Rapport final
Impact of non-HLA susceptibility alleles on the various asymptomatic stages of type 1 diabetes - Van de Casteele Marc
This project screened 25 non-HLA loci generally associated with a slightly to moderately increased genetic risk for developing type 1 diabetes and evaluated their influence on disease progression in a well-characterized and extensively followed-up population of autoantibody-positive relatives recruited by the Belgian Diabetes Registry (BDR, VUB).
We found marked stage-dependent effects on the progression of type 1 diabetes for the risk-associated genes ERBB3/IKZF4, CTSH, SLC30A8, and Nrp-1. Absence of ERBB3/IKZF4 risk alleles slowed progression from single to multiple autoantibody-positivity in females only, coinciding with a male preponderance in multiple -but not in single- autoantibody-positive relatives. The cathepsin-H CTSH locus (genotype CC) accelerated antigen spreading significantly in combination with the HLA-haplotype DQ8+ (p=0.001). Neuropilin-1 (NRP-1) significantly accelerated the overall progression to T1D (p=0.019), as well as the progression from ≥2 autoAbs to onset of T1D. The latter effect was clearest within the HLA-A*24 positive relatives (p=0.003).
These results may have implications for the selection and treatment of participants in future clinical intervention studies.