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

Abstract

Summary Despite adequate immunization and penicillin prophylaxis, bacterial infections remain a leading cause of morbidity and mortality in patients with sickle cell disease (SCD). Besides hyposplenism, inflammatory and genetic factors might modulate their susceptibility to bacterial infections. We performed a candidate gene association of single nucleotide polymorphisms (SNPs) located in Toll‐like receptor (TLR) genes, encoding prominent molecules for innate immune responses, with the occurrence of bacterial infections in patients with SCD. A cohort followed in centres in Brazil, France and Senegal (n = 430) was divided in two groups: patients who presented at least one episode of bacterial infection (n = 235) and patients who never had bacterial infections (n = 195). There were no differences in gender or age distribution among the groups. The frequency of the TLR2 rs4696480 TA genotype was significantly lower in the infected group (50% vs. 67%, odds ratio [OR] = 0·50, 95% confidence interval [CI] 0·34–0·75, P < 0·001), and the TT genotype was significantly higher in the infected group (15% vs. 5%, OR = 3·18, 95% CI 1·53–6·61, P < 0·001). Previous reports demonstrated higher secretion of inflammatory factors in cells from AA individuals, lower occurrence and severity of immune diseases in T carriers. The rs4696480 TA genotype might stand between deleterious effects of over inflammatory response (AA genotype) and inefficient responses (TT genotype) to infectious agents in SCD settings.

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

“…This explains why comparisons between SCD and non-SCD populations, and among SCD patients, may uncover different effects of a given SNP—for instance, alleles and genotypes that modify the function of TLR and modulate the occurrence of infections in this population. Based on our findings and in previous studies on the functional role of this SNP ( 15 , 51 – 56 ), we hypothesized that TA genotype might determine a balanced inflammatory response, whereas the TT genotype would determine a weak inflammatory response, and the AA genotype, an overwhelming inflammatory response pattern. Further studies assessing the role of this SNP and its protein expression are required in SCD settings.…”

“…Of note, the TLR2 rs4696480 TA genotype was significantly associated with occurrence of 0-1 clinical complications. Previously, our group has found that the same genotype was associated with less bacterial infections in SCD (15). Patients with SCD exhibit a marked susceptibility to infections, compared with non-SCD individuals, due to several factors, such as loss of spleen function and the chronic inflammatory status (50).…”

“…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).…”

“…Using TaqMan 5′-nuclease assay (Applied Biosystems, Forster City, CA, USA) pre-designed allele-specific fluorogenic oligonucleotide probes, we genotyped SNPs in genes encoding the following innate and adaptative immune molecules: Toll-like receptor (TLR)1 ( rs 4833095), TLR2 ( rs 4308099, rs 4308100, rs 4696480), TLR6 ( rs 5743810), TLR10 ( rs 11466653, rs 11096957), all located in chromosome 4 and belonging to the TLR1 subfamily ( 20 ); natural killer (NK) group 2 member D (NKG2D) receptor ( rs 1982536, rs 2617160, rs 2617169, rs 2617170, rs 2617171, rs 1049174, rs 2246809, rs 2255336), in chromosome 12; human leukocyte antigen (HLA)-G ( rs 9380142), HLA-E ( rs 2517523), major histocompatibility complex class I polypeptide-related sequence A (MICA, rs 1057192), in the chromosome 6; and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) ( rs 5742909, rs 231775), in the chromosome 2. DNA pre-amplification and real-time polymerase chain reaction (RT-PCR) were performed as previously described ( 15 , 21 ). All SNPs included in this analysis were selected based on the relevance of their biological function.…”

“…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.…”