Two-stage candidate gene study of chromosome 3p demonstrates an association between nonsynonymous variants in the MST1R gene and Crohn's disease

John B. Beckly, Laura Hancock, Alessandra Geremia, J. R Fraser Cummings, Andrew Morris, Rachel Cooney, Saad Pathan, Changcun Guo, Derek P. Jewell

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background: Genomewide linkage studies identified chromosome 3p21 as an IBD locus. Genomewide association studies have supported this locus and the Wellcome Trust Case Control Consortium (WTCCC) study narrowed it to a 0.6 Mb region. Our objectives were to perform a 2-stage candidate gene association study of the 3p locus and to identify linkage disequilibrium (LD) between significant single-nucleotide polymorphisms (SNPs) and an Oxfordshire subset (n = 282) of the WTCCC as well as the HapMap SNPs. Methods: A total of 197 SNPs in 53 genes from the 3p locus were genotyped on the Illumina platform in a screening cohort of 469 Crohn's disease (CD) patients and 461 controls. Significant associations were then genotyped on the iPLEX platform in the original as well as a second cohort of 139 CD patients, 670 ulcerative colitis (UC) patients, and 1131 controls. All cases and controls were Caucasian and from the Oxfordshire region of the UK. Results: An intronic SNP rs1128535 in the TRAIP gene was associated with CD in the screening and validation cohorts (combined [n = 608] P = 0.0004 [corrected 0.002], odds ratio [OR] 0.77, 95% confidence interval [CI], 0.67-0.89]). No association was seen for UC. Epistasis was seen with the common CARD15 mutations (P = 0.00003 [corrected 0.0006], OR 0.48, 95% CI, 0.34-0.68). No LD was demonstrated with the WTCCC SNPs. Strong LD was demonstrated with 2 nonsynonymous HapMap SNPs in the MST1R gene in an adjacent LD block to the peak WTCCC association, suggesting a distinct association signal. Conclusions: The LD with these functional MST1R variants implicate this gene as having a possible role in CD pathogenesis.

Original languageEnglish
Pages (from-to)500-507
Number of pages8
JournalInflammatory Bowel Diseases
Volume14
Issue number4
DOIs
Publication statusPublished - Apr 2008
Externally publishedYes

Fingerprint

Crohn Disease
Linkage Disequilibrium
Single Nucleotide Polymorphism
Chromosomes
HapMap Project
Genes
Ulcerative Colitis
Odds Ratio
Confidence Intervals
Genetic Association Studies
Case-Control Studies
Mutation

Keywords

  • Crohn's disease
  • Genetics
  • Inflammatory bowel disease
  • MST1R
  • TRAIP

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Two-stage candidate gene study of chromosome 3p demonstrates an association between nonsynonymous variants in the MST1R gene and Crohn's disease. / Beckly, John B.; Hancock, Laura; Geremia, Alessandra; Cummings, J. R Fraser; Morris, Andrew; Cooney, Rachel; Pathan, Saad; Guo, Changcun; Jewell, Derek P.

In: Inflammatory Bowel Diseases, Vol. 14, No. 4, 04.2008, p. 500-507.

Research output: Contribution to journalArticle

Beckly, JB, Hancock, L, Geremia, A, Cummings, JRF, Morris, A, Cooney, R, Pathan, S, Guo, C & Jewell, DP 2008, 'Two-stage candidate gene study of chromosome 3p demonstrates an association between nonsynonymous variants in the MST1R gene and Crohn's disease', Inflammatory Bowel Diseases, vol. 14, no. 4, pp. 500-507. https://doi.org/10.1002/ibd.20365
Beckly, John B. ; Hancock, Laura ; Geremia, Alessandra ; Cummings, J. R Fraser ; Morris, Andrew ; Cooney, Rachel ; Pathan, Saad ; Guo, Changcun ; Jewell, Derek P. / Two-stage candidate gene study of chromosome 3p demonstrates an association between nonsynonymous variants in the MST1R gene and Crohn's disease. In: Inflammatory Bowel Diseases. 2008 ; Vol. 14, No. 4. pp. 500-507.
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abstract = "Background: Genomewide linkage studies identified chromosome 3p21 as an IBD locus. Genomewide association studies have supported this locus and the Wellcome Trust Case Control Consortium (WTCCC) study narrowed it to a 0.6 Mb region. Our objectives were to perform a 2-stage candidate gene association study of the 3p locus and to identify linkage disequilibrium (LD) between significant single-nucleotide polymorphisms (SNPs) and an Oxfordshire subset (n = 282) of the WTCCC as well as the HapMap SNPs. Methods: A total of 197 SNPs in 53 genes from the 3p locus were genotyped on the Illumina platform in a screening cohort of 469 Crohn's disease (CD) patients and 461 controls. Significant associations were then genotyped on the iPLEX platform in the original as well as a second cohort of 139 CD patients, 670 ulcerative colitis (UC) patients, and 1131 controls. All cases and controls were Caucasian and from the Oxfordshire region of the UK. Results: An intronic SNP rs1128535 in the TRAIP gene was associated with CD in the screening and validation cohorts (combined [n = 608] P = 0.0004 [corrected 0.002], odds ratio [OR] 0.77, 95{\%} confidence interval [CI], 0.67-0.89]). No association was seen for UC. Epistasis was seen with the common CARD15 mutations (P = 0.00003 [corrected 0.0006], OR 0.48, 95{\%} CI, 0.34-0.68). No LD was demonstrated with the WTCCC SNPs. Strong LD was demonstrated with 2 nonsynonymous HapMap SNPs in the MST1R gene in an adjacent LD block to the peak WTCCC association, suggesting a distinct association signal. Conclusions: The LD with these functional MST1R variants implicate this gene as having a possible role in CD pathogenesis.",
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T1 - Two-stage candidate gene study of chromosome 3p demonstrates an association between nonsynonymous variants in the MST1R gene and Crohn's disease

