Meta-Regression Analysis of Knockdown Resistance Mutations Associated with Pyrethroid Resistance in Anopheles Mosquitoes across Sub-Saharan Africa

The VGSC gene's Kdr mutations (L1014F and L1014S) confer resistance to pyrethroids, which decreases the insecticides' ability to bind to their targets and decreases their effectiveness. These alterations, which are encoded in the voltage-gated sodium channel (VGSC) gene, affect the effectiveness of indoor residual spraying (IRS) and insecticide-treated nets (ITNs). In this study, a comprehensive meta-analysis was conducted to assess the impact of L1014F and L1014S mutations on resistance in Anopheles mosquitoes across sub-Saharan Africa. Data were systematically synthesised from eligible studies conducted within the region, applying both fixed and random effects models to estimate pooled associations between kdr genotypes and resistance phenotypes. Heterogeneity and publication bias were evaluated using Cochran’s Q test, Egger’s test, and funnel plot asymmetry. This study represents the first meta-regression focusing exclusively on Anopheles populations in sub-Saharan Africa, encompassing eight studies with a total of 4,690 mosquito samples. Substantial heterogeneity was observed across studies (I² > 99%), and random effects models were therefore applied. The pooled odds ratio (OR) for the L1014F allele (L vs. F) was 2.14 (95% CI: 1.17–2.93, P<0.001), indicating a significant association with resistance, while the L1014S allele (S vs. F) showed a weaker relationship (OR = 0.899, 95% CI: 0.297–1.293, P<0.001). Sensitivity analysis revealed that excluding highly variable studies reduced the effect estimates, highlighting the influence of publication bias and small sample size. Egger’s test and funnel plot asymmetry further confirmed the presence of significant publication bias. After bias adjustment, the pooled effects remained statistically significant but reduced in magnitude, refining the true genetic contribution of these mutations. The analysis also demonstrated mutation-specific resistance gradients, with L1014F conferring stronger resistance than L1014S. This study offers new insights into the molecular epidemiology of pyrethroid resistance in African malaria vectors, establishing a baseline for continent-wide genomic surveillance and vector management strategies.