title: Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease.
abstract: Genetic variation in both innate and adaptive immune systems is associated with Crohn's disease (CD) susceptibility, but much of the heritability to CD remains unknown. We performed a genome-wide association study (GWAS) in 896 CD cases and 3204 healthy controls all of Caucasian origin as defined by multidimensional scaling. We found supportive evidence for 21 out of 40 CD loci identified in a recent CD GWAS meta-analysis, including two loci which had only nominally achieved replication (rs4807569, 19p13; rs991804, CCL2/CCL7). In addition, we identified associations with genes involved in tight junctions/epithelial integrity (ASHL, ARPC1A), innate immunity (EXOC2), dendritic cell biology [CADM1 (IGSF4)], macrophage development (MMD2), TGF-beta signaling (MAP3K7IP1) and FUT2 (a physiological trait that regulates gastrointestinal mucosal expression of blood group A and B antigens) (rs602662, P=3.4x10(-5)). Twenty percent of Caucasians are 'non-secretors' who do not express ABO antigens in saliva as a result of the FUT2 W134X allele. We demonstrated replication in an independent cohort of 1174 CD cases and 357 controls between the four primary FUT2 single nucleotide polymorphisms (SNPs) and CD (rs602662, combined P-value 4.90x10(-8)) and also association with FUT2 W143X (P=2.6x10(-5)). Further evidence of the relevance of this locus to CD pathogenesis was demonstrated by the association of the original four SNPs and CD in the recently published CD GWAS meta-analysis (rs602662, P=0.001). These findings strongly implicate this locus in CD susceptibility and highlight the role of the mucus layer in the development of CD.
authors.affiliation: Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. mcgovernd@cshs.org
authors.forename: Dermot P B
authors.initials: DP
authors.lastname: McGovern
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Jones
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.forename: Kristin
authors.initials: K
authors.lastname: Marciante
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Yan
authors.forename: Marla
authors.initials: M
authors.lastname: Dubinsky
authors.forename: Andy
authors.initials: A
authors.lastname: Ippoliti
authors.forename: Eric
authors.initials: E
authors.lastname: Vasiliauskas
authors.forename: Dror
authors.initials: D
authors.lastname: Berel
authors.forename: Carrie
authors.initials: C
authors.lastname: Derkowski
authors.forename: Deb
authors.initials: D
authors.lastname: Dutridge
authors.forename: Phil
authors.initials: P
authors.lastname: Fleshner
authors.forename: David Q
authors.initials: DQ
authors.lastname: Shih
authors.forename: Gil
authors.initials: G
authors.lastname: Melmed
authors.forename: Emebet
authors.initials: E
authors.lastname: Mengesha
authors.forename: Lily
authors.initials: L
authors.lastname: King
authors.forename: Sheila
authors.initials: S
authors.lastname: Pressman
authors.forename: Talin
authors.initials: T
authors.lastname: Haritunians
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003424:Crohn Disease / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D005647:Fucosyltransferases / Q000235:genetics* / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult; D000097631:Galactoside 2-alpha-L-fucosyltransferase
chemical_list: D005647:Fucosyltransferases; D000097631:Galactoside 2-alpha-L-fucosyltransferase