Extreme genetic risk for type 1A diabetes in the post-genome era

Abstract

A series of genes and loci influencing the genetic risk of type 1A (immune-mediated) diabetes are now well characterized. These include genes of the major histocompatibility complex (MHC), polymorphisms 5' of the insulin gene, and PTPN22, as well as more recently defined loci from genome-wide association studies. By far the major determinants of risk for type 1A diabetes are genes within or linked to the MHC and in particular alleles of class II genes (HLA-DR, DQ, and DP). There is evidence that MHC class I alleles contribute and there are additional MHC-linked influences such that for a major subset of relatives of patients there is a risk as high as 80% for siblings, and for the general population a risk as high as 20% can be defined at birth just by analyzing the MHC. We believe the search for additional MHC loci will require analysis of the remarkable long-range identity (up to 9 million base pairs) of extended MHC haplotypes. Current prediction algorithms will likely be greatly improved for the general population when the additional contributing loci of the MHC are defined.

Analysis Of Family Cases With Type I Diabetes Mellitus In A Group Of Pediatric Patients From Constanţa County

“…In total we enrolled in the study 10 patients with a family history. this distribution is consistent with that observed in other studies in which over 85% of patients are unique cases [5]. In terms of risk for type 1 diabetes are important cases where there were first-degree relative are affected.…”

A peripheral blood transcriptomic signature predicts autoantibody development in infants at risk of type 1 diabetes

“…Carriage of high risk HLA (DR3/4) and sharing of identical haplotypes with siblings has been shown to confer extreme risk of islet antibody development during childhood (16). Furthermore, testing children with high-risk HLA (17) multiple times during childhood identified individuals with multiple islet antibodies and high rate of progression to T1D (18).…”

Targeting the Trimolecular Complex: The Pathway Towards Type 1 Diabetes Prevention

“…9 It was later discovered that certain HLA molecules, termed DQ8 and DQ2, predispose risk for developing T1D. 10 In fact, genome-wide association studies showed that the odds ratio for developing diabetes ranged from 6.5 to 11 when either of these genes is present. 11,12 Approximately 90% of all individuals with T1D have either a DQ8 and/or a DQ2 gene, with 50-60% of all T1D patients having DQ8.…”