Mutations in IRGM are associated with more frequent need for surgery in patients with ileocolonic crohn's disease

Rishabh Sehgal, Arthur Berg, Joseph I. Polinski, John P. Hegarty, Zhenwu Lin, Kevin McKenna, David Stewart, Lisa Poritz, Walter Koltun

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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 (immunityrelated GTPase family, M) was the most significant singlenucleotide 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.

Original languageEnglish (US)
Pages (from-to)115-121
Number of pages7
JournalDiseases of the Colon and Rectum
Volume55
Issue number2
DOIs
StatePublished - Feb 1 2012

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Crohn Disease
Single Nucleotide Polymorphism
Mutation
Genes
Time and Motion Studies
GTP Phosphohydrolases
Genetic Models
Autophagy
Ambulatory Care
Nonparametric Statistics
Innate Immunity
Smoking
Alleles
Genotype
Recurrence

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

Sehgal, Rishabh ; Berg, Arthur ; Polinski, Joseph I. ; Hegarty, John P. ; Lin, Zhenwu ; McKenna, Kevin ; Stewart, David ; Poritz, Lisa ; Koltun, Walter. / Mutations in IRGM are associated with more frequent need for surgery in patients with ileocolonic crohn's disease. In: Diseases of the Colon and Rectum. 2012 ; Vol. 55, No. 2. pp. 115-121.
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abstract = "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 (immunityrelated GTPase family, M) was the most significant singlenucleotide 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.",
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Mutations in IRGM are associated with more frequent need for surgery in patients with ileocolonic crohn's disease. / Sehgal, Rishabh; Berg, Arthur; Polinski, Joseph I.; Hegarty, John P.; Lin, Zhenwu; McKenna, Kevin; Stewart, David; Poritz, Lisa; Koltun, Walter.

In: Diseases of the Colon and Rectum, Vol. 55, No. 2, 01.02.2012, p. 115-121.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutations in IRGM are associated with more frequent need for surgery in patients with ileocolonic crohn's disease

AU - Sehgal, Rishabh

AU - Berg, Arthur

AU - Polinski, Joseph I.

AU - Hegarty, John P.

AU - Lin, Zhenwu

AU - McKenna, Kevin

AU - Stewart, David

AU - Poritz, Lisa

AU - Koltun, Walter

PY - 2012/2/1

Y1 - 2012/2/1

N2 - 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 (immunityrelated GTPase family, M) was the most significant singlenucleotide 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.

AB - 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 (immunityrelated GTPase family, M) was the most significant singlenucleotide 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.

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