This study confirms that the highest risk HLA-DR3/4-DQB1*0302 genotype has been decreasing in new onset type 1 diabetic subjects in more recent decades. This finding is consistent with several important smaller studies reporting a similar decrease in the percent DR3/4 (8
), although some studies have not found any temporal changes in HLA genotypes (17
). This is the largest study so far with HLA information on new onset subjects over a period of 40 years; other studies have mainly compared two time periods.
Previous studies have mainly selected populations from one geographic region for HLA analysis, whereas the T1DGC includes multiple populations and large numbers of type 1 diabetic patients over many years. The T1DGC data suggests that the change in high-risk HLA frequency can be more precipitous than previously thought.
A stepwise decrease in percent DR3/4 would suggest a relatively acute environmental change with an increase of disease penetrance in individuals with lower-risk HLA genotypes and/or a lower disease penetrance in subjects with high-risk genotypes. We hypothesize that disease penetrance might be increasing for both DR3/4 and non-DR3/4 genotypes, but with the much larger population proportion of non-DR3/4 individuals, the percentage DR3/4 decreases as the incidence of type 1 diabetes is increasing. Multiple environmental changes over the past few decades have been discussed as factors that might relate to the increasing incidence of diabetes, including exposure to infections in early life (enteroviruses) or decreasing frequency of infections (hygiene hypothesis) (18
), eating habits and lifestyle modifications leading to increased obesity and insulin resistance (accelerator hypothesis) (20
). Most of these environmental changes are most likely to change slowly and progressively with time.
Other factors that could influence decreasing DR3/4 frequencies over time include different methods of ascertainment of type 1 diabetes or decreasing DR3/4 frequencies over time in the general population. If detection of type 1 diabetes in very young children had increased in recent years through better ascertainment, we would expect an increase overall in DR3/4 frequency because subjects with younger age of onset are those with the highest percentage of DR3/4. Percentage of DR3/4 is low in the general Colorado population and did not change significantly over time (2.6% in 1945–1975 compared with 1.9% in 2002–2004).
Although triggers of type 1 diabetes are still unknown, it is clear that there is a long prodrome of islet autoimmunity preceding the onset of type 1 diabetes, and there is growing evidence that activation of innate immunity and inflammation can be associated with induction of islet autoimmunity in animal models. In rat strains with the equivalent of high-risk class II HLA alleles, islet autoimmunity leading to diabetes can be induced by infection with Kilham rat virus or even injections of poly-IC that induces interferon-α. In the Kilham infectious model, five injections of dexamethasone, beginning on the day of infection, completely blocks diabetes. Strikingly, a single dose of dexamethasone was sufficient to prevent islet destruction (22
). This raises the possibility that targeting innate immune pathways at the initiation of islet autoimmunity may be a useful strategy for disease prevention.
Because so many environmental factors have changed in the last 4 decades, it would be helpful to narrow down the time frame of change for environmental exposures. For instance in the 1980s, given association with Reyes syndrome, aspirin therapy in children was acutely stopped in many countries including the U.S. with substitution of acetaminophen. Type 1 diabetes is not the only immune-mediated disease with an increasing incidence rate, and it has been suggested that changing anti-inflammatory therapy in children may relate to increasing incidence of asthma. There is epidemiological evidence that the use of acetaminophen may increase the risk of developing asthma (23
) as well as rhinoconjunctivitis and eczema (24
). Larger studies are needed to confirm the apparent stepwise changing pattern of genetic risk; if confirmed, this observation may help define critical environmental determinants of type 1 diabetes and eventually have direct bearing on therapies to prevent islet autoimmunity.