The Rising Incidence of Type 1 Diabetes Is Accounted for by Cases With Lower-Risk Human Leukocyte Antigen Genotypes

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 by either 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, human leukocyte antigen (HLA) class II DRB1 genes known to confer risk for type 1 diabetes were analyzed 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 ± SD age at diagnosis, 8.5 ± 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 (2000–2005, 28% vs. 1950–1969, 79%; P < 0.0001) and a higher proportion of lower-risk genotypes DR4,X and DR3,X (2000–2005, 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.