Lack of Associations Between Polymorphisms in SOD2, NOS3, and PPARδ Genes and Osteoarthritis Risk in a Chinese Han Population: A Case-Control Study
Osteoarthritis (OA), a chronic degenerative joint disorder, remains a leading cause of disability worldwide. Its pathogenesis involves a complex interplay of genetic, environmental, and mechanical factors, with genetic predisposition playing a significant role. Recent studies have highlighted oxidative stress as a critical contributor to OA development. Elevated levels of reactive oxygen species (ROS) promote cartilage degradation by inducing lipid peroxidation, mitochondrial DNA damage, and activation of catabolic signaling pathways. This underscores the importance of antioxidant defense systems in OA pathophysiology. Genes encoding enzymes involved in ROS regulation, such as SOD2 (superoxide dismutase 2), NOS3 (endothelial nitric oxide synthase), and PPARδ (peroxisome proliferator-activated receptor delta), have thus emerged as potential candidates for genetic susceptibility studies.
This study aimed to investigate the associations between specific polymorphisms in SOD2 (rs2758331), NOS3 (rs1808593), and PPARδ (rs9794 and rs10865710) and OA risk in a Chinese Han population. These polymorphisms were selected based on their documented roles in modulating ROS activity. For instance, SOD2 encodes a mitochondrial antioxidant enzyme that neutralizes superoxide radicals, while NOS3 regulates nitric oxide production, which can either mitigate or exacerbate oxidative stress depending on context. PPARδ influences lipid metabolism and inflammation, processes intertwined with ROS dynamics. Despite functional evidence linking these genes to OA mechanisms, their genetic variants had not been evaluated in Chinese Han individuals.
Study Design and Methodology
A hospital-based case-control study was conducted, enrolling 189 OA patients (with knee or hip OA) and 199 healthy controls from two hospitals in Hefei, China, between October 2016 and May 2017. OA diagnosis adhered to the American College of Rheumatology criteria, excluding cases secondary to inflammatory conditions (e.g., rheumatoid arthritis), trauma, infection, or tuberculosis. Controls were individuals without joint-related pathologies. Ethical approval was obtained, and informed consent was secured from all participants.
Genotyping for SOD2 rs2758331, NOS3 rs1808593, PPARδ rs9794, and PPARδ rs10865710 was performed, with Hardy-Weinberg equilibrium (HWE) tested in controls. Statistical analyses utilized logistic regression to compute odds ratios (ORs) and 95% confidence intervals (CIs) for OA risk, adjusting for potential confounders. Subgroup analyses stratified OA cases by joint site (knee vs. hip) and laterality (unilateral vs. bilateral).
Key Findings
Genetic Polymorphisms and Overall OA Risk
None of the investigated polymorphisms demonstrated statistically significant associations with OA risk. For SOD2 rs2758331, the combined variant genotype (CA+AA) showed no increased risk compared to the wild-type (CC) (OR = 0.71, 95% CI: 0.24–2.14). Similarly, NOS3 rs1808593 (GT+GG vs. TT: OR = 1.72, 95% CI: 0.65–4.55) and PPARδ variants rs9794 (CG+GG vs. CC: OR = 0.53, 95% CI: 0.20–1.38) and rs10865710 (CG+GG vs. CC: OR = 1.09, 95% CI: 0.43–2.76) yielded non-significant results.
Stratified Analyses
Further stratification by joint site (knee or hip OA) and laterality (unilateral or bilateral involvement) reinforced the null findings. For knee OA:
- SOD2 rs2758331 (CA+AA vs. CC): OR = 0.88 (95% CI: 0.34–2.31)
- NOS3 rs1808593 (GT+GG vs. TT): OR = 1.60 (95% CI: 0.70–3.66)
- PPARδ rs9794 (CG+GG vs. CC): OR = 1.08 (95% CI: 0.47–2.47)
- PPARδ rs10865710 (CG+GG vs. CC): OR = 1.63 (95% CI: 0.70–3.78)
For hip OA, similar non-significant trends were observed (Table 1). Subanalyses of unilateral vs. bilateral disease also failed to identify risk modifiers.
Discussion
This study represents the first evaluation of SOD2, NOS3, and PPARδ polymorphisms in OA susceptibility among Chinese Han individuals. Despite biological plausibility linking these ROS-related genes to OA, the results suggest that these specific variants do not confer significant risk in this population. Several factors may explain the findings. First, the selected polymorphisms might lack functional relevance in the Chinese Han population, or their effects could be masked by epistatic interactions with other unmeasured genetic or environmental factors. Second, the sample size, though adequate for preliminary analysis, limited statistical power to detect modest genetic effects, particularly for rare homozygous genotypes. Third, OA heterogeneity—encompassing distinct molecular pathways in knee vs. hip OA—might necessitate larger, phenotypically homogenous cohorts for meaningful genetic associations.
The study’s strengths include its focus on a population underrepresented in OA genetics research and the rigorous exclusion of secondary OA cases to minimize confounding. However, limitations must be acknowledged. The cross-sectional design precludes causal inferences, and the lack of biomarker data (e.g., ROS levels) hinders mechanistic interpretations. Additionally, unaccounted variables such as obesity, physical activity, or hormonal status might modulate genetic effects on OA risk.
Implications and Future Directions
While negative, these findings contribute to the growing literature on OA genetics by highlighting population-specific variability. Replication in larger cohorts, incorporation of functional genomics, and exploration of gene-environment interactions are warranted. Future studies should also prioritize multi-omics approaches to unravel the complex interplay between oxidative stress, genetic variants, and OA subphenotypes.
doi.org/10.1097/CM9.0000000000000179
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