CARD15 and HLA DRB1 alleles influence susceptibility and disease localization in Crohn's disease.
OBJECTIVE
Crohn's disease (CD) is a chronic inflammatory disease of the gut associated with allelic variants of CARD15 and HLA-DRB1 genes. We investigated the prevalence and effects of these variants in a Canadian CD cohort.


METHODS
507 unrelated CD patients were genotyped for the three major CD-associated variants (Arg702Trp, Gly908Arg, and Leu1007fsinsC) and for thirteen HLA-DRB1 alleles.


RESULTS
At least one CARD15 variant was present in 32.5% of the CD patients compared with 20% of controls. The prevalence of CARD15 mutation was similar in both sporadic and familial and Jewish and non-Jewish CD patients. The Gly908Arg variant was significantly higher and the Arg702Trp variant significantly lower in Jewish compared to non-Jewish patients. A positive association between the HLA-DRB1*0103 allele and CD was detected in non-Jewish, familial cases (p = 0.0002), with risk for CD increased by 6.7 fold by the presence of an HLA-DRB1*0103 allele as compared to 1.9 fold and 19 fold by a single or two CARD15 variant alleles, respectively. We show a significant association of ileal involvement with CARD15 variants (OR = 1.8; p = 0.02), HLA-DRB1*0701 (OR = 1.9; p = 0.006) and DRB1*04 (OR = 1.7; p = 0.02) alleles and demonstrate the capacity of combined CARD15 and HLA-DRB1 genotyping to predict ileal disease in CD patients. By contrast, the HLA-DRB1*0103 allele was associated with later age of diagnosis (p = 0.02) and pure colonic disease (p = 0.000013).


CONCLUSIONS
These observations confirm the influence of CARD15 and HLA-DRB1 alleles on both CD susceptibility and site of disease and identify genotyping of these variants as a potential tool for improved diagnosis and risk prediction in CD.
Newman
Bill
B
Department of Medicine, University of Toronto, Toronto, Canada.
Silverberg
Mark S
MS
Gu
Xiangjun
X
Zhang
Qing
Q
Lazaro
Ana
A
Steinhart
A Hillary
AH
Greenberg
Gordon R
GR
Griffiths
Anne M
AM
McLeod
Robin S
RS
Cohen
Zane
Z
Fernández-Viña
Marcelo
M
Amos
Christopher I
CI
Siminovitch
Katherine
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002170:Canada / Q000453:epidemiology; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003424:Crohn Disease / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007585:Jews / Q000235:genetics; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein; D015995:Prevalence; D012306:Risk
D002352:Carrier Proteins; D005819:Genetic Markers; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein