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Genetic Risk Profiling and Gene Signature Modeling to Predict Risk of Complications After IPAA

Sehgal, Rishabh M.B., B.Ch., M.R.C.S.1; Berg, Arthur Ph.D.1,2; Polinski, Joseph I. B.S.1; Hegarty, John P. Ph.D.1; Lin, Zhenwu Ph.D.1; McKenna, Kevin J. M.D.1; Stewart, David B. M.D.1; Poritz, Lisa S. M.D.1,3; Koltun, Walter A. M.D.1

Diseases of the Colon & Rectum: March 2012 - Volume 55 - Issue 3 - p 239–248
doi: 10.1097/DCR.0b013e31823e2d18
Original Contributions

BACKGROUND: Severe pouchitis and Crohn's disease-like complications are 2 adverse postoperative complications that confound the success of the IPAA in patients with ulcerative colitis. To date, approximately 83 single nucleotide polymorphisms within 55 genes have been associated with IBD.

OBJECTIVE: The aim of this study was to identify single-nucleotide polymorphisms that correlate with complications after IPAA that could be utilized in a gene signature fashion to predict postoperative complications and aid in preoperative surgical decision making.

DESIGN: One hundred forty-two IPAA patients were retrospectively classified as “asymptomatic” (n = 104, defined as no Crohn's disease-like complications or severe pouchitis for at least 2 years after IPAA) and compared with a “severe pouchitis” group (n = 12, ≥4 episodes pouchitis per year for 2 years including the need for long-term therapy to maintain remission) and a “Crohn's disease-like” group (n = 26, presence of fistulae, pouch inlet stricture, proximal small-bowel disease, or pouch granulomata, occurring at least 6 months after surgery). Genotyping for 83 single-nucleotide polymorphisms previously associated with Crohn's disease and/or ulcerative colitis was performed on a customized Illumina genotyping platform. The top 2 single-nucleotide polymorphisms statistically identified as being independently associated with each of Crohn's disease-like and severe pouchitis were used in a multivariate logistic regression model. These single-nucleotide polymorphisms were then used to create probability equations to predict overall chance of a positive or negative outcome for that complication.

RESULTS: The top 2 single-nucleotide polymorphisms for Crohn's disease-like complications were in the 10q21 locus and the gene for PTGER4 (p = 0.006 and 0.007), whereas for severe pouchitis it was NOD2 and TNFSF15 (p = 0.003 and 0.011). Probability equations suggested that the risk of these 2 complications greatly increased with increasing number of risk alleles, going as high as 92% for severe pouchitis and 65% for Crohn's disease-like complications.

CONCLUSION: In this IPAA patient cohort, mutations in the 10q21 locus and the PTGER4 gene were associated with Crohn's disease-like complications, whereas mutations in NOD2 and TNFSF15 correlated with severe pouchitis. Preoperative genetic analysis and use of such gene signatures hold promise for improved preoperative surgical patient selection to minimize these IPAA complications.

1 Division of Colon and Rectal Surgery, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania

2 Center for Statistical Genetics, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania

3 Department of Cellular and Molecular Physiology, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania

Funding/Support: This work was funded by the Research Foundation of The American Society of Colon and Rectal Surgeons. Dr Sehgal is the International Fellowship Award Recipient for year 2010.

Financial Disclosure: None reported.

Presented at the meeting of The American Society of Colon and Rectal Surgeons, Vancouver, BC, Canada, May 14 to 18, 2011.

Correspondence: Rishabh Sehgal, M.B., B.Ch., or Walter Koltun, M.D., Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Division of Colon & Rectal Surgery, H137, 500 University Dr, PO Box 850, Hershey, PA 17033-0850. E-mail: rishsehgal@gmail.com or wkoltun@hmc.psu.edu.

© The ASCRS 2012