#5795 THE APOPROTEIN E (APOE) POLYMORPHISM AND PROPROTEIN CONVERTASE SUBTILISIN KEXIN 9 (PCSK9) IN HEMODIALYSIS (HD) PATIENTS
Authors: Arita Kazuko , Oda Hiroaki , Kihara Emi , Maeda Katsutoshi , Masaki Takao 
Published: June 2023

Abstract

Background and Aims
The apoE polymorphism and PCSK9 play an important role in lipid metabolism in healthy subjects, however, its role in HD patients remains unclear. We investigated the apoE polymorphism and PCSK9 as well as a lipid profile to clarify the impact of these factors on prognosis in HD patients. We also examined the association of cardiovascular (CVD) events in dead HD patients and clinical features.

Method
HD patients (n = 296, m/f; 207/89, DM; 152, age; 69.8±12.1, HD duration; 68.7±72.0 months) were subjected to this study. Written informed consent was obtained from each patient. Of these patients 85 subjects (m/f; 61/24, DM; 54, HD duration; 98.6±53.5 months) died during this study (from June 2011 to December 2022). Blood samples were collected to analyze the apoE genotypes by the invader method, serum concentrations of PCSK9-heterodimers and PCSK9-free fragments were measured using ELISA (BML Co. Ltd., Tokyo, Japan) and serum concentrations of apoA1, apoA2, apoB, apo C2, apoC3 and apoE were estimated using turbidimetric immunoassay. For the death cases we used multivariable logistic regression to control for the potentially confounding roles of type 2 diabetes mellitus (DM), apoE genotypes, and serum concentrations of PCSK9-heterodimers, PCSK9-free segments, apoA1, apoA2, apoB, apo C2, apoC3 and apoE. Survival probabilities in dead HD patients with CVD events according to the apoE genotypes were analyzed using the Kaplan-Meier curves. A p value less than 0.05 was considered statistically significant.

Results
The spoE allele frequencies in HD patients (n = 296) were ɛ2; 0.044, ɛ3; 0.870 and ɛ4; 0.086, whereas those in Japanese healthy controls were ɛ2; 0.036, ɛ3; 0.848 and ɛ4; 0.116 (Eto M., et al. Clin Genet 30:422-427, 1986.), demonstrating the ɛ2 frequency in HD patients had a trend to be higher than that in Japanese healthy controls (p = 0.096). The serum concentrations of PCSK9-heterodimers and PCSK9-free fragments in female HD patients (n = 89, 227.0±88.0 ng/ml and 41.9±19.1 ng/ml, respectively) were significantly higher than those in male HD patients (n = 207, 195.9±70.3 ng/ml, p = 0.001, and 35.8±15.3 ng/ml, p&lt;0.004, respectively) . The serum concentrations of PCSK9-heterodimers in HD patients with DM (n = 152); 213.8±77.6 ng/ml showed a trend to be higher than those in HD patients without DM (n = 144); 196.3±76.1 ng/ml (p = 0.05). The multivariable logistic regression analysis demonstrated the serum concentration of apoA1 and apoE polymorphism showed statistically significant impact on CVD events in dead HD patients (Table 1). The Kaplan-Meier analysis revealed the apoE polymorphism had a significant impact on the survival probability in dead HD patients with CVD events (Figure 1).

Conclusion
Recent studies reported the association between apoE2 and renal insufficiency in Japanese type2 DM. ApoE2 may be one of the attributable factors that lead to the end stage kidney disease. PCSK9-heterodimers bind to LDL cholesterol receptors (LDLr) and prevent LDLr from shuttling back to the surface and instead target it for degradation, however, PCSK9-free segments have weaker effects to bind to LDLr. Significance of higher serum concentrations of PCSK9-heterodimers andPCSK9-free fragments in female HD patients than male HD patients depends on future investigation. ApoE2 and the serum concentration of apoA1 contribute to CVD events. The prognosis of the HD patients with apoE2 or apoE4 were poorer than that with apoE3/3. The apoE polymorphism and PCSK9 may be key factors in lipid metabolism as well as prognosis of HD patients.