Pandemic influenza A/H1N1 virus infection and TNF, LTA, IL1B, IL6, IL8, and CCLpolymorphisms in Mexican population: a case–control study
- Guadalupe Morales-García†1,
- Ramcés Falfán-Valencia2,
- Román Alejandro García-Ramírez†1,
- Ángel Camarena2,
- Alejandra Ramirez-Venegas2,
- Manuel Castillejos-López2,
- Martha Pérez-Rodríguez1,
- César González-Bonilla3,
- Concepción Grajales-Muñíz3,
- Víctor Borja-Aburto3 and
- Juan Manuel Mejía-Aranguré1Email author
© Morales-García et al.; licensee BioMed Central Ltd. 2012
Received: 24 February 2012
Accepted: 6 November 2012
Published: 13 November 2012
Some patients have a greater response to viral infection than do others having a similar level of viral replication. Hypercytokinemia is the principal immunopathological mechanism that contributes to a severer clinical course in cases of influenza A/H1N1. The benefit produced, or damage caused, by these cytokines in severe disease is not known. The genes that code for these molecules are polymorphic and certain alleles have been associated with susceptibility to various diseases. The objective of the present study was to determine whether there was an association between polymorphisms of TNF, LTA, IL1B, IL6, IL8, and CCL1 and the infection and severity of the illness caused by the pandemic A/H1N1 in Mexico in 2009.
Case–control study. The cases were patients confirmed with real time PCR with infection by the A/H1N1 pandemic virus. The controls were patients with infection like to influenza and non-familial healthy contacts of the patients with influenza. Medical history and outcome of the disease was registered. The DNA samples were genotyped for polymorphisms TNF rs361525, rs1800629, and rs1800750; LTA rs909253; IL1B rs16944; IL6 rs1818879; IL8 rs4073; and CCL1 rs2282691. Odds ratio (OR) and the 95% confidence interval (95% CI) were calculated. The logistic regression model was adjusted by age and severity of the illness in cases.
Infection with the pandemic A/H1N1 virus was associated with the following genotypes: TNF rs361525 AA, OR = 27.00; 95% CI = 3.07–1248.77); LTA rs909253 AG (OR = 4.33, 95% CI = 1.82–10.32); TNF rs1800750 AA (OR = 4.33, 95% CI = 1.48–12.64); additionally, LTA rs909253 AG showed a limited statistically significant association with mortality (p = 0.06, OR = 3.13). Carriers of the TNF rs1800629 GA genotype were associated with high levels of blood urea nitrogen (p = 0.05); those of the TNF rs1800750 AA genotype, with high levels of creatine phosphokinase (p=0.05). The IL1B rs16944 AA genotype was associated with an elevated number of leukocytes (p <0.001) and the IL8 rs4073 AA genotype, with a higher value for PaO2 mm Hg.
The polymorphisms of genes involved in the inflammatory process contributed to the severity of the clinical behavior of infection by the pandemic influenza A/H1N1 virus.
KeywordsTNF IL1B IL8 IL6 LTA CCL1 Influenza AH1N1
The influenza A/H1N1 virus pandemic of 2009 started in Mexico and then spread worldwide, with an alert level of pandemic phase 6 declared by the World Health Organization (WHO) in June of that year . Although the majority of those infected by the influenza A/H1N1 virus presented mild symptoms that were self-limiting, a subgroup of patients followed an adverse clinical course, thus requiring a greater level of medical attention and more aggressive management . In Mexico the lethal rate was estimated to be 1.2% for cases of influenza-like illness (ILI) and 5% for confirmed cases of influenza A/H1N1 . Some co-morbidities (e.g., immunosuppression, pre-existing pulmonary disease, cardiac disease, diabetes, asthma that requires regular medical attention, smoking, and obesity) have been demonstrated to increase the risk of hospitalization for infection with influenza A/H1N1 [4, 5]. The risk is also augmented in the second and third trimesters of pregnancy and when treatment with oseltamivir is prescribed five days after the onset of the illness . In addition, the results of certain laboratory tests (e.g., lactate dehydrogenase (LDH), >600 IU/L; hypoxemia (PaO2, <60 mm Hg); C-reactive protein (CRP), 10 mg/dl; and leukopenia <5000/mm3) have been associated with greater mortality from infection by influenza A/H1N1 virus [7, 8].
