Risk genes and autoantibodies in Egyptian children with type 1 diabetes - low frequency of autoantibodies in carriers of the HLA-DRB1*04:05-DQA1*03-DQB1*02 risk haplotype

Abstract

Background: The study aimed to define the frequencies of type 1 diabetes-associated gene polymorphisms and their associations with various diabetes-associated autoantibodies in Egyptian children.

Methods: One hundred and one children with type 1 diabetes and 160 healthy controls from the same region were studied for HLA-DQB1, HLA-DQA1, and HLA-DRB1 (DR4 subtypes) alleles; for INS and protein tyrosine phosphatase, non-receptor type 22 gene polymorphisms (rs689 and rs2476601); and for diabetes-associated autoantibodies.

Results: Most children with diabetes (77.2%) were positive for the HLA-(DR3)-DQA1*05-DQB1*02 (DR3-DQ2) haplotype compared with 26.2% of the controls (OR = 9.5; p < 0.001). HLA-DRB1*04:02-DQA1*03-DQB1*03:02 (DR4-DQ8) (26.7%, OR = 3.3; p < 0.001), DRB1*04:05-DQA1*03-DQB1*02 (DR4-DQ2) (23.8%, OR 5.2; p < 0.001), and DRB1*04:05-DQA1*03-DQB1*03:02 (DR4-DQ8) (8.9%, OR = 7.7; p = 0.007) were also significantly increased. HLA-(DR15)-DQB1*06:01, (DR13)-DQB1*06:03, and DRB1*04:03-DQA1*03-DQB1*03:02 were the most protective haplotypes with OR values from 0.04 to 0.06. Patients positive for DR3-DQ2 but negative for DR4 haplotypes had a high frequency of glutamic acid decarboxylase antibodies (78%; p < 0.001 versus other genotypes), but only 26.6% of those with DR3-DQ2/DR4-DQ2 tested positive for glutamic acid decarboxylase antibodies (p = 0.006 versus other genotypes). Subjects with the DR4-DQ8 haplotype without DR3-DQ2 or DR4-DQ2 were more often positive for islet antigen-2 and zinc transporter 8 antibodies (55.5%, p = 0.007 and 55.5%, p = 0.01 respectively). The AA genotype of the INS gene was more common in patients than in controls (75.2 versus 59.5%, OR = 2.07; p = 0.018).

Conclusions: Besides a strong HLA-DR3-DQ2 association, a relatively high frequency of the DR4-DQ2 haplotype characterized the diabetic population. The low frequency of autoantibodies in children with HLA-DR4-DQ2 may indicate specific pathogenetic pathways associated with this haplotype.

Keywords: Egypt; HLA; INS; PTPN22; autoantibodies; type 1 diabetes.