The NOD2 p.Leu1007fsX1008 Mutation (rs2066847) Is a Stronger Predictor of the Clinical Course of Crohn's Disease than the FOXO3A Intron Variant rs12212067
| Autor: | Torsten Olszak, Matthias Friedrich, Burkhard Göke, Marianne Angelberger, Stephan Brand, Jürgen Glas, Johannes Stallhofer, Cornelia Tillack, Christiane Wolf, Florian Beigel, Fabian Schnitzler, Julia Diegelmann, Peter Lohse |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Pathology Nod2 Signaling Adaptor Protein lcsh:Medicine Crohn's Disease Severity of Illness Index Inflammatory bowel disease Gastroenterology Crohn Disease Polymorphism (computer science) Genotype Medicine and Health Sciences lcsh:Science Child Aged 80 and over Crohn's disease Multidisciplinary Forkhead Box Protein O3 Homozygote Forkhead Transcription Factors Middle Aged Prognosis Colitis Phenotype Female Research Article Adult medicine.medical_specialty Adolescent Immunology Single-nucleotide polymorphism Gastroenterology and Hepatology Polymorphism Single Nucleotide Autoimmune Diseases Young Adult Internal medicine medicine Humans SNP Genetic Predisposition to Disease Allele Allele frequency Alleles Genetic Association Studies Aged business.industry lcsh:R Inflammatory Bowel Disease Biology and Life Sciences medicine.disease Introns Mutation lcsh:Q Clinical Immunology business |
| Zdroj: | PLOS ONE PLoS ONE PLoS ONE, Vol 9, Iss 11, p e108503 (2014) |
| ISSN: | 1932-6203 1221-2067 |
| DOI: | 10.1371/journal.pone.0108503 |
| Popis: | Background: Very 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 Findings: We genotyped 550 CD patients for rs12212067 (FOXO3A) and the three common CD-associated NOD2 mutations rs2066844, rs2066847, and rs2066847 and performed genotype-phenotype analyses. Results: No 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 x 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 wildtype genotype (p = 0.007). Conclusion/Significance: In 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. |
| Databáze: | OpenAIRE |
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