title: Shared and distinct genetic variants in type 1 diabetes and celiac disease.
abstract: BACKGROUND
  Two inflammatory disorders, type 1 diabetes and celiac disease, cosegregate in populations, suggesting a common genetic origin. Since both diseases are associated with the HLA class II genes on chromosome 6p21, we tested whether non-HLA loci are shared.
  
  
  METHODS
  We evaluated the association between type 1 diabetes and eight loci related to the risk of celiac disease by genotyping and statistical analyses of DNA samples from 8064 patients with type 1 diabetes, 9339 control subjects, and 2828 families providing 3064 parent-child trios (consisting of an affected child and both biologic parents). We also investigated 18 loci associated with type 1 diabetes in 2560 patients with celiac disease and 9339 control subjects.
  
  
  RESULTS
  Three celiac disease loci--RGS1 on chromosome 1q31, IL18RAP on chromosome 2q12, and TAGAP on chromosome 6q25--were associated with type 1 diabetes (P<1.00x10(-4)). The 32-bp insertion-deletion variant on chromosome 3p21 was newly identified as a type 1 diabetes locus (P=1.81x10(-8)) and was also associated with celiac disease, along with PTPN2 on chromosome 18p11 and CTLA4 on chromosome 2q33, bringing the total number of loci with evidence of a shared association to seven, including SH2B3 on chromosome 12q24. The effects of the IL18RAP and TAGAP alleles confer protection in type 1 diabetes and susceptibility in celiac disease. Loci with distinct effects in the two diseases included INS on chromosome 11p15, IL2RA on chromosome 10p15, and PTPN22 on chromosome 1p13 in type 1 diabetes and IL12A on 3q25 and LPP on 3q28 in celiac disease.
  
  
  CONCLUSIONS
  A genetic susceptibility to both type 1 diabetes and celiac disease shares common alleles. These data suggest that common biologic mechanisms, such as autoimmunity-related tissue damage and intolerance to dietary antigens, may be etiologic features of both diseases.
authors.affiliation: Juvenile Diabetes Research Foundation-Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Smyth
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: Neil M
authors.initials: NM
authors.lastname: Walker
authors.forename: Jason D
authors.initials: JD
authors.lastname: Cooper
authors.forename: Kate
authors.initials: K
authors.lastname: Downes
authors.forename: Jennie H M
authors.initials: JH
authors.lastname: Yang
authors.forename: Joanna M M
authors.initials: JM
authors.lastname: Howson
authors.forename: Helen
authors.initials: H
authors.lastname: Stevens
authors.forename: Ross
authors.initials: R
authors.lastname: McManus
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Graham A
authors.initials: GA
authors.lastname: Heap
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Dubois
authors.forename: David G
authors.initials: DG
authors.lastname: Clayton
authors.forename: Karen A
authors.initials: KA
authors.lastname: Hunt
authors.forename: David A
authors.initials: DA
authors.lastname: van Heel
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics; D015551:Autoimmunity / Q000235:genetics*; D060908:CTLA-4 Antigen; D002446:Celiac Disease / Q000235:genetics* / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D053765:Interleukin-12 Subunit p35 / Q000235:genetics; D053728:Interleukin-18 Receptor beta Subunit / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D011506:Proteins / Q000235:genetics; D020710:RGS Proteins / Q000235:genetics; D019713:Receptors, CCR5 / Q000235:genetics; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D003598:Cytoskeletal Proteins; C508858:IL12A protein, human; C115629:IL18RAP protein, human; C508017:IL2RA protein, human; D053765:Interleukin-12 Subunit p35; D053728:Interleukin-18 Receptor beta Subunit; D053645:Interleukin-2 Receptor alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C103594:LPP protein, human; D011506:Proteins; D020710:RGS Proteins; C080831:RGS1 protein, human; D019713:Receptors, CCR5; C490778:SH2B3 protein, human; C516649:PTPN2 protein, human; C516765:PTPN22 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22