Apolipoprotein E genotypes are associated with diabetic peripheral neuropathy in Lebanese adults with type 2 diabetes: a case-control study

Rita Nemr¹SABRINA ZIDI²Akram Echtay³Eddie Racoubian⁴Nisrine Beydoun¹Wassim Almawi^5*

• ¹Lebanese American University School of Medicine, Byblos, Lebanon
• ²Institut Pasteur de Tunis, Tunis, Tunisia
• ³Rafik Hariri University Hospital, Beirut, Lebanon
• ⁴St. Marc Medical Center, Beirut, Lebanon
• ⁵Tunis El Manar University, Tunis, Tunisia

Background: Apolipoprotein E (ApoE) affects lipid metabolism and was associated with type 2 diabetes mellitus (T2DM) complications, including diabetic peripheral neuropathy (DPN). Despite improved glycemic control, DPN prevalence continues to rise, indicating mechanisms beyond hyperglycemia. We assessed the association between APOE genotypes and DPN susceptibility in patients with T2DM, focusing on dyslipidemia-linked pathways underlying neuropathy susceptibility distinct from glycemic effects. Methods: The case-control study included 908 Lebanese patients with T2DM (382 with DPN, 526 without) and 695 healthy controls who underwent multimodal DPN assessment (NCS, QST, and MNSI). APOE genotyping was performed by PCR-RFLP analysis. Logistic regression models were applied to examine the associations between APOE variants and higher odds of DPN. Results: T2DM patients showed significantly higher frequencies of ε2 and ε4 alleles than controls. Among T2DM patients, those with DPN had significantly higher ε2 allele frequency and lower ε3 allele frequency. At the genotype level, ε3/ε3 genotype demonstrated lower odds of DPN, while ε2/ε3, ε2/ε4, and ε3/ε4 were significantly associated with increased odds after adjustment for traditional risk factors. When pooled by allele, ε2-containing genotypes (ε2/ε3 + ε2/ε4; OR (95% CI) = 1.86 [1.38–2.51], and ε4-containing genotypes (ε3/ε4 + ε4/ε4 + ε2/ε4; OR (95% CI) = 1.62 [95% CI = 1.08–2.44]) showed high odds of DPN. Lipid profiles varied by genotype: ε4-containing genotypes displayed atherogenic patterns (elevated total cholesterol and triglycerides, reduced HDL) and were associated with a 1.6-fold higher odds of DPN, while ε2-containing genotypes showed increased total cholesterol and LDL among DPN patients. Genotype-specific clinical correlations were genotype-specific: ε3/ε3 was associated with retinopathy and hypertension but protective against nephropathy, while ε3/ε4 correlated with diabetic complications and dyslipidemia, and ε4/ε4 linked to a higher BMI. Conclusion: APOE genetic variants, especially ε4-containing genotypes, are associated with DPN susceptibility among Lebanese T2DM patients, independent of traditional risk factors including glycemic control. These population-specific findings require validation in prospective cohorts before clinical use but indicate potential value for APOE genotyping in DPN precision-risk models.