Association of single nucleotide variants in the anti-inflammatory interleukins IL4, IL10, and IL13 genes with primary knee osteoarthritis

Abstract

Introduction. Inflammation plays an important role in the pathogenesis of primary OA. Inflammation stimulates chondrocytes and synovium to produce inflammatory cytokines such as interleukin-1 beta and tumor necrosis factor alpha, among others. These have a catabolic effect on the cartilage extracellular matrix. Another group of cytokines with an antagonistic effect is known as anti-inflammatory cytokines, including IL4, IL10, and IL13. Some single nucleotide variants (SNVs) in inflammatory cytokine genes are known to be associated with primary OA; however, the association of SNVs in anti-inflammatory cytokine genes has not been well studied.

Objective. The aim is to determine the association of SNVs in the IL4, IL10, and IL13 genes with the development of primary knee osteoarthritis in Mexican mestizo patients.

Methodology. A case-control study was conducted in Mexican mestizo subjects. Cases were patients over 40 years of age, diagnosed with knee OA, with radiological grade ≥ 2 based on the Kellgren-Lawrence scale, body mass index < 28 (BMI, kg/m2), no history of severe trauma or knee surgery, and no other joint diseases. Controls were subjects over 40 years of age, without clinical knee OA, and with a radiological grade < 2. A blood sample was obtained for DNA extraction. SNVs rs2070874 and rs2243250 of IL4, rs1800872 and rs1800896 of IL10, rs20541 and rs1800925 of IL13 were determined by TaqMan probes. Hardy-Weinberg equilibrium (HWE), allele and genotype frequencies were analyzed. Logistic regression was performed, reporting odds ratios and 95% confidence intervals [OR (95% CI)]. The α level was 0.05, and data were analyzed using STATA 15.0. Epistasis (gene-gene interaction) was analyzed using MDR software.

Results. A total of 375 cases and 490 controls were studied. The most common sex was female (74.9% vs. 70.2%, respectively; p = 0.1); the mean age was 64.8 ± 11.4 and 59.0 ± 11.4 years, respectively (p < 0.05); and the BMI was 25.2 ± 2.3 and 24.9 ± 2.3, respectively (p = 0.08). All SNVs were in the E-HE group. No epistasis was found. Significant differences were observed in the AA genotype of IL10 rs1800896 [OR: 1.4 (1.1 - 1.8)]. When stratifying the sample by radiological grade, differences in IL10 SNVs were observed in grade 2 OA, specifically in CC homozygotes of rs1800872 [1.7 (1.1 - 2.7)], as well as in GA heterozygotes and AA homozygotes of rs1800896 [0.6 (0.4 - 0.9) and [1.7 (1.1 - 2.6)]; respectively].

Conclusions. The results suggest that the IL10 SNVs, rs1800872 and rs1800896, are associated with primary knee OA, primarily with radiological grade 2 OA.