Polymorphisms in the IL-18 and IL-12B genes and their association with the clinical outcome in Croatian patients with Type 1 diabetes.

Genetic variants of IL-18 and IL-12B may be important in immunoregulatory abnormalities, observed in the patients with Type 1 diabetes mellitus (T1DM), that contribute to individual differences in response to a treatment. Therefore, we examined the significance of IL-18-137G/C, IL-18-607C/A, and IL-12B A/C polymorphisms in Croatians (187 patients, 236 controls), not only as factors that contribute to susceptibility to T1DM, but also as determinants of the clinical presentation of disease. The polymorphism screening has been performed using PCR sequence-specific primers (IL-18) or PCR-RFLP (IL-12B) approach. Results were evaluated by GraphPad Prism and Sigma Stat 3.5, Arlequin software and calculator for Hardy-Weinberg equilibrium. The genotype, allele and haplotype distribution were not statistically different between the patients and control subjects. The clinical parameter analysis revealed that patients with minor alleles at each locus, IL-18-137C/-607A, were significantly younger at T1DM onset than carriers of major alleles, IL-18-137G/-607C (20 vs 23.5 years). Moreover, the concomitant presence of minor alleles not only of IL-18 but also of IL-12B, is associated with the risk of disease progression even at younger age. These patients developed diabetes at 16 years of age, what is significantly earlier (p=0.044) compared to 25.5 years of age in patients with common alleles IL-18-137G/-607C/IL-12B A. Furthermore, combined genotype analysis of IL-18 and IL-12B has pointed out that patients with CC/AA/AA genotype have the worst glucose control based on HbA1c (8.7%, range 6.8-13.1%). In conclusion, susceptibility to T1DM in Croatians is not strongly associated with IL-18-137/-607 and IL-12B polymorphisms. These SNPs are associated with the higher risk of earlier disease development and might be implicated in the effectiveness of glycemic control.