Genetic polymorphism of interleukin-1β is associated with risk of type 1 diabetes mellitus in children

Type 1 diabetes mellitus (T1DM) is an auto-immune disease characterised by the selective destruction of pancreatic b-cells. The events that trigger b-cell damage have remained elusive: however, the importance of local inflammatory processes has been established. Interleukin-1 (IL-1) is a crucial cytokine causing b-cell inhibition. Screening of a number of available cytokine preparations at relevant concentrations showed that no other single cytokine had similar effects on intact rat islets and IL-1 alone is cytotoxic to human pancreatic islet cells in monolayer cultures [2]. The biological activity of IL-1 resided in two major polypeptide species, called interleukin-1alpha (IL-1a) and interleukin-1beta (IL-1b). IL-1b plays a central role in b-cell dysfunction and death [1, 2]. The production of IL-1b is, at least partly determined by the C3954T polymorphism in exon 5 of the IL-1b gene. The carrier state of the 3954T allele is associated with enhanced cytokine production [5]. Limited data are available about its impact on the risk of T1DM [5, 6]. Therefore in our investigation the association between IL-1b C3954T polymorphism and T1DM was studied. Blood samples were taken from 312 children with T1DM (162 boys and 150 girls, mean age: 14±4 years, mean duration of diabetes: 6.3±3.7 years). The healthy reference population consisted of 171 healthy blood donors. Total genomic DNA was extracted from whole blood using the method of Miller et al. [3]. IL-1b C3954T polymorphism was determined by PCR and RFLP methods as previously described [4]. PCR products were digested at 65 C with TaqI. The products were separated in a 3% agarose gel, stained with ethidium bromide and visualised under UV illumination. The study was approved by the Institutional Ethics Committee and informed consent was obtained from the subjects and/or their parents. Allele-frequencies were compared using the chi-squared test. The Mann-Whitney test was used for the comparison of the age at the onset of T1DM between patients with different genotypes. Hardy-Weinberg criteria were fulfilled in the healthy reference population, but not in diabetic children. The prevalence of the 3954T allele was higher among children with T1DM than the healthy reference group (0.34 versus 0.26; P=0.0002; Odds Ratio =2.02, 95% confidence interval: 1.384–2.950) (Table 1). The age at the onset of T1DM was not associated with IL-1b genotype. This study is the first that investigates the importance of IL1-b C3954T polymorphism in a relatively large number of diabetic children. Our results indicate that the 3954T carrier state might be associated with the risk of T1DM. We suggest that when b-cells are exposed to harmful events, 3954T allele carrier children respond with elevated IL-1b production. This higher level of IL1b might play a role in the maintenance of auto-immune damage of pancreatic b-cells and contribute to the development of T1DM. Eur J Pediatr (2002) 161: 507–508 DOI 10.1007/s00431-002-1030-9