Association between single nucleotide polymorphisms (SNPs) of IL1, IL12, IL28 and TLR4 and symptoms of congenital cytomegalovirus infection

Abstract

Congenital cytomegalovirus (cCMV) infection is the most common intrauterine infection. A non-specific immune response is the first line of host defense mechanism against human cytomegalovirus (HCMV). There is limited data on associations between Single Nucleotide Polymorphisms (SNPs) in genes involving innate immunity and the risk and clinical manifestation of cCMV infection. The aim of the study was to investigate association between selected SNPs in genes encoding cytokines and cytokine receptors, and predisposition to cCMV infection including symptomatic course of disease and symptoms. A panel of eight SNPs: IL1B rs16944, IL12B rs3212227, IL28B rs12979860, CCL2 rs1024611, DC-SIGN rs735240, TLR2 rs5743708, TLR4 rs4986791, TLR9 rs352140 was analyzed in 233 infants (92 cCMV-infected and 141 healthy controls). Associations between genotyped SNPs and predisposition to cCMV infection and symptoms were analyzed. The association analysis was performed using SNPStats software. No statistically significant association was found between any genotyped SNPs and predisposition to cCMV infection and symptomatic course of disease. In relation to particular symptoms, polymorphism of IL12B rs3212227 was linked to decreased risk of prematurity (OR = 0.37;95%CI,0.14-0.98;p = 0.025), while polymorphism of IL1B rs16944 was linked to reduced risk of splenomegaly (OR = 0.36;95% CI,0.14-0.98; p = 0.034) in infants with cCMV infection. An increased risk of thrombocytopenia was associated with IL28B rs12979860 polymorphism (OR = 2.55;95%CI,1.03-6.32;p = 0.042), while hepatitis was associated with SNP of TLR4rs4986791 (OR = 7.80;95% CI,1.49-40,81; p = 0.024). This is the first study to demonstrate four new associations between SNPs in selected genes (IL1B, IL12B, IL28B, TLR4) and particular symptoms in cCMV disease. Further studies on the role of SNPs in the pathogenesis of cCMV infection and incorporation of selected SNPs in the clinical practice might be considered in the future.

Single Nucleotide Polymorphisms of Interleukins and Toll-like Receptors and Neuroimaging Results in Newborns with Congenital HCMV Infection

“…Eight selected SNPs were genotyped successfully in the study population [ 33 ]. The genotypic frequencies of SNPs for the overall study population are shown in Table 4 .…”

“…We prospectively enrolled Caucasian neonates with confirmed cCMV admitted into the Neonatal Intensive Care Unit of The Children’s Memorial Health Institute in Warsaw between 2016 and 2019 [ 33 ]. Inclusion criteria were positive real-time PCR DNA CMV in urine ≤ 21st day of life, and parental consent.…”

“…The following definitions for laboratory abnormalities were used: elevated direct bilirubin >1 mg/dL for cholestasis, elevated level of aspartate transaminase (ASPAT) > 84 U/L and/or elevated level of alanine aminotransferase (ALTAT) > 60 U/L for hepatitis, thrombocytopenia below 100 K/μL, and neutropenia below 1000 K/μL for bone marrow involvement. As a part of routine work-up, blood and urine samples were collected for qualitative and quantitative real-time PCR DNA HCMV assessment, as described previously [ 22 , 33 ]. The same blood samples were used for the SNPs’ genotyping test.…”

“…So far, SNPs has been quite extensively studied in the context of acquired HCMV infection in organ transplant patients and stem cells recipients [ 16 , 23 , 27 , 28 , 29 , 30 , 31 ]. However, there are still only a few studies linking the SNPs of ILs or TLRs to a predisposition to cCMV and symptoms of the disease in newborn infants [ 16 , 17 , 20 , 22 , 25 , 32 , 33 ]. Based on the abovementioned reports, we selected for this study SNPs of eight candidate genes which we considered to be potentially important in cCMV infection.…”

Malformações congênitas causadas por vírus

“…No estudo é apresentada a relação entre o polimorfismo da IL12B rs3212227 e o risco reduzido de um nascimento prematuro, a partir de sua participação na defesa imunológica do hospedeiro contra infecções, já que a IL-12 é uma citoquina inflamatória responsável por influenciar as células Th1. Esse é um estudo recente e pioneiro acerca desse assunto, trazendo associações entre SNPs nos genes IL1B, IL12B, IL28B, TLR4 e os sintomas da infecção por cCMV como prematuridade, esplenomegalia, trombocitopenia e hepatite respectivamente (Jedlińska-Pijanowska et al, 2020).…”