# 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.

## Key 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.