New Serological Markers for Inflammatory Bowel Disease Are Associated With Earlier Age at Onset, Complicated Disease Behavior, Risk for Surgery, and NOD2/CARD15 Genotype in a Hungarian IBD Cohort

Papp, Maria M.D.¹; Altorjay, Istvan M.D., Ph.D.¹; Dotan, Nir Ph.D.²; Palatka, Karoly M.D., Ph.D.¹; Foldi, Ildiko M.D.¹; Tumpek, Judit M.D.³; Sipka, Sandor M.D., Ds.C.³; Udvardy, Miklos M.D., Ds.C.¹; Dinya, Tamas M.D.⁴; Lakatos, Laszlo M.D., Ph.D.⁵; Kovacs, Agota M.D., Ph.D.⁶; Molnar, Tamas M.D., Ph.D.⁷; Tulassay, Zsolt M.D., Ds.C.⁸; Miheller, Pal M.D.⁸; Norman, Gary L. Ph.D.⁹; Szamosi, Tamas M.D.^10,11; Papp, Janos M.D., Ph.D.¹⁰; Lakatos, Peter L. M.D., Ph.D.¹⁰ the Hungarian IBD Study Group

Author Information

¹2nd Department of Medicine, University of Debrecen, Debrecen, Hungary;²Glycominds Ltd., Lod, Israel;³Laboratory of Clinical Immunology, University of Debrecen, Debrecen, Hungary;⁴Institute of Surgery, University of Debrecen, Debrecen, Hungary;⁵1st Department of Medicine, Csolnoky F. County Hospital, Veszprem, Hungary;⁶1st Department of Medicine, Peterfi Hospital, Budapest, Hungary;⁷1st Department of Medicine, University of Szeged, Szeged, Hungary;⁸2nd Department of Medicine, Semmelweis University, Budapest, Hungary;⁹INOVA Diagnostics, Inc., San Diego, California;¹⁰1st Department of Medicine, Semmelweis University, Budapest, Hungary; and¹¹Department of Medicine, National Medical Center, Budapest, Hungary

Reprint requests and correspondence: Peter L. Lakatos, M.D., Ph.D., 1st Department of Medicine, Semmelweis University, Koranyi St. 2/A, H-1083 Hungary.

CONFLICT OF INTEREST

Guarantor of the article: Peter L. Lakatos, M.D., Ph.D.

Specific author contributions: Maria Papp: designed the study, performed serology analysis, was involved in patient recruitment, supervised the collection of patients and controls and manuscript preparation; Ildiko Foldi, Judit Tumpek, Sandor Sipka, and Miklos Udvardy: performed serology analysis and were involved in manuscript preparation; Istvan Altojay, Tamas Dinya, Laszlo Lakatos, Agota Kovacs, Tamas Molnar, Zsolt Tulassay, Pal Miheller, Tamas Szamosi, and Janos Papp: were involved in patient recruitment and manuscript preparation; Nir Dotan and Gary L. Norman: were involved in manuscript preparation and in overseeing data analysis; Peter L. Lakatos: designed the study, was involved in patient recruitment, data analysis, and supervised the collection of patients and controls and manuscript preparation. All authors have approved the final draft submitted.

Financial support: We thank the Mecenatura Trust 11/2005, the Richter Gedeon Gastroenterology Research, and the ETT Health Research Council (ETT041/2006) for their financial support of this work. None of the funding bodies were involved in the study design, collection, analysis, and interpretation of the data, or in the preparation of the manuscript.

Potential competing interests: Nir Dotan is an employee of Glycominds Ltd. and Gary L. Norman is an employee of Inova Diagnostics Inc.

Received June 13, 2007; accepted October 2, 2007.

American Journal of Gastroenterology103(3):p 665-681, March 2008.

Abstract

BACKGROUND

Antibodies toSaccharomyces cerevisiae (S. cerevisiae) (ASCA) and porin protein-C ofEscherichia coli (anti-OmpC) are associated with disease phenotype and may be of diagnostic importance in inflammatory bowel diseases (IBD). Our aim was to determine whether a panel of new antibodies against bacterial proteins and carbohydrates could help differentiate among the various forms of IBD, and whether they were associated with particular clinical manifestations in a Hungarian cohort of IBD patients.

METHODS

Six hundred fifty-two well-characterized, unrelated, consecutive IBD patients (CD [Crohn's disease] 557, men/women 262/295, duration 8.1 ± 11.3 yr; ulcerative colitis [UC] 95, men/women 44/51, duration 8.9 ± 9.8 yr) and 100 healthy and 48 non-IBD gastrointestinal (GI) controls were investigated. Sera were assayed for anti-OmpC and antibodies against a mannan epitope ofS. cerevisiae (gASCA), laminaribioside (ALCA), chitobioside (ACCA), and mannobioside (AMCA). TLR4 and NOD2/CARD15 variants were tested by polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP). Detailed clinical phenotypes were determined by reviewing the patients' medical charts.

RESULTS

Sixty-six percent of the CD patients had at least one of the investigated antibodies. Among glycan antibodies, gASCA or the combination of gASCA and atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) was most accurate for differentiating between CD and UC. ASCA and gASCA assays performed similarly. Increasing amount and level of antibody responses toward gASCA, ALCA, ACCA, AMCA, and OmpC were associated with more complicated disease behavior (P < 0.0001) and need for surgery in CD (P= 0.023). A serological dosage effect was also observed. gASCA and AMCA antibodies were associated with NOD2/CARD15, in addition to a gene-dosage effect. No serotype-phenotype associations were found in UC.

CONCLUSIONS

Antibody response to this new panel of serological markers was associated with complicated disease phenotype, NOD2/CARD15 genotype, and a need for surgery in this eastern European IBD cohort.