Interleukin 10 Polymorphisms as Risk Factors for Progression to Chagas Disease Cardiomyopathy: A Case-Control Study and Meta-Analysis

Abstract

BackgroundChagas disease is a lifelong infection caused by the protozoa Trypanosoma cruzi endemic in Latin-America and emergent worldwide. Decades after primary infection, 20-30% of infected people develop chronic Chagas cardiomyopathy (CCC) while the others remain asymptomatic. CCC pathogenesis is complex but associated with sustained pro-inflammatory response leading to tissue damage. Hence, levels of IL-10 could have a determinant role in CCC etiology. Studies with Latin-American populations have addressed the association of genetic variants of IL-10 and the risk of developing CCC with inconsistent results. We carried out a case control study to explore the association between IL-10-1082G>A (rs18008969), -819C>T (rs1800871), -592A>C (rs1800872) polymorphisms and CCC in a population attending a hospital in Buenos Aires Argentina. Next, a systematic review of the literature and a meta-analysis were conducted combining present and previous studies to further study this association.MethodsOur case control study included 122 individuals with chronic T. cruzi infection including 64 patients with any degree of CCC and 58 asymptomatic individuals. Genotyping of IL-10 -1082G>A, -819C>T, -592A>C polymorphisms was performed by capillary sequencing of the region spanning the three polymorphic sites and univariate and multivariate statistical analysis was undertaken. Databases in English, Spanish and Portuguese language were searched for papers related to these polymorphisms and Chagas disease up to December 2021. A metanalysis of the selected literature and our study was performed based on the random effect model.ResultsIn our cohort, we found a significant association between TT genotype of -819 rs1800871 and AA genotype of -592 rs1800872 with CCC under the codominant (OR=5.00; 95%CI=1.12-23.87 P=0,04) and the recessive models (OR=5.37; 95%CI=1.12-25.68; P=0,03). Of the genotypes conformed by the three polymorphic positions, the homozygous genotype ATA was significantly associated with increased risk of CCC. The results of the meta-analysis of 754 cases and 385 controls showed that the TT genotype of -819C>T was associated with increased CCC risk according to the dominant model (OR=1.13; 95% CI=1.02–1.25; P=0,03).ConclusionThe genotype TT at -819 rs1800871 contributes to the genetic susceptibility to CCC making this polymorphism a suitable candidate to be included in a panel of predictive biomarkers of disease progression.

Trypanocidal and Anti-Inflammatory Effects of Three ent-Kaurane Diterpenoids from Gymnocoronis spilanthoides var. subcordata (Asteraceae)

“…In the chronic phase of Chagas disease, IL-10 participates in delaying the onset of chronic Chagas heart disease (CCD) in infected individuals. A comprehensive analysis of the cytokine profile revealed that the decrease in IL-10 levels shifts the immune response from the anti-inflammatory profile of asymptomatic patients to that of cardiac patients [ 11 ]. Considering the anti-inflammatory potential of the compound in macrophage cell lines, we decided to evaluate the secretion capacity of IL-10 as an immunoregulatory cytokine.…”

“…On the other hand, the anti-inflammatory cytokine IL-10 is involved in delaying the onset of CCC in infected individuals. A comprehensive analysis of the cytokine profile has revealed that a reduction in IL-10 levels alters the immune response from the anti-inflammatory profile seen in asymptomatic patients compared to that observed in cardiac patients [ 11 ]. In this sense, modulating the inflammatory response in individuals with Chagas disease could have therapeutic potential [ 12 ].…”

Cytokine profile levels and their relationship with parasitemia and cardiomyopathy in people with Chagas disease in Spain. A prospective observational study

“…A recent case-control study and meta-analysis identified an IL-10 polymorphism, the genotype TT at -819 rs1800871, as a contributor to genetic susceptibility in chronic cardiac cardiomyopathy, making this polymorphism a suitable candidate to be included in a panel of predictive biomarkers of disease progression (Grijalva et al 2022 ). These genetic variations in the IL-10 gene promoter induce high IL-10 production (Grijalva et al 2022 ).…”

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 ).…”