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© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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.

Details

Title
Dissect Gender-Dependent Susceptibility SNPs in Progressive Osteoarthritis Using Regulator Motif Candidate of Genetic Association Strategy (RMCGA)
Author
Yin-Shiuan, Bai 1 ; Ding-Lian, Wang 2 ; Meng-Chang, Lee 3   VIAFID ORCID Logo  ; Chih-Chien, Wang 4   VIAFID ORCID Logo  ; Wen-Hui, Fang 5   VIAFID ORCID Logo  ; Su-Wen, Chuang 3   VIAFID ORCID Logo  ; Chen, Yu-Hsuan 3   VIAFID ORCID Logo  ; Su, Hao 6 ; Cheng-Jung, Chen 7 ; Sui-Lung, Su 2   VIAFID ORCID Logo 

 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114201, Taiwan; [email protected] (Y.-S.B.); [email protected] (D.-L.W.) 
 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114201, Taiwan; [email protected] (Y.-S.B.); [email protected] (D.-L.W.), School of Public Health, National Defense Medical Center, Taipei 114201, Taiwan; [email protected] (M.-C.L.); [email protected] (S.-W.C.); [email protected] (Y.-H.C.); [email protected] (H.S.) 
 School of Public Health, National Defense Medical Center, Taipei 114201, Taiwan; [email protected] (M.-C.L.); [email protected] (S.-W.C.); [email protected] (Y.-H.C.); [email protected] (H.S.) 
 Department of Orthopedics, Tri-Service General Hospital, National Defense Medical Center, Taipei 114202, Taiwan; [email protected], School of Medicine, National Defense Medical Center, Taipei 114201, Taiwan; [email protected] 
 School of Medicine, National Defense Medical Center, Taipei 114201, Taiwan; [email protected], Department of Family and Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114202, Taiwan 
 School of Public Health, National Defense Medical Center, Taipei 114201, Taiwan; [email protected] (M.-C.L.); [email protected] (S.-W.C.); [email protected] (Y.-H.C.); [email protected] (H.S.), Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114201, Taiwan 
 Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114202, Taiwan; [email protected], Taichung Veterans General Hospital Chiayi Branch, Chiayi City 60090, Taiwan 
First page
4117
Publication year
2025
Publication date
2025
Publisher
MDPI AG
ISSN
16616596
e-ISSN
14220067
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3203200188
Copyright
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.