The EIF2AK4/rs4594236 AG/GG Genotype Is a Hazard Factor of Immunoglobulin Therapy Resistance in Southern Chinese Kawasaki Disease Patients

Abstract

Background: Kawasaki disease (KD) is an acute, self-limited vasculitis disorder of unknown etiology in children. Immunologic abnormalities were detected during the acute phase of KD, which reflected that the effect cells of the activated immune system markedly increased cytokine production. High-dose intravenous immunoglobulin (IVIG) therapy is effective in resolving inflammation from KD and reducing occurrence of coronary artery abnormalities. However, 10%–20% of KD patients have no response to IVIG therapy, who were defined as IVIG resistance. Furthermore, these patients have persistent inflammation and increased risk of developing coronary artery aneurysm (CAA). EIF2AK4 is a stress sensor gene and can be activated by pathogen infection. In addition, the polymorphisms of EIF2AK4 were associated with various blood vessel disorders. However, it remains unclear whether the EIF2AK4 gene polymorphisms were related to IVIG therapy outcome in KD patients.Methods:EIF2AK4/rs4594236 polymorphism was genotyped in 795 IVIG response KD patients and 234 IVIG resistant KD patients through TaqMan, a real-time polymerase chain reaction. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association between EIF2AK4/rs4594236 polymorphism and IVIG therapeutic effects.Results: Our results showed that the EIF2AK4/rs4594236 AG/GG genotype was significantly associated with increased risk to IVIG resistance compared to the AA genotype (AG vs. AA: adjusted ORs = 1.71, 95% CIs = 1.17–2.51, and p = 0.0061; GG vs. AA: adjusted ORs = 2.09, 95% CIs = 1.36–3.23, and p = 0.0009; AG/GG vs. AA: adjusted ORs = 1.82, 95% CIs = 1.27–2.63, and p = 0.0013; and GG vs. AA/AG: adjusted ORs = 1.45, 95% CI = 1.04–2.02, and p = 0.0306). Furthermore, the stratified analysis of age and gender in the KD cohort indicated that male patients carrying the rs4594236 AG/GG genotype tends to be more resistant to IVIG therapy than female patients.Conclusion: These results suggested that EIF2AK4/rs4594236 polymorphism might be associated with increased risk of IVIG resistance in southern Chinese KD patients.

Classification of Colorectal Cancer Subtypes Based on Endoplasmic Reticulum Stress

“…Therefore, more studies may be needed to elucidate the specific mechanisms by which GORASP2 affects the prognosis of CRC. Mutations in eukaryotic translation initiation Factor 2-αkinase 4 (EIF2AK4), a member of the kinase family that phosphorylates the alpha subunit of eukaryotic translation initiation Factor 2 (eIF2a), are common in pulmonary vein occlusive diseases and pulmonary capillary hemangiomatosis [35,36]. Alasiri et al [37] found that EIF2AK4 can cooperate with PERK and regulate the FOXO3 response to chemotherapy through JNK and AKT, thereby improving the prognosis of breast cancer patients.…”

The Associated of the Risk of IVIG Resistance in Kawasaki Disease with ZNF112 Gene and ZNF180 Gene in a Southern Chinese Population

“…In the early years, our team has been focused on the progress of KD disease and the therapeutic effect, and achieved some exciting results. We found that single nucleotide polymorphisms (SNPs) of several genes (P2RY12, MRP4 and EIF2AK4 [35][36][37] ) were closely associated with IVIG treatment efficacy in KD; interestingly, these genes played important roles in immune response and cardiovascular-related functions. This study was the first one to focus on the effect of ZNF family (ZNF180 and ZNF112) on IVIG treatment resistance of KD.…”