Aims/hypothesis Natural killer (NK) cells serve as primary immune surveillance and are partially regulated by combinations of killer immunoglobulin-like receptor (KIR) genes and their HLA class I ligands. Alterations in NK cell activity have been associated with type 1 diabetes. The aim of this study was to determine whether KIR-HLA class I gene frequency: (1) is altered in a current population with type 1 diabetes compared with healthy controls; and (2) has changed over the half century in which the incidence of type 1 diabetes has increased rapidly.Methods KIR-HLA class I gene frequencies were compared in 551 individuals diagnosed with type 1 diabetes ≤15 years of age (394 in a current cohort and 157 from the historical 'Golden Years' cohort) and 168 healthy controls. The overall balance of activation and inhibition was analysed using KIR-HLA genotype models. Results Children with type 1 diabetes who were positive for KIR2DS2/KIR2DL2 and KIR2DL3 were more often homozygous for HLA-C group 1 and this effect was strongest in children diagnosed with diabetes before the age of 5 years (p=0.003, corrected p [p corr ]=0.012) and (p=0.001, p corr = 0.004), respectively. Children with type 1 diabetes have fewer inhibitory KIRs with their corresponding ligands compared with healthy controls (p=1.9×10 −4 ). This pattern of NK activation has not changed significantly in individuals with type 1 diabetes over the last half century. Conclusions/interpretation Activating combinations of KIR-HLA genes are more frequent in young children with type 1 diabetes diagnosed in the first 5 years of life, suggesting that NK cell responses may be altered in this group.
Combinations of susceptibility genes interact with environmental modifiers to precipitate autoimmune destruction of islet beta cells and type 1 diabetes (T1D). This interaction has become increasingly penetrant in recent decades with annual increases in incidence of T1D of 3% per year and the greatest increase occurring in young children. Although the major genetic determinant the human leucocyte antigen (HLA) on chromosome 6 has been known for decades, recent advances in genetic technology coupled with deoxyribonucleic acid (DNA) collections from large cohorts of individuals with T1D and controls have resulted in an explosion of information on the genetic determinants of autoimmune diabetes. To date, more than 40 predisposing loci have been identified and hundreds are in the pipeline but the molecular effects of most remain to be determined. Key Concepts: The incidence of T1D is increasing at a rate of 3% per year. Multiple susceptibility genes and environmental determinants interact to precipitate disease. The HLA is currently the best genetic determinant of risk of future T1D. Improving methodologies have resulted in identification of multiple susceptibility genes.
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