Abstract
PURPOSE: Current evidence suggests that apolipoprotein E (APOE) is associated with lipid metabolism, cardiovascular diseases, and neurodegenerative disorders. However, the physiological pathways of APOE-mediated inflammation remain incompletely elucidated, and a specific inflammatory marker that captures the pro-inflammatory activity of the APOE ε4 allele remains elusive. As a composite peripheral blood biomarker, Systemic immune-inflammation index (SII) is a novel marker of inflammation. This study aimed to investigate the association between APOE alleles and Systemic Immune-Inflammation Index. PATIENTS AND METHODS: A total of 13,926 participants (9,098 males and 4,828 females) were recruited from The People’s Liberation Army General Hospital (November 2017 to July 2019). APOE alleles (ε2, ε3, and ε4) were determined by genotyping rs429358 and rs7412 SNPs. SII was calculated as (platelet count × neutrophil count)/lymphocyte count. Multivariable linear regression models (adjusted for demographics, lifestyle, and clinical covariates) and subgroup analyses were performed to assess the APOE-SII associations, with ε3 as the reference. RESULTS: The frequencies of APOE alleles ɛ3, ɛ2, and ɛ4 were70.7%, 13.8%, and 15.5% respectively in 13,926 Chinese patients. The mean SII was lower in ɛ2 carriers than in ɛ3 (373.74*10^9/L vs. 403.53*10^9/L, p < 0.001), and higher in ɛ4 carriers (430.22*10^9/L, p < 0.001). APOE ε4 carriers showed a significantly elevated SII versus ε3 in all models (β = 0.059, 95% CI: 0.041–0.077, p < 0.05), independent of the covariates. Conversely, ε2 carriers exhibited a reduced SII (β=-0.077, 95% CI: -0.096 to -0.058, p < 0.05). The SII correlated significantly with the APOE gene in subgroups stratified by sex, age, hypertension, and diabetes (p < 0.05). CONCLUSION: APOE contributes to elevated disease risk by inducing a state of chronic low-grade inflammation, resulting from modulation of both adaptive and innate immune responses.