Association of non-HLA genes with type 1 diabetes autoimmunity.
Approximately 50% of the genetic risk for type 1 diabetes is attributable to the HLA region. We evaluated associations between candidate genes outside the HLA region-INS, cytotoxic T-lymphocyte-associated antigen (CTLA)-4, interleukin (IL)-4, IL-4R, and IL-13 and islet autoimmunity among children participating in the Diabetes Autoimmunity Study in the Young (DAISY). Children with persistent islet autoantibody positivity (n = 102, 38 of whom have already developed diabetes) and control subjects (n = 198) were genotyped for single nucleotide polymorphisms (SNPs) in the candidate genes. The INS-23Hph1 polymorphism was significantly associated with both type 1 diabetes (OR = 0.30; 95% CI 0.13-0.69) and persistent islet autoimmunity but in the latter, only in children with the HLA-DR3/4 genotype (0.40; 0.18-0.89). CTLA-4 promoter SNP was significantly associated with type 1 diabetes (3.52; 1.22-10.17) but not with persistent islet autoimmunity. Several SNPs in the IL-4 regulatory pathway appeared to have a predisposing effect for type 1 diabetes. Associations were found between both IL-4R haplotypes and IL-4-IL-13 haplotypes and persistent islet autoimmunity and type 1 diabetes. This study confirms the association between the INS and CTLA-4 loci and type 1 diabetes. Genes involved in the IL-4 regulatory pathway (IL-4, IL-4R, IL-13) may confer susceptibility or protection to type 1 diabetes depending on individual SNPs or specific haplotypes.
Steck
Andrea K
AK
Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Mail Stop A140, P.O. Box 6511, Aurora, CO 80045-6511, USA. andrea.steck@uchsc.edu
Bugawan
Teodorica L
TL
Valdes
Ana Maria
AM
Emery
Lisa M
LM
Blair
Alan
A
Norris
Jill M
JM
Redondo
Maria J
MJ
Babu
Sunanda R
SR
Erlich
Henry A
HA
Eisenbarth
George S
GS
Rewers
Marian J
MJ
D000293:Adolescent; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics; D015551:Autoimmunity / Q000235:genetics*; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007328:Insulin / Q000235:genetics; D018793:Interleukin-13 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D007515:Islets of Langerhans / Q000276:immunology*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D019948:Receptors, Interleukin-4 / Q000235:genetics
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007328:Insulin; D018793:Interleukin-13; D019948:Receptors, Interleukin-4; D015847:Interleukin-4