Analysing the association of IL-6 rs1800796 with bone mineral density and fracture risk in Malta

Abstract

Osteoporosis is a common degenerative bone disease which is characterised by reduced bone mass, bone strength, and microarchitectural deterioration increasing fragility fracture risk. Interleukin-6 encoded by the IL-6 gene, acts as a pro-inflammatory cytokine increasing osteoclastogenesis and bone resorption by upregulating the Receptor Activator of NF-Kb Ligand (RANKL). The IL-6 rs1800796 variant (G>C) is located in the gene’s promoter region, 572 bases upstream from the translational start site which is hypothesizes to alter regulatory modifiers decreasing IL-6 transcriptional activity. The study aimed to determine whether the IL-6 rs1800796 is associated with BMD at the lumbar spine and hip, and if it increases all-type of low-trauma fracture risk, as well as site-specific fractures. Genotyping using the TaqMan® fluorogenic 5’ nuclease allelic discrimination assay was carried out in the MOFS case-control collection consisting of 1,045 Maltese postmenopausal women. Genotype-phenotype associations were investigated using the Kruskal-Wallis and Mann-Whitney U tests, whilst odds ratios were computed using logistic regression models with 95% confidence intervals (CI) adjusted for confounders. Genotyping was successful in 1,039 samples, with the reference (G) and alternative (C) allele frequencies detected at a frequency of 87.9% and 12.1% respectively. Genotype-phenotype associations demonstrated that homozygosity for the alternative C allele exhibited a protective effect on BMD at the lumbar spine (LS sBMD p=0.048), femoral neck (FN sBMD p=0.039, FN T-score p=0.025) and total hip (TH sBMD p=0.026, TH T-Score p=0.023) when compared to women with the homozygous reference GG genotype for the IL6 rs1800796. Additionally, women with the CC genotype had a decreased risk of low BMD at the LS (adj-OR: 0.207 [95% CI 0.055–0.775], p=0.019), FN (adj-OR: 0.203 [95% CI 0.041- 0.993], p=0.049) and TH (adj-OR: 0.207 [95% CI 0.041–0.993], p=0.019). No association between the IL-6 rs1800796 variant and all-type of low-trauma fractures or site-specific fracture risk was observed. This is possibly due to a relatively low sample size. In conclusion, the findings indicate that the IL-6 rs1800796 C allele exerts a protective effect on vertebral and hip BMD, reflecting its effect on both trabecular and cortical bone. The results support the hypothesis suggesting that transcriptional activity of IL-6 is increased in the presence of reference G allele. Therefore, the variant is a plausible genetic factor underlying the complex genetics of osteoporosis in Malta.