title: Association of IL23R, TNFRSF1A, and HLA-DRB1*0103 allele variants with inflammatory bowel disease phenotypes in the Finnish population.
abstract: BACKGROUND
  Crohn's disease (CD) and ulcerative colitis (UC), 2 major forms of inflammatory bowel disease (IBD), are complex disorders with significant genetic predisposition. The first CD-associated gene, CARD15/NOD2, was recently identified and since then several reports on novel IBD candidate genes have emerged. We investigated disease phenotype association to genetic variations in IL23R, ATG16L1, DLG5, ABCB1/MDR1, TLR4, TNFRSF1A, chromosome 5 risk haplotype including SLC22A4 and SLC22A5, and HLA-DRB1*0103 allele among Finnish IBD patients.
  
  
  METHODS
  A total of 699 IBD patients were genotyped for disease-associated variants by polymerase chain reaction (PCR) and restriction enzyme digestion or Sequenom iPLEX method.
  
  
  RESULTS
  Five markers spanning the IL23R gene were associated with CD. The SNP (single nucleotide polymorphism) rs2201841 gave the strongest association (P = 0.002). The rare HLA-DRB1*0103 allele was found to associate with UC (P = 0.008), and the TNFRSF1A A36G variant was associated with familial UC (P = 0.007). Upon phenotypic analysis we detected association between familial UC and rare TNFRSF1A alleles 36G and IVS6+10G (P = 0.001 and P = 0.042, respectively). In addition, IL23R markers were associated with stricturing CD (P = 0.010-0.017), and ileocolonic CD was more prevalent in the carriers of the same 2 TNFRSF1A variants (P = 0.021 and P = 0.028, respectively). Less significant genotype-phenotype associations were observed for the TLR4 and HLA variants.
  
  
  CONCLUSIONS
  We were able to replicate the association of the IL23R variants with CD as well as HLA-DRB1*0103 with UC; confirmation of TNFRSF1A association with UC needs additional studies. Our findings also suggest that polymorphisms at IL23R and TNFRSF1A, and possibly HLA and TLR4, loci may account for phenotypic variation in IBD.
authors.affiliation: Research Program for Molecular Medicine, Biomedicum Helsinki, Finland.
authors.forename: Maarit
authors.initials: M
authors.lastname: Lappalainen
authors.forename: Leena
authors.initials: L
authors.lastname: Halme
authors.forename: Ulla
authors.initials: U
authors.lastname: Turunen
authors.forename: Päivi
authors.initials: P
authors.lastname: Saavalainen
authors.forename: Elisabet
authors.initials: E
authors.lastname: Einarsdottir
authors.forename: Martti
authors.initials: M
authors.lastname: Färkkilä
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kontula
authors.forename: Paulina
authors.initials: P
authors.lastname: Paavola-Sakki
mesh_terms: D003093:Colitis, Ulcerative / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics; D005260:Female; D005387:Finland; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018123:Receptors, Interleukin / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: D005819:Genetic Markers; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C515500:IL23R protein, human; D018123:Receptors, Interleukin; D047888:Receptors, Tumor Necrosis Factor, Type I; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4