Multidimensional Prognostic Risk Assessment Identifies Association Between IL12B Variation and Surgery in Crohn’s Disease
| Autor: | Nick Teleten, Andrew Ippoliti, Gary Silber, Antonio Quiros, Phillip Fleshner, Ghassan Wahbeh, Dermont P. B McGovern, Subramaniam Kugathasan, Jerome I. Rotter, Eric A. Vasiliauskas, Michael C. Stephens, Talin Haritunians, Carol J. Landers, Marla Dubinsky, Deepa Panikkath, Soonil Kwon, Iwona Wrobel, Sharmayne Farrior, Chadwick Williams, Ron Bahar, Kent D. Taylor, Stephan R. Targan |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Male medicine.medical_specialty Time Factors Multivariate analysis Adolescent Genotype Genome-wide association study Disease Polymorphism Single Nucleotide Risk Assessment Article Young Adult Crohn Disease Humans Immunology and Allergy Medicine Genetic Predisposition to Disease Child Survival rate Aged Genetic association Crohn's disease Interleukin-12 Subunit p40 business.industry Proportional hazards model Gastroenterology Chromosome Mapping Infant Middle Aged Prognosis medicine.disease Surgery Survival Rate Genetic Loci Child Preschool Female business Risk assessment Follow-Up Studies Genome-Wide Association Study |
| Zdroj: | Inflammatory Bowel Diseases. 19:1662-1670 |
| ISSN: | 1078-0998 |
| DOI: | 10.1097/mib.0b013e318281f275 |
| Popis: | Background The ability to identify patients with Crohn's disease (CD) at highest risk of surgery would be invaluable in guiding therapy. Genome-wide association studies have identified multiple IBD loci with unknown phenotypic consequences. The aims of this study were to: (1) identify associations between known and novel CD loci with early resective CD surgery and (2) develop the best predictive model for time to surgery using a combination of phenotypic, serologic, and genetic variables. Methods Genotyping was performed on 1,115 subjects using Illumina-based genome-wide technology. Univariate and multivariate analyses tested genetic associations with need for surgery within 5 years. Analyses were performed by testing known CD loci (n = 71) and by performing a genome-wide association study. Time to surgery was analyzed using Cox regression modeling. Clinical and serologic variables were included along with genotype to build predictive models for time to surgery. Results Surgery occurred within 5 years in 239 subjects at a median time of 12 months. Three CD susceptibility loci were independently associated with surgery within 5 years (IL12B, IL23R, and C11orf30). Genome-wide association identified novel putative loci associated with early surgery: 7q21 (CACNA2D1) and 9q34 (RXRA, COL5A1). The most predictive models of time to surgery included genetic and clinical risk factors. More than a 20% difference in frequency of progression to surgery was seen between the lowest and highest risk groups. Conclusions Progression to surgery is faster in patients with CD with both genetic and clinical risk factors. IL12B is independently associated with need and time to early surgery in CD patients and justifies the investigation of novel and existing therapies that affect this pathway. |
| Databáze: | OpenAIRE |
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