Smyth, DJ; Plagnol, V; Walker, NM; Cooper, JD; Downes, K; Yang, JHM; ... Todd, JA; + view all Smyth, DJ; Plagnol, V; Walker, NM; Cooper, JD; Downes, K; Yang, JHM; Howson, JMM; Stevens, H; McManus, R; Wijmenga, C; Heap, GA; Dubois, PC; Clayton, DG; Hunt, KA; van Heel, DA; Todd, JA; - view fewer (2008) Shared and Distinct Genetic Variants in Type 1 Diabetes and Celiac Disease. NEW ENGL J MED , 359 (26) 2767 - 2777.
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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<1.00 x 10(-4)). The 32-bp insertion-deletion variant on chromosome 3p21 was newly identified as a type 1 diabetes locus (P=1.81 x 10(-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.
|Title:||Shared and Distinct Genetic Variants in Type 1 Diabetes and Celiac Disease|
|Keywords:||GENOME-WIDE ASSOCIATION, INTESTINAL MICROBIOTA, RHEUMATOID-ARTHRITIS, RISK VARIANTS, SUSCEPTIBILITY, CHEMOKINE, MELLITUS, POLYMORPHISMS, PREVALENCE, MULTIPLE|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Genetics, Evolution and Environment > UCL Genetics Institute|
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