Low risk HLA-DQ and increased body mass index in newly diagnosed type 1 diabetes children in the Better Diabetes Diagnosis study in Sweden

Abstract

Objective: Type 1 diabetes and obesity has increased in childhood. We therefore tested the hypothesis that type 1 diabetes human leukocyte antigen DQ (HLA-DQ) risk genotypes may be associated with increased body mass index (BMI).

Design: The type 1 diabetes high-risk HLA-DQ A1*05:01-B1*02:01/A1*03:01-B1*03:02 genotype along with lower risk DQ genotypes were determined at the time of clinical onset by PCR and hybridization with allele-specific probes. BMI was determined after diabetes was stabilized.

Subjects: A total of 2403 incident type 1 diabetes children below 18 years of age were ascertained in the Swedish national Better Diabetes Diagnosis (BDD) study between May 2005 to September 2009. All children classified with type 1 diabetes, including positivity for at least one islet autoantibody, were investigated.

Results: Overall, type 1 diabetes HLA-DQ risk was negatively associated with BMI (P<0.0008). The proportion of the highest risk A1*05:01-B1*02:01/A1*03:01-B1)03:02 genotype decreased with increasing BMI (P<0.0004). However, lower risk type 1 diabetes DQ genotypes were associated with an increased proportion of patients who were overweight or obese (P<0.0001). Indeed, the proportion of patients with the low-risk A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype increased with increasing BMI (P<0.003). The magnitude of association on the multiplicative scale between the A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype and increased BMI was significant (P<0.006). The odds ratio in patients with this genotype of being obese was 1.80 (95% confidence interval 1.21-2.61; P<0.006). The increased proportion of overweight type 1 diabetes children with the A1*05:01-B1*02:01 haplotype was most pronounced in children diagnosed between 5 and 9 years of age.

Conclusions: Susceptibility for childhood type 1 diabetes was unexpectedly found to be associated with the A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype and an increased BMI. These results support the hypothesis that overweight may contribute to the risk of type 1 diabetes in children positive for HLA-DQ A1*05:01-B1*02:01.

Figure 1. Frequency of HLA genotypes among antibody positive type 1 diabetes patients and controls

The HLA-DQ genotype frequencies among 2403 islet autoantibody positive type 1 diabetes patients (open bars) diagnosed compared to the frequencies among 2000 controls (grey bars). Numbers given in the figures are OR and the 95^th confidence interval. * p <0.05, ** p<1 10⁻⁸ X = DQA alleles that have not been genotyped, Z = any DQA1-DQB1 haplotype, for further details see table 1. GT is genotype.

Figure 2. Proportion of overweight or obese islet autoantibody positive type 1 diabetes patients by HLA genotype

A total of 2183 patients were available to be classified with normal weight, overweight and obese using ISO-BMI determined after stabilization of diabetes. X = DQA alleles that have not been genotyped, Z = any DQA1-DQB1 haplotype, for further details see table 1. GT is genotype. * p<0.05, ** p<0.002

Figure 3. The proportion of overweight and obese islet autoantibody positive type 1 diabetes children vary with age at onset and HLA genotype

A total of 2183 patients were classified with normal weight, overweight and obese using ISO-BMI determined after stabilization of diabetes. X = DQA alleles that have not been genotyped, Z = any DQA1-DQB1 haplotype. Details are shown in Supplementary table 1. * p<0.05, ***p<0.0005

Figure 4. Change in HLA genotype frequency with increasing BMI

Patients were classified with normal weight (n=1680, white bars), overweight (n=413, grey bars) and obese (n=81, black bars) using ISO-BMI determined after stabilization of diabetes. Proportion of islet autoantibody positive type 1 diabetes patients carrying A1*X-B1*03:02/A1*05:01-B1*02:01 or A1*X-B1*03:02/Z and A1*05:01-B1*02:01/Z genotypes is plotted by BMI class. A test for trend was carried out for each of the genotype groups. X = DQA alleles that have not been genotyped, Z = any DQA1-DQB1 haplotype. Details are shown in Supplementary table 1.

Figure 5. Correlation between HLA genotype and BMI among antibody positive type 1 diabetes patients

Correlation between BMI SDS and HLA genotypes using two-sided Spearman’s rank correlation among 2278 antibody positive type 1 diabetes patients with BMI SDS value. Error bars represents 95% confidence intervals of BMI SDS. X = DQA alleles that have not been genotyped, Z = any DQA1-DQB1 haplotype. Details are shown in table 1.