Two-stage candidate gene study of chromosome 3p demonstrates an association between nonsynonymous variants in the MST1R gene and Crohn's disease.
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.
Beckly
John B
JB
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. jbeckly@yahoo.com
Hancock
Laura
L
Geremia
Alessandra
A
Cummings
J R Fraser
JR
Morris
Andrew
A
Cooney
Rachel
R
Pathan
Saad
S
Guo
Changcun
C
Jewell
Derek P
DP
D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D004843:Epistasis, Genetic; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008264:Macrophages; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D018123:Receptors, Interleukin / Q000235:genetics
C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C515500:IL23R protein, human; D053473:Nod2 Signaling Adaptor Protein; D018123:Receptors, Interleukin; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases