Basic Research
Copyright ©2005 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2005; 11(10): 1489-1495
Published online Mar 14, 2005. doi: 10.3748/wjg.v11.i10.1489
Toll-like receptor 4 and NOD2/CARD15 mutations in Hungarian patients with Crohn’s disease: Phenotype-genotype correlations
Peter Laszlo Lakatos, Laszlo Lakatos, Ferenc Szalay, Claudia Willheim-Polli, Christoph Österreicher, Zsolt Tulassay, Tamas Molnar, Walter Reinisch, Janos Papp, Gyula Mozsik, Hungarian IBD Study Group, Peter Ferenci
Peter Laszlo Lakatos, Ferenc Szalay, Janos Papp, Hungarian IBD Study Group, 1st Department of Medicine, Semmelweis University, Budapest, Hungary
Laszlo Lakatos, 1st Department of Medicine, Csolnoky F. County Hospital, Veszprem, Hungary
Claudia Willheim-Polli, Christoph Österreicher, Walter Reinisch, Peter Ferenci, Department of Internal Medicine 4, University of Vienna, Austria
Zsolt Tulassay, 2nd Department of Medicine, Semmelweis University, Budapest, Hungary
Tamas Molnar, 1st Department of Medicine, University of Szeged, Szeged, Hungary
Gyula Mozsik, 1st Department of Medicine, University of Pecs, Pecs, Hungary
Hungarian IBD Study Group: Semmelweis University, 1st Department of Medicine, Budapest: Peter Fuszek, Peter Vargha; Semmelweis University, 2nd Department of Medicine, Semmelweis University, Budapest: Laszlo Pronai†, Annamaria Nemeth, Pal Miheller; Erzsebet Hospital, 1st Department of Medicine, Budapest: Agota Kovacs, Laszlo Bene; Szent Janos Hospital, 1st Department of Medicine: Gyorgy Szekely; University of Pecs, 1st Department of Medicine, Pecs: Beata Gasztonyi; University of Szeged, 1st Department of Medicine, Szeged: Ferenc Nagy, Janos Lonovics; Semmelweis Hospital, 1st Department of Medicine, Miskolc: Laszlo Ujszaszy; University of Debrecen, 2nd Department of Medicine, Debrecen: Istvan Altorjai, Karoly Palatka; Kenezi Gy. County Hospital, 2nd Department of Medicine, Debrecen: Gyula G. Kiss; County Hospital, 2nd Department of Medicine, Zalaegerszeg; Ferenc Tarnok, Markusovszky Hospital, 2nd Department of Medicine, Szombathely: Zoltan Dobronte; Csolnoky F. County Hospital, 1st Department of Medicine, Veszprem: Zsuzsanna Erdelyi, Tunde Pandur, Gabor Mester
Author contributions: All authors contributed equally to the work.
Correspondence to: Peter Laszlo Lakatos, M.D., Ph.D., 1st Department of Medicine, Semmelweis University, Koranyi str. 2/A, H-1083, Hungary. kislakpet@bel1.sote.hu
Telephone: +36-1-210-0278/1500-1520 Fax: +36-1-313-0250
Received: July 26, 2004
Revised: July 28, 2004
Accepted: September 9, 2004
Published online: March 14, 2005
Abstract

AIM: To determine common NOD2/CARD15 mutations and TLR4 D299G polymorphism in Hungarian patients with CD.

METHODS: A total of 527 unrelated patients with CD (male/female: 265/262, age: 37.1 (SD 7.6) years) and 200 healthy subjects were included. DNA was screened for possible NOD2/CARD15 mutations by denaturing high-performance liquid chromatography (confirmed by direct sequencing). TLR4 D299G was tested by PCR-RFLP.

RESULTS: NOD2/CARD15 mutations were found in 185 patients (35.1%) and in 33 controls (16.5%, P<0.0001). SNP8/R702W (10.8% vs 6%, P = 0.02), SNP13/3020insC (19.4% vs 5%, P<0.0001) and exon4 R703C (2.1% vs 0%, P = 0.02) mutations were more frequent in CD, while the frequency of SNP12/G908R was not increased. The frequency of TLR4 D299G was not different (CD: 9.9% vs controls: 12.0%). Variant NOD2/CARD15 allele was associated with an increased risk for CD (ORhet = 1.71, 95%CI = 1.12-2.6, P = 0.0001, ORtwo-risk alleles = 25.2, 95%CI = 4.37-∞, P<0.0001), early disease onset (carrier: 26.4 years vs non-carrier: 29.8 years, P = 0.0006), ileal disease (81.9% vs 69.5%, OR = 1.99, 95%CI = 1.29-3.08, P = 0.02, presence of NOD2/CARD15 and TLR4: 86.7% vs 64.8%), stricturing behavior (OR = 1.69, 95%CI = 1.13-2.55, P = 0.026) and increased need for resection (OR=1.71, 95%CI: 1.13-2.62, P = 0.01), but not with duration, extra-intestinal manifestations, familial disease or smoking. TLR4 exhibited a modifier effect: age of onset in wt/TLR4 D299G carriers: 27.4 years vs NOD2mut/TLR D299G: 23 years (P = 0.06), in NOD2mut/wt: 26.7 years.

CONCLUSION: These results confirm that variant NOD2/CARD15 (R702W, R703C and 3020insC) alleles are associated with earlier disease onset, ileal disease, stricturing disease behavior in Hungarian CD patients. In contrast, although the frequency of TLR4 D299G polymorphism was not different from controls, NOD2/TLR4 mutation carriers tended to present at earlier age.

Keywords: Crohn’s disease; NOD2; CARD15; TLR4; Extraintestinal manifestation; Phenotype