Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism and Susceptibility to Osteoarthritis of the Knee: A Case-Control Study and Meta-Analysis

Abstract

Background: Studies of angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphisms and the risks of knee osteoarthritis (OA) have yielded conflicting results.

Objective: To determine the association between ACE I/D and knee OA, we conducted a combined case-control study and meta-analysis.

Methods: For the case-control study, 447 knee OA cases and 423 healthy controls were recruited between March 2010 and July 2011. Knee OA cases were defined using the Kellgren-Lawrence grading system, and the ACE I/D genotype was determined using a standard polymerase chain reaction. The association between ACE I/D and knee OA was detected using allele, genotype, dominant, and recessive models. For the meta-analysis, PubMed and Embase databases were systematically searched for prospective observational studies published up until August 2015. Studies of ACE I/D and knee OA with sufficient data were selected. Pooled results were expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CI) for the D versus I allele with regard to knee OA risk.

Results: We found no significant association between the D allele and knee OA [OR: 1.09 (95% CI: 0.76-1.89)] in the present case-control study, and the results of other genetic models were also nonsignificant. Five current studies were included, and there were a total of six study populations after including our case-control study (1165 cases and 1029 controls). In the meta-analysis, the allele model also yielded nonsignificant results [OR: 1.37 (95% CI: 0.95-1.99)] and a high heterogeneity (I2: 87.2%).

Conclusions: The association between ACE I/D and knee OA tended to yield negative results. High heterogeneity suggests a complex, multifactorial mechanism, and an epistasis analysis of ACE I/D and knee OA should therefore be conducted.

Fig 1. Flow diagram of the identification process for eligible studies.

Fig 2. Selected results from the meta-analysis of angiotensin-converting enzyme insertion/deletion (ACE I/D) and knee osteoarthritis (OA).

The top left subplot is a forest plot based on an allele model assumption (reference: I allele), and the top right subplot is a funnel plot based on the allele model assumption. The allele model is the most common method for detecting gene–disease associations; however, we found no significant signal in the allele model. However, the funnel plot indicates good symmetry in this meta-analysis. Results obtained with the dominant and recessive models are presented at the bottom. All results were nonsignificant.

Fig 3. Trial Sequential Analysis (TSA) in this meta-analysis.

TSA is a methodology that includes a sample size calculation for a meta-analysis with the threshold of statistical significance. We performed a TAS using an allele model assumption, but replaced the allele count with the sample size (divided by 2). Detailed settings: Significance level = 0.05; Power = 0.95; ratio of controls to cases = 1; hypothetical proportion of controls with D allele = 49; least extreme OR to be detected = 1.5; I² (heterogeneity) = 90%.