Response to “Unaddressed Confounding Factors Undermine Causal Inference in the Study on IL‐6 Promoter Region Polymorphism and Type 2 Diabetes Mellitus in an Egyptian Centre”

Dear Editor, We would like to thank Dr. Hua-Qin Su (Sue etal., 2025) and colleagues for their interest in our article “Interleukin-6 Promoter Region Polymorphism in Patients with Type 2 Diabetes Mellitus: Study in One Egyptian Centre” (Motawea et al. 2025) and for their constructive comments regarding potential confounding factors and study design. We appreciate the opportunity to clarify and expand upon several methodological aspects of our work. Our study was designed as an exploratory, single-centre, case-control investigation aiming to identify whether the IL-6 promoter polymorphism (rs1800796) is associated with type 2 diabetes mellitus (T2DM) in an Egyptian cohort. As we acknowledged in our Discussion section, this pilot study was intended as a preliminary step towards larger, multicentre investigations that could confirm and generalize our findings. We agree that the single-centre design and modest sample size may limit external validity; however, all participants were recruited under the same clinical conditions, minimizing site-to-site variation. We fully agree that lifestyle and metabolic variables—such as body mass index (BMI), dietary patterns, smoking, physical activity and family history—are important determinants of both systemic inflammation and T2DM risk. Although our dataset did not include detailed quantitative records of these variables, several measures were implemented to reduce their confounding impact: • Participant selection: Patients with chronic inflammatory or hepatic diseases and individuals with morbid obesity (BMI > 30 kg/m2) were excluded. • Matching: Controls were age- and sex-matched to cases to minimize demographic bias. • Clinical homogeneity: All samples were collected from the same hospital unit using uniform protocols for biochemical and genetic analyses. We therefore believe that the internal consistency of our data supports the observed association, although we concur that unmeasured confounding cannot be entirely excluded. As clearly stated in our paper, our conclusion was cautious: the GC and CC genotypes may represent genetic risk factors for T2DM in Egyptians. This wording reflects a correlative, not causal, interpretation. Our study was not designed to infer causation but to highlight a potential genetic signal that warrants further investigation. We agree with Dr. Su and colleagues that causal inference would require adjustment for additional covariates in a larger, prospective design. We value the correspondents’ suggestion to include confounder-adjusted and stratified analyses. Our research group is currently developing a multicentre prospective study incorporating BMI, dietary intake and lifestyle data. This future work will allow a more comprehensive understanding of how the rs1800796 polymorphism interacts with environmental factors to influence IL-6 expression and diabetes susceptibility. We thank Dr. Su and co-authors for their thoughtful observations, which have provided valuable input for refining future work. We remain confident that our findings contribute to the growing body of evidence on the immunogenetic mechanisms underlying type 2 diabetes in diverse populations. The authors declare no conflicts of interest. The authors have nothing to report. The datasets generated and analyzed during the current study are available in the Fighshare repository at https://doi.org/10.6084/m9.figshare.26414731.v1