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Mutations in IRGM Are Associated With More Frequent Need for Surgery in Patients With Ileocolonic Crohn's Disease

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

doi: 10.1097/DCR.0b013e31823ccea8
Original Contributions

BACKGROUND: There are no clear criteria for judging the severity of disease in patients with Crohn's disease. Yet classification of patients into low- and high-risk severity groups would benefit both medical and surgical management. At the time of this study, approximately 80 single-nucleotide polymorphisms within 55 genes had been associated with IBD.

OBJECTIVE: The aim of this study was to identify genetic determinants (single-nucleotide polymorphisms) that could be markers of Crohn's disease severity by the use of frequency of ileocolic surgery as a surrogate for disease severity.

DESIGN: Sixty-six patients (30 male) with ileocolonic Crohn's disease who previously underwent ileocolectomy were retrospectively studied. The severity of Crohn's disease was quantified by dividing the total number of ileocolectomy procedures by the time between IBD diagnosis and the patient's last clinic visit, the rationale being that more severe disease would be associated with a more frequent need for surgery. Genotyping for the 83 single-nucleotide polymorphisms associated with IBD was done on a customized Illumina Veracode genotyping platform. Three genetic models (general, additive, and dominant) were used to statistically quantify the genetic association of the studied single-nucleotide polymorphisms to the frequency of surgery after adjusting for covariates (age, smoking, family history, disease location, and disease behavior).

RESULTS: For the entire group the average number of ileocolectomies per patient was 1.7 (range, 1–5) with an average duration of disease of 14.7 years. Single-nucleotide polymorphism rs4958847 in the IRGM gene (immunity-related GTPase family, M) was the most significant single-nucleotide polymorphism in all 3 models tested (p = 0.007) as being associated with ileocolectomy, and it remained significant even after a Benjamini-Hochberg false-discovery correction for multiple observations. Patients carrying the “at-risk” allele for this single-nucleotide polymorphism (n = 20) had an average of 1 surgery every 6.87 ± 1.33 years in comparison with patients carrying the wild-type genotype (n = 46) who averaged 1 surgery in 11.43 ± 1.21 years (p = 0.007, Mann-Whitney U test).

CONCLUSIONS: Single-nucleotide polymorphism rs4958847 in the IRGM gene correlated very significantly with frequency of surgery in patients with ileocolonic Crohn's disease. IRGM is a mediator of innate immune responses and is involved in autophagy. The presence of this IRGM SNP may be a marker for disease severity and/or early recurrence after ileocolectomy and may assist in surgical and medical decision making.

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

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

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

Financial Disclosures: None reported.

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

Recipient the 2011 ASCRS Harry E. Bacon Foundation Award for Best Basic Science Podium Presentation.

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 and 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