Sequence Analysis of the Diabetes-Protective Human Leukocyte Antigen-DQB1¹0602 Allele in Unaffected, Islet Cell Antibody-Positive First Degree Relatives and in Rare Patients with Type 1 Diabetes¹

Abstract

The human leukocyte antigen (HLA)-DQA1*0102/DQB1*0602/DRB1*1501 (DR2) haplotype confers strong protection from type 1 diabetes. Growing evidence suggests that such protection may be mostly encoded by the DQB1*0602 allele, and we reported that even first degree relatives with islet cell antibodies (ICA) have an extremely low diabetes risk if they carry DQB1*0602. Recently, novel variants of the DQB1*0602 and *0603 alleles were reported in four patients with type 1 diabetes originally typed as DQB1*0602 with conventional techniques. One inference from this observation is that DQB1*0602 may confer absolute protection and may never occur in type 1 diabetes. By this hypothesis, all patients typed as DQB1*0602 positive with conventional techniques should carry one of the above diabetes-permissive variants instead of the protective DQB1*0602. Such variants could also occur in ICA/DQB1*0602-positive relatives, with the implication that their diabetes risk could be significantly higher than previously estimated. We therefore sequenced the DQB1*0602 and DQA1*0102 alleles in all ICA/DQB1*0602-positive relatives (n = 8) previously described and in six rare patients with type 1 diabetes and DQB1*0602. We found that all relatives and patients carry the known DQB1*0602 and DQA1*0102 sequences, and none of them has the mtDNA A3243G mutation associated with late-onset diabetes in ICA-positive individuals. These findings suggest that diabetes-permissive DQB1*0602/3 variants may be very rare. Thus, although the protective effect associated with DQB1*0602 is extremely powerful, it is not absolute. Nonetheless, the development of diabetes in individuals with DQB1*0602 remains extremely unlikely, even in the presence of ICA, as confirmed by our further evaluation of ICA/DQB1*0602-positive relatives, none of whom has yet developed diabetes.

Genetics of Type 1A Diabetes

“…These individuals were first typed with standard SSO techniques, then confirmed by direct sequencing of the second exon of DQB 1*0602 and DQA I*0 102 alleles. All subjects carried conventional DQA1*0102-DQB1*0602 exon 2 sequences (Pugliese et al, 1999). Type 1A diabetes can develop in individuals carrying the DQBl*O602 allele, indicating that the protective effect associated with this allele is not absolute.…”

Humoral Autoimmunity in Type 1 Diabetes: Prediction, Significance, and Detection of Distinct Disease Subtypes

“…Ã 0602 are associated with dominant protection from T1D in multiple populations (Pugliese et al 1999). (A) The rate of progression to T1D development in relatives negative for ICA512bdc carrying GAD65 in the absence (dashed line) or presence (solid line) of autoantibodies reacting with IA-2 full-length (IA-2FL) (amino acids 1 -979) (log rank, P ¼ 0.016).…”