The NOD2 p.Leu1007fsX1008 mutation (rs2066847) is a stronger predictor of the clinical course of Crohn's disease than the FOXO3A intron variant rs12212067.

Peter Lohse,Matthias Friedrich,Torsten Olszak,Cornelia Tillack,Marianne Angelberger,Johannes Stallhofer,Stephan Brand,Florian Beigel,Fabian Schnitzler,Jürgen Glas,Julia Diegelmann,Burkhard Göke,Christiane Wolf

doi:10.1371/journal.pone.0108503

Abstract

BackgroundVery recently, a sub-analysis of genome-wide association scans revealed that the non-coding single nucleotide polymorphism (SNP) rs12212067 in the FOXO3A gene is associated with a milder course of Crohn's disease (CD) (Cell 2013;155:57–69). The aim of our study was to evaluate the clinical value of the SNP rs12212067 in predicting the severity of CD by correlating CD patient genotype status with the most relevant complications of CD such as stenoses, fistulas, and CD-related surgery.Methodology/Principal FindingsWe genotyped 550 CD patients for rs12212067 (FOXO3A) and the three common CD-associated NOD2 mutations rs2066844, rs2066847, and rs2066847 and performed genotype-phenotype analyses.ResultsNo significant phenotypic differences were found between the wild-type genotype TT of the FOXO3A SNP rs12212067 and the minor genotypes TG and GG independently from NOD2 variants. The allele frequency of the minor G allele was 12.7%. Age at diagnosis, disease duration, body mass index, surgery rate, stenoses, fistula, need for immunosuppressive therapy, and disease course were not significantly different. In contrast, the NOD2 mutant p.Leu1007fsX1008 (rs2066847) was highly associated with penetrating CD (p = 0.01), the development of fistulas (p = 0.01) and stenoses (p = 0.01), and ileal disease localization (p = 0.03). Importantly, the NOD2 SNP rs2066847 was a strong separator between an aggressive and a mild course of CD (p = 2.99×10−5), while the FOXO3A SNP rs12212067 did not separate between mild and aggressive CD behavior in our cohort (p = 0.35). 96.2% of the homozygous NOD2 p.Leu1007fsX1008 carriers had an aggressive disease behavior compared to 69.3% of the patients with the NOD2 wild-type genotype (p = 0.007).Conclusion/SignificanceIn clinical practice, the NOD2 variant p.Leu1007fsX1008 (rs2066847), in particular in homozygous form, is a much stronger marker for a severe clinical phenotype than the FOXO3A rs12212067 SNP for a mild disease course on an individual patient level despite its important impact on the inflammatory response of monocytes.

Highlights

Crohn’s disease (CD) and ulcerative colitis (UC) are the two main forms of inflammatory bowel disease (IBD) characterized by a chronic relapsing disease course based on a chronic inflammation of the intestine, frequently resulting in a stricturing and penetrating disease phenotype in CD patients
For defining the most appropriate treatment algorithm in CD patients, prediction of the subsequent disease course is indispensable for lowering the risk of overtreatment and limiting the use of potentially harmful immunosuppressive therapy in mild CD, and for initiating a therapy with biologicals in early ‘‘aggressive’’ CD to lower CDrelated complications and surgery
The present study demonstrates that the NOD2 mutant p.Leu1007fsX1008 strongly correlates with a severe CD course

Summary

Introduction

Crohn’s disease (CD) and ulcerative colitis (UC) are the two main forms of inflammatory bowel disease (IBD) characterized by a chronic relapsing disease course based on a chronic inflammation of the intestine, frequently resulting in a stricturing and penetrating disease phenotype in CD patients. Since the introduction of biological therapies in the treatment of IBD, therapeutic options have dramatically improved [1]. Anti-TNF therapies have been proven in various clinical trials to alleviate the IBD disease course by rapidly inducing and maintaining clinical remission and mucosal healing in IBD patients [1]. These therapies are indispensable for the management of moderate to severe forms of IBD. Several novel compounds and ‘‘biosimilars’’ are currently undergoing clinical trials and will further increase the treatment options in IBD [1]. The early prediction of the disease course after initial diagnosis becomes increasingly important for subsequent therapeutic decisions. The aim of our study was to evaluate the clinical value of the SNP rs12212067 in predicting the severity of CD by correlating CD patient genotype status with the most relevant complications of CD such as stenoses, fistulas, and CDrelated surgery

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Conclusion