Through experimental and clinical studies, it has been determined that the most important pathological mechanism in this infection is systemic dysregulation of the inflammatory response, which is correlated with the severity and progression of the illness [9, 10]. The secretion of cytokines by infected cells appears to be necessary for the initiation of the immunological response that controls the replication of the virus ; in addition, the presence of immunopathological mechanisms, such as hypercytokinemia (“cytokine storm”), generally is considered to contribute to the severest evolution of the infection [11–13]. Elevated levels of pro-inflammatory cytokines and chemokines (e.g., TNFα, IFNγ, IL-1, IL-6, IL-8, IL-9, IL-12 IL-15, and IL-17) have been found, up to ten days after the onset of symptoms, in the plasma of patients with acute respiratory distress syndrome (ARDS) caused by influenza A/H1N1 [9, 10, 14]. The genes that code for these molecules are polymorphic and certain alleles have been associated with susceptibility to various diseases that cover a wide range of pathologies, from infectious to oncological, including pulmonary and systemic diseases [15–30]. The role that the polymorphisms of the genes encoding these cytokines play in the severity of the disease is not clear.
The extensive polymorphism of these molecules may be associated with the high mortality rate during the 2009 influenza A/H1N1 pandemic in Mexico. Because we think that genetic factors of the host may influence the nature and intensity of the inflammatory immune response, the objective of this study was to determine whether the polymorphisms of genes that are associated with inflammation may be associated with the development of the infection and with the clinical severity in Mexican mestizo patients with influenza A/H1N1.
The rapid QuickVue Influenza A+B test (Quidel, San Diego, CA, USA) was used to analyze the nasopharyngeal swab samples obtained from the patients in 94 cases of suspected infection by influenza A/H1N1, following the recommendations for collection and testing of the U.S. Centers for Disease Control and Prevention (CDC) and of the WHO [31, 32]. The patients were then separated into two groups: those positive for influenza A/H1N1 (A/H1N1 group) and those negative, as having influenza-like illness (ILI group). A total of 44 patients were positive for the influenza A/H1N1 virus (A/H1N1 group); the remaining 50 patients who had tested negative for the influenza A/H1N1 virus, were diagnosed as having influenza-like illness (ILI).
In addition, a group of 176 asymptomatic healthy contacts (AHC group) voluntarily participated in the study. Those in the AHC group, although not biologically related to any patient, were in personal contact with at least one of the patients during the period of the illness. To ensure that those in the AHC group had been exposed to the virus, their titers of anti-influenza A/H1N1 antibodies were determined. To evaluate the presence of antibody, we use haemagglutination inhibition technique (HAI); contacts exhibited significant titers of specific anti-A/H1N1 antibodies, supporting the fact that they were in contact with the A/H1N1 virus. By serially diluted aliquots of serum samples; those individuals with titers greater than 1:16 were considered positive for A/H1N1 infection/exposure. The two patient groups and the AHC group were Mexican mestizos (age range: 18–85 years). All patients suspected of influenza A/H1N1 infection were treated with anti-viral therapy (oseltamivir) upon admittance at the hospital.
The information collected in this study included demographic, clinical history, laboratory test data, pharmacological treatment, and follow-up. This study was approved by the Institutional Committee of Science and Bioethics of the National Institute of Respiratory Diseases (code B05-10). The study protocol was explained to all participants and signed informed consent was duly obtained from each participant. This information was obtained by means of a clinical form in accord with Official Mexican Standards Mexicana NOM-168-SSA1-1998; topics covered included age; gender; tobacco smoking; body-mass index (BMI; patients with BMI >30 k/m2); and disease morbidity (pulmonary, hepatic, renal, cardiac, neurological diseases, diabetes mellitus, hypertension, and cancer). The symptoms evaluated were fever, cough, rhinorrhea, dyspnea, nasal congestion, thoracic pain, headache, diarrhea, and vomiting. The begin of anti-viral therapy was evaluated in relation to the days with previous symptomatology. The laboratory parameters included were leukocyte titer; lactate dehydrogenase (LDH); creatine phosphokinase (CPK); blood urea nitrogen (BUN); and arterial gases (with PaO2 <60 mm Hg defined as severe disease). Pneumonia was verified by radiological findings. All patients admitted to the intensive care unit (ICU) and those put on assisted mechanical ventilation (AMV) were identified.
Genotyping of allelic variants (single nucleotide polymorphism, SNPs)
DNA samples were genotyped by using Taqman commercial probes
Gene (reference SNP)
Genetic data of the single nucleotide polymorphisms (SNPs) analyzed
When the polymorphisms were evaluated, the ancestral genotype was used for comparison. The odds ratio (OR) and the 95% confidence interval (95% CI) were calculated. In the logistic regression model, the OR was adjusted by age and severity of the illness. The χ2 test was used to evaluate the differences between the proportions of the groups. The differences among the clinical parameters, continuous variables, and polymorphisms were evaluated by using the Mann–Whitney U test. Software packages SPSS 19 (IBM, Chicago, IL) and Epi-Info 6.04b were used (Atlanta, CDC).
The patients were separated into two groups depending whether they were positive or negative for influenza A/H1N1, thereby forming the groups, influenza A/H1N1 and ILI, respectively. In both the A/H1N1 and ILI groups, the majority was male (68.0% and 58.0%, respectively), whereas in the AHC group, 61.93% were female. The mean age of the A/H1N1 and ILI groups was <45 years (68.18% and 60.0%, respectively), compared to that of the AHC group, 56.82% of who were 45–64 years of age.
Demographical and clinical characteristics of influenza A/H1N1 patients, influenza-like illness (ILI) patients, and healthy control subjects
P a O 2 <60 mm Hg (severe)
Analysis of genetic association
Genetic frequency of the genotypes of eight SNPs in six genes and their association with infection by influenza A/H1N1 virus
Gene and genotype
For the A/H1N1 and AHC groups, of the eight SNPs used, 24 genotype products were generated; in the ILI group, only 23 genotypes were determined, as the genotype AA does not exist for the rs361525 of the gene TNF. For the A/H1N1 group, five genotypes associated with risk were identified (p <0.05; OR >2.0). Of particular interest was the finding of homozygous A genotype in SNPs rs361525 and rs1800750 in TNF, both with values of OR >5.0. In addition, the genotypes rs2282691 AA, rs4073 AT, and rs909253 CT (CCL1, IL8, and LTA, respectively) demonstrated statistically significant association with risk. For the ILI group, three of the five associations previously reported for the A/H1N1 group were found. It is of note that these associations, which coincided in both patient groups, showed statistically significant data (p values and OR) that were very similar. On the other hand, our findings demonstrated the existence of three genotypes with association to protection (p <0.05; OR ≤1.0): IL1B rs16944 AA, LTA rs909253, and TNF rs1800750 GG, in both patient groups, as compared to the AHC group (Table 4).
Risk of influenza A/H1N1 infection in relation to the different polymorphisms studied
Risk of influenza A/H1N1 infection
OR (95% CI)
OR allelic (95% CI)
Association of genotypes with clinical variables
Risk of death from influenza A/H1N1 in relation to the different polymorphisms studied
OR (CI 95%)
OR allelic (CI 95%)
Polymorphisms and laboratory tests
No changes in laboratory parameters were found with respect to the genotypes of the SNPs in TNF rs361525, LTA rs909253, CCL1 rs2282691, or IL6 rs1818879 ( Additional file 1: Table S1). For the homozygous genotype AA of rs16944 in IL1B, an elevated number of leukocytes was found (mean: 44.9 × 103/mm3), whereas for the heterozygous genotype AG and the homozygous genotype GG, the mean titer values were 8.62 ×103/mm3 and 6.96 ×103/mm3, respectively (p <0.001). The genotype AG in rs1800629 in TNF was associated with elevated levels of BUN (33mg/dl), whereas for the genotype GG, the BUN levels were lower (p =0.05) (Additional file 1: Table S1). The genotype AA of rs1800750 in TNF showed high levels of CPK (mean: 2246.25 IU/L), whereas the genotypes GG and AG had mean values of 366.32 IU/L and 450.00 IU/L, respectively (p=0.05).
Although it has been reported that some of the genes involved in inflammation are associated with pulmonary and infectious diseases [16, 17, 21, 25–28], to date, no direct association between these polymorphisms and infection by influenza A/H1N1 virus has been reported. In the present study, the logistic regression analysis of cases and controls showed that TNF rs361525 (AA), rs1800750 (AA), and LTA rs909253 (AG) were associated with high risk of infection by pandemic influenza A/H1N1. Although mortality of the A/H1N1 patients was greater than that of the ILI patients (p <0.001), only genotype AG of LTA rs909253 demonstrated an association with mortality (p = 0.06) just missing being statistically significant. This finding may indicate that being a carrier of genotype AG LTA at rs909253 entails a poorer prognosis for this illness.
Some biomarkers, such as CRP, LDH, leukopenia, and hypoxemia [7, 8] have been considered as predictors for severe illness by influenza A/H1N1 virus. In this study, we found that elevated values of laboratory test parameters (BUN, CPK, and leukocyte titer) were associated with TNF (rs1800629 AG, rs1800750 AA), and IL1B (genotype AA). These results may indicate that being a carrier of these polymorphisms in particular may be associated with severer organic damage by infection by influenza A/H1N1 virus. However, in the case of IL8, the homozygous AA appeared to offer a certain degree of protection against severe illness; this may be explained, in part, by the association of a higher concentration of oxygen in the blood (PaO2 >60 mm Hg) with this genotype.
Although susceptibility for presenting an adverse clinical course (i.e., sepsis, septic shock, multiples organ failure, or death) varies due to different degrees of inflammatory response , genetic factors of the host may influence the nature and intensity of this response. The present study is the first to demonstrate that the polymorphisms in genes related to the inflammatory response may, in some manner, be influencing the risk of infection by influenza A/H1N1 virus and of death from this illness. One possible mechanism may be the formation of disequilibria in the bond between alleles, creating haplotypes that differentially affect the expression and activity of cytokines and chemokines, thereby resulting in a severer clinical course for the infection.
To avoid variability in our results, we studied a homogeneous population of Mexican mestizos. Although the sampling size was a limitation in our study, we were able to demonstrate statistically significant differences in the distribution of genotypes in terms of infection, mortality, and biomarkers between cases and controls, thus suggesting a strong association with the illness. However, infection by influenza A/H1N1 virus is a very complex illness that involves not only the association of environmental factors and the genetic make-up and biology of the individual per se, but also the presence of co-morbidities that may contribute to a greater severity of the illness [4, 5].
We had limitations. For example, contacts exhibited significant titers of specific anti-A/H1N1 antibodies, supporting the fact that they were in contact with the A/H1N1 virus. Additionally is necessary clear that is not a patients group, we just include unrelated contacts in this study (e.g. family in law persons, home workers, etc.). They were in close contact with patients when the latter exhibited acute respiratory illness. None of these household contacts developed respiratory illness. However, the presence of antibody would not confirm infection with A/H1N1 virus because there is the likelihood of cross-reactivity . But, when a person with positivity of antibodies that had contact with an A/H1N1 virus infected patient, the infection cannot be excluded . The gold standard for identifying the infection to A/H1N1 virus is real time PCR test; however to identify the presence of the virus in symptomatic patients is necessary that the patients be assessed during the first days from the beginning of the disease, the probability of identifying the virus by molecular test in asymptomatic patients is very low and not practical .
With the high mortality rate from the 2009 influenza A/H1N1 pandemic in Mexico , the approach used in this work could acquire great importance, as the study of polymorphisms may be useful in predicting the conduct that the infection would follow during future outbreaks of influenza A/H1N1 in Mexico.
The TNF polymorphisms studied were associated with risk of infection by influenza A/H1N1 virus during the pandemic in Mexico in 2009. These genetic variants may contribute to the severest clinical manifestations in Mexican mestizos.
Asymptomatic healthy contacts
Acute respiratory distress syndrome
Body mass index
Blood urea nitrogen
Chemokine (C-C motif) ligand 1
U.S: Centers for Disease Control and Prevention
95% Confidence interval
C- reactive protein
Global lethal rate
Intensive Care Unit
Partial pressure of oxygen in arterial blood
Single nucleotide polymorphism
Tumor necrosis factor
World Health Organization.
This study was funded by the Consejo Nacional de Ciencia y Tecnología (CONACyT), México and by CONACyT-Básica, SALUD2009-C02-127089. and CONACyT-FOSIS SALUD2009-C02-126699. The authors thank Veronica Yakoleff for translating the original Spanish manuscript and for helpful comments. The authors thank the Coordinación de Investigación en Salud of the IMSS for covering the cost of the translation and publication.
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