Tumor necrosis factor alpha promoter polymorphisms in Mexican patients with dengue fever
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.
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-α −308 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-α −238 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.
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