Population-based genetic screening for the estimation of Type 1 diabetes mellitus risk in Finland: selective genotyping of markers in the HLA-DQB1, HLA-DQA1 and HLA-DRB1 loci

Aims To improve sensitivity and specificity of the diabetes risk assessment of the population-based genetic screening used in the Finnish Diabetes Pre diction and Prevention (DIPP) trial. Methods One thousand consecutive newborns enrolled in the DIPP were compare d with 316 samples from children with Type 1 diabetes mellitus. A modificat ion of the previously described technique based on hybridization of relevan t PCR products with five lanthanide-labelled probes detected by time-resolv ed fluorometry (TRF) was used. A new probe was designed and allowed discrim ination between DQB1*0602 and *0603 alleles, in addition to DQB1*02, *0301 or *0302, each of which required specific probes. A new, added screening st rategy was developed for individuals carrying low-risk genotypes through sp ecific typing of DQA1*05 and *0201 alleles in DQB1*02 positive, and DRB1 ty ping for DR4 subtypes in DQB1*0302 positive subjects, with a new specifical ly designed high-resolution TRF-based DR4 subtyping technique. Results This two-step screening approach enhanced the sensitivity of the de tection of genetic risk for Type 1 diabetes mellitus in this cohort up to 8 5.4%. In the general population cohort, 24.4% were identified for prospecti ve follow-up, 2.6% of these are expected to develop Type 1 diabetes mellitu s before the age of 15 years. Exclusive typing for HLA-DQB1 locus as an alt ernative screening strategy had sensitivities of 26.3-77.2% with general po pulation cohorts of 2.3-23.1% identified for follow-up. Conclusions The described strategy for genetic prediction of Type 1 diabete s mellitus relies on the convenient genotyping procedure and could be appli ed in large scale screening projects such as DIPP.