Variants in the non-coding region of the TLR2 gene associated with infectious subphenotypes in pediatric sickle cell anemia

Abstract

Sickle cell anemia (SCA) is characterized by chronic hemolysis, severe vasoocclusive crises (VOCs), and recurrent often severe infections. A cohort of 95 SCA pediatric patients was the background for genotype-to-phenotype association of the patient's infectious disease phenotype and three non-coding polymorphic regions of the TLR2 gene, the -196 to -174 indel, SNP rs4696480, and a (GT)n short tandem repeat. The infectious subphenotypes included (A) recurrent respiratory infections and (B) severe bacterial infection at least once during the patient's follow-up. The absence of the haplotype [Del]-T-[n ≥ 17] (Hap7) in homozygocity protected against subphenotype (B), in a statistically significant association, resisting correction for multiple testing. For the individual loci, the same association tendencies were observed as in the haplotype, including a deleterious association between the SNP rs4696480 T allele and subphenotype (A), whereas the A/A genotype was protective, and a deleterious effect of the A/T genotype with subphenotype (B), as well as including the protective effect of -196 to -174 insert (Ins) and deleterious effect of the deletion (Del) in homozygocity, against subphenotype (B). Moreover, a reduction in the incidence rate of severe bacterial infection was associated to a rise in the hemolytic score, fetal hemoglobin levels (prior to hydroxyurea treatment), and 3.7-kb alpha-thalassemia. Interestingly, differences between the effects of the two latter covariables favoring a reduction in the incidence rate of subphenotype (B) contrast with a resulting increase in relation to subphenotype (A). These results could have practical implications in health care strategies to lower the morbidity and mortality of SCA patients.

A Toll‐like receptor 2 genetic variant modulates occurrence of bacterial infections in patients with sickle cell disease

“…Conflicting results were reported by David et al (2018). In a cohort of 95 paediatric infected and non-infected homozygous SS patients, the TA genotype was associated with more severe infections, and the AA genotype was protective against respiratory infections.…”

“…Patients with SCD present a steady-state inflammatory status (Pitanga et al, 2016). Although some studies addressed the role of inflammatory proteins and cells in SCD (Styles et al, 2000;Tamouza et al, 2002;Hoppe et al, 2003;Adekile et al, 2005;Wallace et al, 2009;Wallace & Linden, 2010;Vingert et al, 2015;Godefroy et al, 2016;Pitanga et al, 2016;Tatari-Calderone et al, 2016), few studies have investigated the potential associations between SCD complications and polymorphisms in genes encoding inflammatory proteins (Norris et al, 1996;Neonato et al, 1999;Styles et al, 2000;Tamouza et al, 2002;Hoppe et al, 2003;Adekile et al, 2005;Fertrin & Costa, 2010;Tatari-Calderone et al, 2016;Sippert et al, 2017;David et al, 2018). In this context, Toll-like receptors (TLRs) are a family of transmembrane and intra-cellular proteins expressed on immune cells that sense pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs).…”

Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell Disease

“…In addition, SCD has a marked phenotype variability not fully understood. It was previously demonstrated that polymorphisms in genes encoding inflammatory proteins play a role in the susceptibility to some complications in patients with SCD (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)26). NKG2D is a transmembrane receptor expressed on the surface of NK cells, iNKT cells, T CD8+ and some subsets of TCD4+ lymphocytes (27).…”

“…Some studies have addressed the influence of inflammatory markers in SCD complications, but few of them have evaluated the role of polymorphisms in genes encoding pivotal inflammatory proteins belonging to both innate and adaptive immune processes in the occurrence of complications (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). We hypothesize that such genes can modulate the occurrence of some complications in patients with SCD.…”

Immunogenetics in sickle cell disease

“…For instance, stroke risk was associated with variants in genes encoding IL-4R, TNF-α, β2 adrenergic receptor (ADBR2), VCAM-1, human leukocyte antigen (HLA) class I and class II alleles, among other genes (STYLES et al, 2000;TAYLOR et al, 2002;HOPPE et al, 2003HOPPE et al, , 2004HOPPE et al, , 2007SEBASTIANI et al, 2005). Occurrence of viral and bacterial infections were modulated by HLA class I, class II, HLA-E, HLA-G alleles, polymorphisms in genes encoding mannose binding lectin (MBL), chemokines, TLR and Fc-receptor ligands (NORRIS et al, 1996;NEONATO et al, 1999;TAMOUZA et al, 2002TAMOUZA et al, , 2007AL-OLA et al, 2008;CORDERO et al, 2009;DOSSOU-YOVO et al, 2009;DAVID et al, 2018). Polymorphisms in HLA, TNFalpha and cytotoxic-T-lymphocyte associated antigen 4 (CTLA-4) (TATARI-CALDERONE et al, 2016;OLIVEIRA et al, 2017;SIPPERT et al, 2017) had effects on allo-immunisation; priapism, avascular necrosis and acute chest syndrome were associated with polymorphisms in inflammatory genes (ADEKILE et al, 2005;ELLIOTT et al, 2007;MARTINEZ-CASTALDI et al, 2007) .…”