Relative and absolute HLA-DQA1-DQB1 linked risk for developing type I diabetes before 40 years of age in the Belgian population: implications for future prevention studies

Seasonality in clinical onset of Type 1 diabetes in Belgian patients above the age of 10 is restricted to HLA-DQ2/DQ8-negative males, which explains the male to female excess in incidence

“…Because older age at diagnosis is associated with a striking male predominance and a lower prevalence of the HLA-DQ2/DQ8 risk genotype [14,15,16,18], all patients under age 10 at diagnosis were compared with an equal number of patients aged between 10 and 40 years after matching for sex and HLA-DQ2/DQ8. The observed difference in seasonality persisted after matching for both confounders (0-9 years: n=364, χ 2 =3.0, p=0.221; 10-39 years: n=364, χ 2 =8.0, p=0.018; not shown).…”

“…In addition, regardless of sex, seasonality in those diagnosed over the age of 10 was significant in the absence of the DQ2/DQ8 genotype (n=1257; χ 2 =27.2, p<0.001) but only borderline in carriers of DQ2/DQ8 (n=418; χ 2 =7.5, p=0.024; not shown). Furthermore, we com- pared the seasonal pattern in patients carrying susceptible HLA-DQ genotypes other than DQ2/DQ8 (as identified in the Belgian population) [18] with that of patients with a protective, rare or neutral genotype (see Methods for genotype classification) [18]. In both groups a significant seasonality was found (susceptible genotypes other than DQ2/DQ8: n=538, χ 2 =15.8, p<0.001; protective/rare/neutral HLA-DQ genotypes: n=719, χ 2 =14.1, p<0.001; not shown).…”

“…DNA was extracted from K-EDTA blood, amplified and HLA-DQA1*-DQB1* genotyped as described previously [23]. [18]. In the present study, patients aged 10 to 39 years at diagnosis (n=1675) were further stratified according to the presence (n=418) or absence (n=1257) of the highest risk HLA-DQ2/DQ8 genotype preferentially associated with young age at diagnosis [18].…”

“…In the present study, patients aged 10 to 39 years at diagnosis (n=1675) were further stratified according to the presence (n=418) or absence (n=1257) of the highest risk HLA-DQ2/DQ8 genotype preferentially associated with young age at diagnosis [18]. Furthermore, additional stratification was carried out according to the presence of one of the other susceptible genotypes (DQ2/DQ2, DQ8/DQ8 or DQ8 in combination with a neutral genotype, not preferentially associated with young age at diagnosis; n=538) or the presence of one of the protective, rare or neutral genotypes (n=719) as described previously [18].…”

“…Indeed, compared with childhood-onset diabetes, adult-onset diabetes has a less severe clinical presentation with a striking male to female excess, in sharp contrast with other autoimmune diseases, and less biological evidence of islet autoimmunity [14,15,16]. This includes less prominent insulitis and better preserved beta cell mass [17], lower prevalences and levels of islet antibodies except for glutamate decarboxylase autoantibodies (GADA), and a lower frequency of the high-risk HLA-DQ2/DQ8 genotype, a genetic accelerator associated with early onset of Type 1 diabetes and with a more rapid progression toward Type 1 diabetes in non-diabetic antibody-positive siblings [18,19].…”