Dissect Gender-Dependent Susceptibility SNPs in Progressive Osteoarthritis Using Regulator Motif Candidate of Genetic Association Strategy (RMCGA)

TL;DR

This study identifies gender-specific genetic variants linked to severe osteoarthritis by analyzing regulatory DNA sequences.

Contribution

The study introduces and validates a new strategy (RMCGA) to identify gender-specific SNPs in OA regulatory regions.

Findings

A male-protective SNP (rs73164856) in the aldose reductase gene enhancer was found to reduce severe OA risk.

A female-risk SNP (rs545654) in the nNOS gene was associated with increased severe OA risk.

Gene expression analysis confirmed functional effects of these SNPs on AKR1B15 and nNOS genes.

Abstract

The role of gender in osteoarthritis (OA) has been reported. However, knowledge on whether gender-specific regulatory SNPs are determining factors in OA is limited. We aimed to identify susceptible gender-specific SNPs of transcription factor binding sites in OA. We used a modified NF-κB binding motif from an RNA sequencing data-inferred OA-associated upstream regulator to define genome-wide potential NF-κB binding sites, which were aligned to the Taiwan BioBank SNP database to identify susceptible SNPs. A case-control study was conducted to verify SNPs with OA determined by a logistic model. The functional assessment was validated using the Genotype-Tissue Expression Portal database. We collected 533 OA patients and 614 healthy controls. Two of nine novel OA-associated SNPs were identified to be significant. For males, the variant of rs73164856 in the aldose reductase gene enhancer was identified to be a protective factor of severe OA patients [odds ratio (OR): 0.17, 95% confidence interval (CI): 0.04–0.73]. For females, the variant of the rs545654 in the neuronal NOS (nNOS) gene was identified to be a detrimental factor of severe OA patients (OR: 2.07, 95% CI: 1.15–3.73). The gene expression analysis demonstrated a lower expression of the AKR1B15 gene (p = 0.00019) upon the rs73164856 T allele; meanwhile, it showed a higher expression of the nNOS gene (p = 1.2 × 10−17) upon the rs545654 T allele. This study identifies susceptible gender-specific SNPs of NF-κB binding sites in severe OA and validates the RMCGA, which sheds light on genetic determinants by gender in advanced OA.

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