title: Contrasting the Genetic Background of Type 1 Diabetes and Celiac Disease Autoimmunity.
abstract: Type 1 diabetes (T1D) and celiac disease (CeD) cluster in families and can occur in the same individual. Genetic loci have been associated with susceptibility to both diseases. Our aim was to explore the genetic differences between individuals developing both these diseases (double autoimmunity) versus those with only one. We hypothesized that double autoimmunity individuals carry more of the genetic risk markers that are shared between the two diseases independently. SNPs were genotyped in loci associated with T1D (n=42) and CeD (n=28) in 543 subjects who developed double autoimmunity, 2,472 subjects with T1D only, and 2,223 CeD-only subjects. For identification of loci that were specifically associated with individuals developing double autoimmunity, two association analyses were conducted: double autoimmunity versus T1D and double autoimmunity versus CeD. HLA risk haplotypes were compared between the two groups. The CTLA4 and IL2RA loci were more strongly associated with double autoimmunity than with either T1D or CeD alone. HLA analyses indicated that the T1D high-risk genotype, DQ2.5/DQ8, provided the highest risk for developing double autoimmunity (odds ratio 5.22, P=2.25×10(-29)). We identified a strong HLA risk genotype (DQ2.5/DQ8) predisposing to double autoimmunity, suggesting a dominant role for HLA. Non-HLA loci, CTLA4 and IL2RA, may also confer risk to double autoimmunity. Thus, CeD patients who carry the DQ2.5/DQ8 genotype may benefit from periodic screening of autoantibodies related to T1D.
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Javier
authors.initials: J
authors.lastname: Gutierrez-Achury
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Jihane
authors.initials: J
authors.lastname: Romanos
authors.affiliation: Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Sjoerd F
authors.initials: SF
authors.lastname: Bakker
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Esther C
authors.initials: EC
authors.lastname: de Haas
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Gosia
authors.initials: G
authors.lastname: Trynka
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Isis
authors.initials: I
authors.lastname: Ricaño-Ponce
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Andrea
authors.initials: A
authors.lastname: Steck
authors.affiliation: Center for Public Health Genomics and Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
authors.affiliation: Center for Public Health Genomics and Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA.
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut-Gumuscu
authors.affiliation: Department of Internal Medicine, Medical Center Alkmaar, Alkmaar, the Netherlands.
authors.forename: Suat
authors.initials: S
authors.lastname: Simsek
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Marian
authors.initials: M
authors.lastname: Rewers
authors.affiliation: Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Mulder
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Ed
authors.initials: E
authors.lastname: Liu
authors.affiliation: Center for Public Health Genomics and Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands c.wijmenga@umcg.nl.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
mesh_terms: D015551:Autoimmunity / Q000235:genetics; D060908:CTLA-4 Antigen / Q000235:genetics; D016022:Case-Control Studies; D002446:Celiac Disease / Q000235:genetics* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D000068617:Genetic Background; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012306:Risk
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D006680:HLA Antigens; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit