Elsevier

Acta Tropica

Volume 120, Issues 1–2, October–November 2011, Pages 67-71
Acta Tropica

Tumor necrosis factor alpha promoter polymorphisms in Mexican patients with dengue fever

https://doi.org/10.1016/j.actatropica.2011.06.002Get rights and content

Abstract

Increased levels of tumor necrosis factor alpha (TNF-α) in patients with dengue have been reported. Various polymorphisms have been identified in the promoter region of the TNF-α gene that may affect its transcription. The purpose of the present study was to evaluate the relationship between polymorphisms of TNF-α gene and the genetic susceptibility to dengue fever in a group of patients from Morelos State, Mexico. The TNF-α polymorphisms (positions −238 and −308) were determined by PCR-RFLP technique in 130 patients with dengue (85 with dengue fever and 45 with dengue hemorrhagic fever) and 169 healthy controls. The patients were selected from cases reported in Morelos State from 1997 to 2003. The whole group of dengue patients showed a decreased frequency of TNF-α238 A allele when compared to healthy controls (p = 0.01, OR = 0.19, 95%CI = 0.02–0.78). When the analysis was made separately in dengue fever and dengue hemorrhagic fever patients, the decreased frequency of TNF-α238 A allele only remained significant in patients with DHF when compared to healthy controls (p = 0.034). This work suggests a possible association of TNF-α238 A allele with protection to develop symptomatic disease.

Graphical abstract

The TNF-α polymorphisms were determined in patients with dengue. This work suggests a possible association of TNF-α −238 A allele with the susceptibility to the disease.

  1. Download : Download full-size image

Highlights

► Two TNF-αpolymorphisms were analyzed in patients with dengue fever. −238 A allele was decreased in patients with DHF and DHF/DF when compared to healthy controls. ► TNF-α −238 A allele was associated with the susceptibility to dengue in Mexican patients.

Introduction

Dengue fever (DF) is characterized by high fever, headache, myalgia, arthralgia, nausea, vomiting, maculopapular rash and moderate hepatomegaly. Besides fever, dengue hemorrhagic fever (DHF) presents more severe clinical symptoms, such as hemorrhagic manifestations, plasma leakage and thrombocytopenia (World Health and Organization, 1997, Halstead, 2007, Kurane, 2007, Guzman and Kouri, 2008).

The pathogenesis of DHF is multifactorial, however some patients have exhibited elevated interleukins and interferon-gamma (INF-γ) production, this could explains T lymphocyte activation in patients with DF and DHF (Chaturvedi et al., 2000, Luhn et al., 2007, Chen et al., 2007, Green et al., 1999, Rothman, 2010).

Previous studies have reported increased levels of tumor necrosis factor alpha (TNF-α) and INF-γ in patients with DF and DHF (Chakravarti and Kumaria, 2006, Bashyam et al., 2006), as well as a positive association between TNF-α soluble receptors (TNFSR) and the severity of DHF (Yadav et al., 1991, Bethell et al., 1998). Although TNF-α can act as an antiviral molecule to protect the host from cellular damage (Mestan et al., 1986), it has also been demonstrated that it can increase pulmonary vascular permeability (Horvath et al., 1988). Although some of the clinical and biological alterations caused by DHF can explain this manifestation, unlike many other hemorrhagic fevers, in DHF there is not evidence that the vascular endothelium is damaged when endothelial cells are infected (Jessie et al., 2004). TNF-α has diverse effects on endothelial cells, including increased inflammation, production of selectins and ligands for integrins and leukocytes during diapedesis, as well as the stimulation of chemokine production, which contributes to diapedesis, chemotaxis and leukocyte recruitment (Bradley, 2008).

The TNF-α gene is located on the short arm of chromosome 6 of the human genome, in region III of the Major Histocompatibility Complex (MHC), where other molecules such as heat shock protein 70 (HSP70), C3 and C4 components of the complement system are also encoded (Horton et al., 2004). Various alleles have been identified in the promoter region of the TNF-α gene that may affect transcription. Wilson et al. (1992) identified a consistent bi-allelic polymorphism consisting in the substitution of a guanine (G) by an adenine (A) in position −308 of the promoter, designated as TNF1 (G) and TNF2 (A) alleles, respectively. The TNF2 allele is less common, and is associated with an increase in the production of TNF-α (Wilson et al., 1997). In addition, some studies have associated it with serious complications of autoimmune and infectious diseases, characterized by high levels of TNF-α in serum, such as cerebral malaria (McGuire et al., 1994), leishmaniasis (Cabrera et al., 1995), Chagas disease (Drigo et al., 2006), hepatitis B (Kim et al., 2003), septic shock and bacterial infections (Mira et al., 1999, Cipriano et al., 2005). The polymorphism in position −238 has been associated with the absence of erosive disease in patients with rheumatoid arthritis (Brinkman et al., 1997) and chronic hepatitis C (Höhler et al., 1998). A recent study identified the TNF-α308 A allele as a possible risk factor for the development of DHF in a Venezuelan population (Fernández-Mestre et al., 2004).

Thus, the aim of the present study was to establish the role of the TNF-α promoter polymorphisms (positions −238 and −308) in the risk of developing DF or DHF in a group of Mexican Mestizo patients.

Section snippets

Study population

Forty five patients with DHF (n = 45) and eighty five with DF (n = 85) were selected from a database of patients who were confirmed to dengue virus infection in the state of Morelos during January 1997 to December 2003. One hundred and sixty nine healthy controls (n = 169) were also included and matched for ethnicity. The patients and controls were Mexican Mestizos according to the definition of the National Institute of Anthropology and History and residents of state of Morelos (Serrano-Sánchez, 1996

Results

The −308 polymorphism was studied in 130 patients (DF: 85, DHF: 45) and 163 controls, whereas the −238 polymorphism was analyzed in 73 patients (DF: 41, DHF: 32) and 169 controls. Patients with DF/DHF showed a decreased frequency of TNF-α238 A allele when compared to healthy controls (p = 0.01, OR = 0.19, 95%CI = 0.02–0.78). Statistical significance was only conserved in the DHF group when patients were compared with healthy controls (p = 0.034) (Table 1). Similar allele and genotype distribution of

Discussion

The large amount of epidemiological studies performed with DHF patients confirm that it is a multifactorial disease; the infecting serotype and the immunological state of the patient are factors that are involved in the physiopathology of the illness (Halstead, 2007, Kurane, 2007). Even though the role of host genetic factors in the pathophysiology of the disease is not yet fully understood. Published evidence from studies on polymorphisms of diverse genes such as HLA (Stephens et al., 2002,

Acknowledgement

We thank Gloria Tavera for revising the English version of this work.

References (54)

  • I. Kurane

    Dengue hemorrhagic fever with special emphasis on immunopathogenesis

    Comp. Immunol. Microbiol. Infect. Dis.

    (2007)
  • C. LaFleur et al.

    HLA-DR antigen frequencies in Mexican patients with dengue virus infection: HLA-DR4 as a possible genetic resistance factor for dengue hemorrhagic fever

    Hum. Immunol.

    (2002)
  • A.B. Perez et al.

    Tumor necrosis factor-alpha, transforming growth factor-β1, and interleukin-10 gene polymorphisms: implication in protection or susceptibility to dengue hemorrhagic fever

    Hum. Immunol.

    (2010)
  • B. Sierra et al.

    Secondary heterologous dengue infection risk: disequilibrium between immune regulation and inflammation?

    Cell. Immunol.

    (2010)
  • B. Sierra et al.

    HLA-A, -B -C, and -DRB1 allele frequencies in Cuban individuals with antecedents of dengue 2 disease: advantages of the Cuban population for HLA studies of dengue virus infection

    Hum. Immunol.

    (2007)
  • M. Yadav et al.

    Dengue haemorrhagic fever and dengue shock syndrome: are they tumour necrosis factor-mediated disorders?

    FEMS Microbiol. Immunol.

    (1991)
  • H.S. Bashyam et al.

    Dengue virus-reactive CD8+ T cells display quantitative and qualitative differences in their response to variant epitopes of heterologous viral serotypes

    J. Immunol.

    (2006)
  • D. Bethell et al.

    Pathophysiology and prognostic role of cytokines in dengue hemorrhagic fever

    J. Infect. Dis.

    (1998)
  • J.R. Bradley

    TNF-mediated inflammatory disease

    J. Pathol.

    (2008)
  • E.L. Braga et al.

    Detection of circulant tumor necrosis factor-alpha, soluble tumor necrosis factor p75 and interferon-gamma in Brazilian patients with dengue fever and dengue hemorrhagic fever

    Mem. Inst. Oswaldo Cruz

    (2001)
  • B.M. Brinkman et al.

    Tumour necrosis factor alpha gene polymorphisms in rheumatoid arthritis: association with susceptibility to, or severity of, disease?

    Br. J. Rheumatol.

    (1997)
  • M. Cabrera et al.

    Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis

    J. Exp. Med.

    (1995)
  • J.M. Carr et al.

    Supernatants from dengue virus type-2 infected macrophages induce permeability changes in endothelial cell monolayers

    J. Med. Virol.

    (2003)
  • A. Chakravarti et al.

    Circulating levels of tumour necrosis factor-alpha & interferon-gamma in patients with dengue & dengue haemorrhagic fever during an outbreak

    Indian J. Med. Res.

    (2006)
  • L.C. Chen et al.

    Correlation of serum levels of macrophage migration inhibitory factor with disease severity and clinical outcome in dengue patients

    Am. J. Trop. Med. Hyg.

    (2006)
  • C. Cipriano et al.

    The −308G/A polymorphism of TNF-alpha influences immunological parameters in old subjects affected by infectious diseases

    Int. J. Immunogenet.

    (2005)
  • M.T. Fernández-Mestre et al.

    TNF-α −308A allele, a possible severity risk factor of hemorrhagic manifestation in dengue fever patients

    Tissue Antigens

    (2004)
  • Cited by (26)

    • Association of single nucleotide polymorphisms in TNF-α (−308G/A and −238G/A) to dengue: Case-control and meta-analysis study

      2020, Cytokine
      Citation Excerpt :

      For SNP-238G/A no significant association between SNP and dengue was observed. There have been a small number of case-control studies performed for the polymorphism [28,30,34,35]. However, in the analysis of the GA genotype for DHF versus control groups, it was observed that work by Garcia-Trejo et al. [28] caused heterogeneity and was excluded.

    • Host genetics and dengue fever

      2017, Infection, Genetics and Evolution
    • Association of TNFA (−308G/A), IFNG (+874 A/T) and IL-10 (−819 C/T) polymorphisms with protection and susceptibility to dengue in Brazilian population

      2017, Asian Pacific Journal of Tropical Medicine
      Citation Excerpt :

      Interestingly, the Brazilian studies that investigated the role of several cytokines polymorphisms concluded that TNFA (−308G/A) were not related with predisposition to dengue [26,27]. Studies conducted in population Thai [28] and Mexican [29] did not identify association of the polymorphism of this cytokine with dengue. Some studies have shown the association of the A allele of TNFA (−308G/A) polymorphism with severity of dengue in Cuban population with secondary infection with DENV-2 [30].

    • Associations of tumor necrosis factor-α-308 polymorphism with dengue infection: A systematic review and meta-analysis

      2017, Acta Tropica
      Citation Excerpt :

      Six (Alagarasu et al., 2015, 2013; Garcia-Trejo et al., 2011; Perez et al., 2010; Sam et al., 2015; Xavier-Carvalho et al., 2013) of the nine articles explicitly used matching in their studies of which 67% (4/6) were based on sex and/or ethnicity. RFLP (Restriction Fragment Length Polymorphism) genotyping platform was used in six articles (Alagarasu et al., 2013; Cansancao et al., 2016; Chuansumrit et al., 2013; Feitosa et al., 2016; Garcia-Trejo et al., 2011; Sam et al., 2015). Methodological quality of the 10 articles, determined by NOS, was high with a mean of 7.0 ± 1.1 and a median of 7.0.

    View all citing articles on Scopus
    View full text