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

S. Fourlanos, M.D. Varney, B.D. Tait, Grant Morahan, M.C. Honeyman, P.G. Coleman, L.C. Harrison

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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. Type 1 diabetes is an autoimmune disease that destroys the insulin-producing β-cells in the islets of the pancreas, resulting in hyperglycemia and associated complications. It is one of the most common chronic diseases from childhood, requiring continuous or multiple daily insulin injections and blood glucose monitoring at substantial personal and economic cost. Genetic susceptibility accounting for at least half the lifetime risk, together with environmental conditions, leads to the development of type 1 diabetes (1). Although type 1 diabetes is a polygenic disease, the human leukocyte antigen (HLA) genes, which code for molecules that bind and present peptide antigens to T-cells, account for approximately half of the genetic risk (2,3). The incidence of childhood-onset type 1 diabetes has been increasing progressively over the last half century (4,5). Gillespie et al. (6) reported that the proportion of children with the highest-risk HLA genotype for type 1 diabetes (DR3,4 and DQ2,8) was significantly lower in the Bart's-Oxford cohort of children in the U.K. diagnosed between 1985 and 2002 compared with children in the Golden Years cohort diagnosed between 1920 and 1946. On the other hand, the proportion of children with lower-risk genotypes (DR4,X and DR3,X) was higher in the Bart's-Oxford cohort. Their findings were consistent with a Finnish study by Hermann et al. (7) in which children who developed type 1 diabetes between 1939 and 1965 carried a higher proportion of high-risk HLA genes compared with those diagnosed between 1990 and 2001. Gillespie et al. (6) concluded that “the rising incidence of type 1 diabetes in children has resulted from exposure of a genetically susceptible subgroup of the population to an environment that is increasingly conducive to diabetes development.” Both Hermann et al. (7) and Gillespie et al. (6) compared contemporary subjects with cohorts diagnosed in previous eras when survival from type 1 diabetes was significantly less than it is today. Their analyses were based on the assumption that the HLA profile of long-term survivors was representative of that of the whole population of children with diabetes in the past, which is not necessarily the case. In fact, Gillespie et al. (6) acknowledge that only a minority of children who developed diabetes in the 1940s and 1950s are likely to have survived to the present. Many studies have documented improved survival rates, especially since the 1960s (8–10). If the environment increasingly impacts on the expression of type 1 diabetes, then the contribution of genetic susceptibility in newly diagnosed cases may change over time, and, for the same degree of genetic susceptibility, age at diagnosis may decrease over time. We wanted to test these possibilities while avoiding selection bias in the reference population.
Original languageEnglish
Pages (from-to)1546-1549
JournalDiabetes Care
Issue number8
Publication statusPublished - 2008


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