Osteoarthritis (OA) is a frequent, destructive joint disease, with debilitating impact on a society regarding medical, social, and economic issues. Although causes of primary OA were still not fully elucidated, evidence points to complex genetic risk that varies among different population groups, including the interleukin-1 (IL-1) gene cluster. Here, we sought to determine allelic and genotypic frequencies of the IL-1β (IL1B) and the IL-1 receptor antagonist (IL1RN) genes using single nucleotide polymorphism (SNP) at -511(G>A; rs16944) and the variable number tandem repeat (VNTR) in a case-control study with 238 patients that have undergone total or partial knee replacement and 495 healthy blood donors as controls in Croatia. The alleles of the IL1B gene at -511G>A were detected by Taqman real-time polymerase chain reaction (PCR) method and IL1RN VNTR by amplifying its DNA by PCR. The genotypes 1-2/1-2 and 2-1/2-2 at IL1B G -511A-IL1RN (VNTR) showed trends for association with the occurrence of the knee OA in this population (P = 0.09; P = 0.07, respectively). Furthermore, neither the alleles nor the haplotypes were found associated with the predisposition to knee OA. Our findings suggest that knee OA might have a different genetic risk in this Caucasian population. We did not found significant association of the IL1 gene cluster (IL1B-IL1RN) with severe knee OA. However, we found that two genotypes (1-2/1-2 and 2-1/2-2) show a trend toward association with susceptibility to disease.

We analysed the association of a single nucleotide polymorphism (SNP) in the gene encoding the IL‐12 subunit p40 (IL12B, rs3212227, A>C) with breast cancer. The SNPs allelic and genotypic frequencies were compared between patients (n = 191) and healthy (n = 194) women in a case–control study from Croatia. The major allele (A) was associated with susceptibility to breast cancer (P = 0.003; OR = 1.67; 95% CI: 1.17–2.38). Likewise, the minor allele (C) was significantly correlated with protection (P = 0.003; OR = 0.60; 95% CI: 0.42–0.86). At the genotype level, AA homozygosity was significantly associated with predisposition to disease (P = 0.013; OR = 1.68, 95% CI: 1.09–2.59), whereas the minor allele homozygosity (CC) was correlated with protection to disease (P = 0.020, OR = 0.28, 95% CI: 0.09–0.91). The heterozygous genotype showed no significant correlation with disease. The product of the IL12B gene (IL‐12 p40) can either form a homodimeric cytokine or be part of two pro‐inflammatory (IL‐12 and IL‐23) cytokines. It is presently unclear whether the major allele is associated with higher or lower protein levels of IL‐12 p40 and IL‐12 p70, which are critical in inflammation and adaptive immune responses. However, as the A allele is high producer of IL12B (p40) mRNA, these results might imply that higher levels of IL‐12 p40 (either as homodimers or joined with one or both of the other two subunits) predispose to breast cancer.

Genetic predisposition to the complex hereditary disease like osteoarthritis (OA) of the large joints (hip and knee) includes the interleukin-1 gene (IL-1) cluster on chromosome 2. Using a case-control study with 500 OA patients (240 knee and 260 hip OA patients, all with joint replacement), we analysed frequencies of IL-1 gene cluster polymorphisms in Croatian Caucasian population. The control samples came from 531 healthy individuals including blood donors. We genotyped two single nucleotide polymorphisms in the IL-1 gene locus at IL-1A (À889, C>T, rs1800587) and IL-1B (+3594, C>T, rs1143634) and compared their frequencies between patients and controls. We predicted haplotypes by combining current data with our previous results on gene polymorphisms (IL-1B, rs16944 and the IL-1 receptor antagonist gene [IL-1RN] variable number tandem repeat [VNTR]) for the same population. Haplotype analyses revealed gender disparities and showed that women carriers of the 1-2-1-1 haplotype [IL-1A(rs1800587) -IL-1B(rs1143634) -IL-1B(rs16944) -IL-1RN(VNTR)] had sixfold lower risk to develop knee OA. However, carriers of the 1-1-1-2 haplotype of both sexes had over twofold higher predisposition to hip OA. Our results differ from some earlier studies in Caucasian subpopulations, which may be due to the fact that this is the first study to separate genders in assessing the IL-1-locus genetic risk of OA. The results suggest that inflammatory mediators like IL-1 might be implicated in the pathogenesis of primary OA in large joints and that as yet unidentified gender-specific factors exist in a Croatian Caucasian population.