ACE–ACE2 Gene–Gene Interaction in Knee Osteoarthritis Severity: Evidence for Context-Dependent Genetic Effects

Audrey Suryani Soetjipto; Haerani Rasyid; Endy Adnan; Syakib Bakri; Andi Makbul Aman; Andi Alfian  Zainuddin; Muhammad Nasser Mustari; Achmad Fikry

doi:10.23750/abm.2026.18999

Authors

Audrey Suryani Soetjipto Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Makassar, South Sulawesi, Indonesia
Haerani Rasyid Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Makassar, South Sulawesi, Indonesia
Endy Adnan Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Makassar, South Sulawesi, Indonesia
Syakib Bakri Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Makassar, South Sulawesi, Indonesia
Andi Makbul Aman Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Makassar, South Sulawesi, Indonesia
Andi Alfian Zainuddin Department of Public Health, Faculty of Medicine, Hasanuddin University, Makassar, South Sulawesi, Indonesia
Muhammad Nasser Mustari Division of Orthopaedic and Traumatology, Department of Surgery, Faculty of Medicine, Hasanuddin University, Makassar, South Sulawesi, Indonesia
Achmad Fikry Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Makassar, South Sulawesi, Indonesia

Keywords:

ACE polymorphism, ACE2 polymorphism, gene–gene interaction, knee osteoarthritis, Osteoarthritis Severity

Abstract

Background and aim:

Osteoarthritis (OA) is a multifactorial disease involving biomechanical, inflammatory, and metabolic pathways. The renin–angiotensin system (RAS) has been implicated in OA pathogenesis, yet most studies assess genetic variants independently. The combined effect of angiotensin-converting enzyme (ACE) and ACE2 polymorphisms, and their interaction with metabolic factors, remains unclear. This study aimed to evaluate the independent and combined contributions of ACE I/D and ACE2 G8790A polymorphisms to knee OA severity.

Methods:
This cross-sectional study included 80 women aged ≥40 years with primary knee OA, classified as mild (n=40) or severe (n=40) using Kellgren–Lawrence grading. ACE I/D and ACE2 G8790A polymorphisms were analyzed individually and as a combined genetic model, categorized into low-risk and intermediate–high risk groups. Associations were assessed using chi-square or Fisher’s exact test, with odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analysis was performed based on obesity.

Results:
A significant association emerged in the combined model, with increased odds of severe OA in the intermediate–high risk group (OR 3.78; 95% CI 1.33–10.7; P=0.02). The effect was stronger in obese individuals (OR 5.91; 95% CI 1.05–32.8; P=0.03) but not significant in non-obese participants (OR 2.42; 95% CI 0.57–10.3; P=0.25).

Conclusions: The association between RAS-related polymorphisms and knee OA severity becomes evident at the level of gene–gene interaction and is amplified under metabolically unfavorable conditions. These findings support a context-dependent model of genetic risk, in which ACE–ACE2 imbalance contributes to inflammatory and degenerative processes in osteoarthritis.

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