Genetic association of HLA DQB1 with CD4+CD25+(high) T-cell apoptosis in type 1 diabetes.
Type 1 diabetes (T1D) has a strong genetic component and the major locus lies in the HLA DQB1 region. We found earlier an increased apoptosis with decreased viability and function of the CD4+CD25+(high) T-cell subset (Treg) in human subjects with recent-onset T1D and in multiple autoantibody-positive, high at-risk individuals. Tregs normally inhibit or delay onset of T1D in animal models and increased Treg apoptosis could bring on or accelerate disease from effector T-cell-mediated destruction of insulin-producing beta cells. In this study, we test the hypothesis that HLA DQB1 genotypes are associated with increased CD4+CD25+(high) T-cell apoptosis. HLA DQ-based genetic risk status was significantly associated with CD4+CD25+(high) T-cell apoptosis, after adjustment for age, gender and phenotypic status (n=83, F=4.04 (d.f.=3), P=0.01). Unaffected, autoantibody-negative high risk HLA DQB1 control subjects showed increased CD4+CD25+(high) apoptosis levels compared with low risk HLA DQB1 control subjects (n=26, P=0.002), confirming that the association precedes disease. The association of specific HLA DQB1 genotypes with Treg apoptosis was also tested, showing significance for HLA DQB1*0302, DQB1*0201 and HLA DQB1*0602 alleles. Our study shows an association of HLA DQB1 genotypes with CD4+CD25+(high) T-cell apoptosis, which implicates CD4+CD25+(high) T-cell apoptosis as a new intermediate trait for T1D.
Glisic
S
S
Department of Pediatrics, Max McGee National Center for Juvenile Diabetes and Human Molecular Genetic Center, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA.
Klinker
M
M
Waukau
J
J
Jailwala
P
P
Jana
S
S
Basken
J
J
Wang
T
T
Alemzadeh
R
R
Hagopian
W
W
Ghosh
S
S
D000293:Adolescent; D000328:Adult; D000483:Alleles; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics* / Q000276:immunology; D059866:HLA-DQ beta-Chains; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D055815:Young Adult
D015704:CD4 Antigens; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D053645:Interleukin-2 Receptor alpha Subunit; D008562:Membrane Glycoproteins