AU - Beckly, John B.

AU - Hancock, Laura

AU - Geremia, Alessandra

AU - Cummings, J. R Fraser

AU - Morris, Andrew

AU - Cooney, Rachel

AU - Pathan, Saad

AU - Guo, Changcun

AU - Jewell, Derek P.

PY - 2008/4

Y1 - 2008/4

N2 - Background: Genomewide linkage studies identified chromosome 3p21 as an IBD locus. Genomewide association studies have supported this locus and the Wellcome Trust Case Control Consortium (WTCCC) study narrowed it to a 0.6 Mb region. Our objectives were to perform a 2-stage candidate gene association study of the 3p locus and to identify linkage disequilibrium (LD) between significant single-nucleotide polymorphisms (SNPs) and an Oxfordshire subset (n = 282) of the WTCCC as well as the HapMap SNPs. Methods: A total of 197 SNPs in 53 genes from the 3p locus were genotyped on the Illumina platform in a screening cohort of 469 Crohn's disease (CD) patients and 461 controls. Significant associations were then genotyped on the iPLEX platform in the original as well as a second cohort of 139 CD patients, 670 ulcerative colitis (UC) patients, and 1131 controls. All cases and controls were Caucasian and from the Oxfordshire region of the UK. Results: An intronic SNP rs1128535 in the TRAIP gene was associated with CD in the screening and validation cohorts (combined [n = 608] P = 0.0004 [corrected 0.002], odds ratio [OR] 0.77, 95% confidence interval [CI], 0.67-0.89]). No association was seen for UC. Epistasis was seen with the common CARD15 mutations (P = 0.00003 [corrected 0.0006], OR 0.48, 95% CI, 0.34-0.68). No LD was demonstrated with the WTCCC SNPs. Strong LD was demonstrated with 2 nonsynonymous HapMap SNPs in the MST1R gene in an adjacent LD block to the peak WTCCC association, suggesting a distinct association signal. Conclusions: The LD with these functional MST1R variants implicate this gene as having a possible role in CD pathogenesis.

AB - Background: Genomewide linkage studies identified chromosome 3p21 as an IBD locus. Genomewide association studies have supported this locus and the Wellcome Trust Case Control Consortium (WTCCC) study narrowed it to a 0.6 Mb region. Our objectives were to perform a 2-stage candidate gene association study of the 3p locus and to identify linkage disequilibrium (LD) between significant single-nucleotide polymorphisms (SNPs) and an Oxfordshire subset (n = 282) of the WTCCC as well as the HapMap SNPs. Methods: A total of 197 SNPs in 53 genes from the 3p locus were genotyped on the Illumina platform in a screening cohort of 469 Crohn's disease (CD) patients and 461 controls. Significant associations were then genotyped on the iPLEX platform in the original as well as a second cohort of 139 CD patients, 670 ulcerative colitis (UC) patients, and 1131 controls. All cases and controls were Caucasian and from the Oxfordshire region of the UK. Results: An intronic SNP rs1128535 in the TRAIP gene was associated with CD in the screening and validation cohorts (combined [n = 608] P = 0.0004 [corrected 0.002], odds ratio [OR] 0.77, 95% confidence interval [CI], 0.67-0.89]). No association was seen for UC. Epistasis was seen with the common CARD15 mutations (P = 0.00003 [corrected 0.0006], OR 0.48, 95% CI, 0.34-0.68). No LD was demonstrated with the WTCCC SNPs. Strong LD was demonstrated with 2 nonsynonymous HapMap SNPs in the MST1R gene in an adjacent LD block to the peak WTCCC association, suggesting a distinct association signal. Conclusions: The LD with these functional MST1R variants implicate this gene as having a possible role in CD pathogenesis.

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