Polymorphisms and haplotypes of IL2RA, IL10, IFNG, IRF5, and CCR2 are associated with Epstein–Barr virus‐associated hemophagocytic lymphohistiocytosis in children

Abstract

Objective Cytokine storms are central to the development of Epstein–Barr virus‐associated hemophagocytic lymphohistiocytosis (EBV‐HLH). Previous studies have shown that single‐nucleotide polymorphisms (SNPs) of cytokine genes may be associated with the development of EBV‐HLH in children. As such, we investigated the association between susceptibility to EBV‐HLH in children and SNPs and haplotypes of genes encoding interleukin‐2 receptor subunit alpha (IL2RA), interleukin‐10 (IL10), interferon gamma (IFNG), interferon regulatory factor 5 (IRF5), and C–C chemokine receptor 2 (CCR2). Methods Sixty‐six children with EBV‐HLH and 58 healthy EBV‐seropositive controls were enrolled in this study. SNPs of IL2RA rs2104286, rs12722489, and rs11594656; IL10 rs1800896, rs1800871, and rs1800872; IFNG rs2430561, IRF5 rs2004640, and CCR2 rs1799864 were assayed and genotyped using the SNaPshot technique. Results Frequencies of the A allele of IL2RA rs2104286 and IL10 rs1800896, and C allele of IL‐10 rs1800872 were significantly higher in the EBV‐HLH group than in the control group. The AA genotype of IL2RA rs2104286 and IL10 rs1800896, and the CC genotype of IL10 rs1800872 might be associated with a significantly high risk of EBV‐HLH. However, the frequencies of genotypes and alleles of IL2RA rs2104286, IL10 rs1800871, IFNG rs2430561, IRF5 rs2004640, and CCR2 rs1799864 were similar in both groups. Additionally, IL2RA AGT (rs2104286–rs12722489–rs11594656) and IL10 ACC (rs1800896–rs1800871–rs1800872) haplotypes were also associated with an increased risk of EBV‐HLH. Conclusions SNPs of IL2RA rs2104286, IL10 rs1800896 and rs1800872 and the haplotypes of IL2RA AGT and IL10 ACC were highly associated with susceptibility to EBV‐HLH in children.

Association of IL-10–592 C > A /-1082 A > G and the TNFα -308 G > A with susceptibility to COVID-19 and clinical outcomes

“…Interestingly, the GA genotype of IL-10-1082 A > G had a significant association with case fatality in influenza A/H1N1pdm09 infections in Indian patients [ 22 , 40 ] and other viruses [ 41 ]. A possible explanation to the association of the IL-10 polymorphisms, the AA in IL-10 -592 and the GG in IL-10 -1082 , with viral infection susceptibility/persistence, is that the increase in IL-10 serum levels exerts sustained inhibitory effects on immune cells that are responsible for viral clearance [ 42 ].…”

Association of IL6 and IL10 gene promotor polymorphisms with susceptibility to acute necrotizing encephalopathy

“…In various infectious diseases, rs1800871C and/or rs1800872C is reportedly associated with the onset of chronic infections: a decreased susceptibility to tuberculosis ( Yu et al, 2019 ; Chen and Ma, 2020 ), increased susceptibility to leprosy ( Cardona-Castro et al, 2012 ; Dos Santos et al, 2021 ), decreased susceptibility to herpes zoster ( Haanpää et al, 2002 ), and increased susceptibility to HBV infection ( Ye et al, 2020 ). These alleles are also associated with the course, progression, response to therapy and outcome: a better outcome of leprosy ( Alvarado-Arnez et al, 2015 ), low infection intensity of Schistosoma mansoni in schistosomiasis ( Mewamba et al, 2023 ), reduced risk of cardiomyopathy in Chagas disease ( Grijalva et al, 2022 ), reduced risk of anemia in newborns in Plasmodium falciparum malaria infection ( Lokossou et al, 2013 ), increased risk of Epstein–Barr virus (EBV)-associated hemophagocytic lymphocytosis ( Tang et al, 2021 ), reduced risk of breast cancer after EBV infection ( He et al, 2012 ), increased risk of AIDS-related non-Hodgkin lymphoma ( Wong et al, 2010 ), increased risk of progressive liver disease in chronic hepatitis B ( Miyazoe et al, 2002 ), reduced chance of seroclearance after antiviral treatment of chronic hepatitis B ( Rybicka et al, 2020 ), poor reduced disease severity of chronic hepatitis C ( Świątek-Kościelna et al, 2017 ), and reduced risk of hepatocellular carcinoma in chronic hepatitis C ( Aroucha et al, 2016 ; Sghaier et al, 2017a ). For acute infections, s1800871C and/or rs1800872C is reportedly associated with a decreased risk of dengue infection ( Eloisa Monroy-Muñoz et al, 2023 ) and dengue hemorrhagic fever ( Alagarasu et al, 2015 ), decreased risk of asthma after bronchiolitis in infancy ( Korppi et al, 2017 ), and reduced severity (requiring admission to intensive care unit) of sepsis ( Montoya-Ruiz et al, 2016 ).…”