Abstract
The incidence of type 1 diabetes has, progressively, increased worldwide over the last decades and also in Continental Italian population. Previous studies performed in northern European countries, showed, alongside a general increase in the disease incidence, a decreasing frequency of the highest risk HLA genotype in type 1 diabetes populations, thus emphasizing the role of environmental factors. The aim of the study was to evaluate whether a decreasing trend of high risk HLA, CTLA-4 and PTPN22 genotypes would be present in type 1 diabetes subjects of Continental Italy, a country considered at low incidence of the disease compared to northern European populations. N = 765 type 1 diabetes patients diagnosed from 1980 to 2012 in Lazio region were included. For HLA, CTLA4 and PTPN22 temporal trend evaluation, subjects were subdivided into groups of years according to age at diagnosis. All subjects were typed for HLA-DRB1 and DQB1 by a reverse line blot. The CT60 polymorphism of the CTLA4 and C1858T of the PTPN22 gene were genotyped using ABI PRISM 7900HT (n = 419 and n = 364 respectively). HLA genotypes were divided in high, moderate and low risk categories. The proportion of the HLA risk categories was not statistically different over the three decades in subjects with age of onset <15 years and ≥15 years. The genotype distribution of CT60 polymorphism of CTLA4 gene did not show any change in the frequencies during time. The analysis of the PTPN22 C1858T variant revealed, instead, that the frequency of CT+TT susceptibility genotypes decreased during time (23.9% vs 13.6%, p = 0.017). We can hypothesize that the pressure of the diabetogenic environment could be milder and therefore not sufficient to reduce the need of a strong genetic background (HLA) “to precipitate” diabetes; the increased pressure of the environment could have, instead, some effects on minor susceptibility genes in our population.
Highlights
The incidence of type 1 diabetes has increased progressively over the last half century [1] especially in young children
The genotype distribution of CT60 polymorphism of CTLA4 gene did not show any change in the frequencies during time
Data are expressed as number (%). {High: DRB1*03-DQB1*0201/DRB1*04-DQB1*0302 genotype (DRB1*04 different from 0403, 06, 11). `Moderate: DRB1*04-DQB1*0302/DRB1*04-DQB1*0302,DRB1*03-DQB1*0201/
Summary
The incidence of type 1 diabetes has increased progressively over the last half century [1] especially in young children. In Continental Italian population (Lazio region), characterized by a low incidence of the disease, we observed that the type 1 diabetes incidence has doubled in the 2004–2009 period compared to the 1989–1993 period, considering the 0–14 year age group [2]. The disease is a complex disorder caused by multiple genes, which interact with environmental factors. The genetic susceptibility will determine the probability of an unwanted outcome to the initial exposure but some environmental factors may influence the rate of progression [1]. The major genes responsible for at least 50% of the type 1 diabetes genetic component are human leukocyte antigen (HLA) linked [3]. Other polymorphisms have been reported to be associated with type 1 diabetes, among those the Cytotoxic T Lymphocyte–Associated Antigen-4 (CTLA-4) and in the Protein Tyrosine Phosphatase
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