Chen, FF ;
Foster, SJ ;
Duerr, RH ;
Brant, SR ;
Cho, JH ;
Nuñez, G .
GASTROENTEROLOGY, 2003, 124 (01) :140-146
[10]   A Y chromosome census of the British Isles [J].
Capelli, C ;
Redhead, N ;
Abernethy, JK ;
Gratrix, F ;
Wilson, JF ;
Moen, T ;
Hervig, T ;
Richards, M ;
Stumpf, MPH ;
Underhill, PA ;
Bradshaw, P ;
Shaha, A ;
Thomas, MG ;
Bradman, N ;
Goldstein, DB .
CURRENT BIOLOGY, 2003, 13 (11) :979-984