Abstract

Objective: The rising incidence of type 1 diabetes has been attributed to environment, implying a lesser role for genetic susceptibility. However, the rise could be accounted for either by more cases with classic high risk genes or by cases with other risk genes. Separately, for any degree of genetic susceptibility, age at presentation may decrease in a permissive environment. To examine these possibilities, HLA class II DRB1 genes known to confer risk for type 1 diabetes were analysed in relation to year of birth and age at diagnosis over the last five decades.

Research Design and Methods: Caucasoid subjects (n=462) diagnosed with type 1 diabetes before age 18 between 1950 and 2005 were DRB1 genotyped.

Results: Mean age at diagnosis, 8.5 years (SD 4.5 years), did not differ across decades. Recent diagnosis was associated with a lower proportion but unchanged incidence of the highest risk DRB1 genotype DR3,4 (2000-05: 28% vs 1950-1969: 79%; p<0.0001) and a higher proportion of lower risk genotypes DR4,X and DR3,X (2000-05: 48% vs 1950-1969: 20%; p=0.0002). The frequency of the DRX,X genotype was low (≤ 3%) across decades. Recent birth was associated with a lower age at diagnosis for lower risk DR3,3 and DR4,4 (p<0.0001) and DR4,X (p<0.0001) and DR3,X (p=0.015) genotypes, but not for DR3,4.

Conclusions: The rising incidence and decreasing age at diagnosis of type 1 diabetes is accounted for by the impact of environment on children with lower risk HLA class II genes, who previously would not have developed type 1 diabetes in childhood.