Research Article: Polymorphisms in the TOLLIP Gene Influence Susceptibility to Cutaneous Leishmaniasis Caused by Leishmania guyanensis in the Amazonas State of Brazil

Date Published: June 24, 2015

Publisher: Public Library of Science

Author(s): Felipe Jules de Araujo, Luan Diego Oliveira da Silva, Tirza Gabrielle Mesquita, Suzana Kanawati Pinheiro, Wonei de Seixas Vital, Anette Chrusciak-Talhari, Jorge Augusto de Oliveira Guerra, Sinésio Talhari, Rajendranath Ramasawmy, Kenji Hirayama.

Abstract: IntroductionThe clinical outcome to Leishmania-infection is determined by the individual adaptive immune T helper cell responses and their interactions with parasitized host cells. An early development of a proinflammatory immune response (Th1 response) is necessary for Leishmania-infection resolution. The Toll-interacting protein (TOLLIP) regulates human Toll-like receptors signaling pathways by down regulating the proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) and inducing the ant-inflammatory cytokine interleukin-10 (IL-10). Polymorphisms in the TOLLIP gene are associated with infectious diseases.Material and MethodsThe polymorphisms rs5743899 and rs3750920 in the TOLLIP gene were genotyped by polymerase chain reaction and restriction fragment length polymorphism (RFLP) analysis in 631 patients with cutaneous leishmaniasis (CL) caused by L. guyanensis and 530 individuals with no history of leishmaniasis.ResultsThe G and T alleles of the rs5743899 and rs3750920 were more common in patients with CL than in healthy individuals (P = 2.6 x10-8 ; odds ratio [OR], 1.7 [ 95% confidence interval (CI) 1.4–2.0] and P = 1.9 x10-8 ; OR, 1.6 [95% CI 1.4–1.9] respectively). The r2 and D’ linkage disequilibrium between the two polymorphisms are 0.05 and 0.473 with a confidence bounds of 0.37 to 0.57 respectively.ConclusionThe two polymorphisms are independently associated with an increased risk of developing CL.

Partial Text: Leishmaniasis, a vector-borne disease, is caused by the intracellular protozoan parasites of the Leishmania genus, which are transmitted by the phlebotomine sand fly. Leishmania-infection, depending on the Leishmania (L.) species and on the host specific immune response, presents a broad spectrum of clinical phenotypes ranging from asymptomatic, self-healing or non-healing cutaneous leishmaniasis (CL) to severe mucosal or life threatening visceral leishmaniasis (VL). Leishmaniasis affects nearly 12 million people, mostly in the tropical and subtropical countries, with a yearly incidence of more than 58,000 VL cases and 220,000 CL cases and is estimated to be the ninth largest infectious disease burden [1,2]. In Brazil, the estimated annual incidence of VL and CL cases is 4200 to 6300 and 72,000 to 119,000 respectively [2].

The genotypes and allele frequencies of rs5743899 and rs3750920 are shown in Table 2. There was no evidence of deviation from Hardy-Weinberg equilibrium for both polymorphisms in either groups of patients with CL or controls. Comparison of patients with CL to controls showed significant allele-wise and genotype-wise associations. Genotype distributions were different between patients with CL and controls (rs5743899, p = 5.2×10-8; rs3750920, p = 2.9×10-8). There were an excess of genotypes of the rs5743899 G allele (AG + GG; 54%) and of the rs3750920 T allele (TT + CT; 64%) in the patients with CL group compared to 40% and 51% respectively in the control group. Individuals homozygous for rs5743899 G allele or rs3750920 T allele had three times risks of developing CL compared to individuals homozygous for the rs5743899 A allele (P = 1.2×10-6; OR, 3.0 [95% CI 1.9–4.8]) or rs3750920 C allele (P = 6.0×10-8; OR, 2.9 [95% CI 1.9–4.2]). In the dominant model, carriers of the rs5743899 G allele or rs3750920 T allele were compared with homozygous individuals for the A or C allele respectively and the difference were highly significant (P = 1.9×10-6 OR, 1.8 [95% CI 1.4–2.2] and (p = 5.4×10-6; OR, 1.7 [95% CI 1.4–2.2]). A similar trend was observed when heterozygous individuals for both polymorphisms (rs5743899 AG or rs3750920 CT) were compared to rs5743899 AA or rs3750920 CC homozygous individuals.

Enormous headway has been achieved in the understanding of Leishmaniasis but the molecular mechanism that underlies the development of the clinical outcome still remains obscure. In endemic areas of tegumentary leishmaniasis, only a fraction of individuals infected by the Leishmania parasite develop CL and a very small proportion evolves to mucosal leishmaniasis. Increasing interest in the relationship between host genetics and the outcome of Leishmania-infection has emerged. The identification of genes involves in the susceptibility to Leishmania-infection may pave the way for a better understanding of the disease and for designing vaccine. Dysregulation and genetic polymorphisms in the immune system are associated to many infectious diseases.



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