Polymorphism of interleukins and interleukin receptor genes: population distribution and association with atopic bronchial asthma

Population distribution and pathogenetic significance for bronchial asthma (BA) of the eight polymorphic variants of six interleukin--(IL) and interleukin receptor genes, C-589T, G/C 3'-UTR IL4, C-703T IL5, T113M IL9, Q551R, 150V IL4RA, and G1972A IL5RB, was examined. In the population samples of Russians, Tajiks, Buryats, and Tuvinians racial and ethnic specificity of these polymorphisms was established. These specific features were manifested as population-specific "enetic portraits" in respect of polymorphic allele frequencies. Analysis of the BA patients and their relatives from Tomsk by use of transmission/disequilibrium test (TDT) revealed the presence of a statistically significant association between the C-703 IL5 allele and the disease (P = 0.005). This is the first evidence of an association between the IL5 gene polymorphism and BA.     

M31R and R335C polymorphic variants of the IL8RA gene in Russian and Buryat patients with atopic bronchial asthma

To test the M31R and R335C polymorphisms of the Il8RA gene for association with atopic bronchial asthma (BA), the allele and genotype frequency distributions of the polymorphisms were studied in Russian patients from Moscow and Buryat patients from Ulan-Ude. The study involved two Russian groups, one including 291 DNA samples of patients with atopic BA, and the other, 266 DNA samples of healthy people. The two Buryat groups included 124 and 152 DNA samples from patients with atopic BA and healthy people, respectively. The M31R polymorphism proved to be associated with atopic BA in Russians. Allele Arg and genotype Met/Arg suggested a higher risk of BA (OR= 4.45, P = 0.003 and OR = 4.58, P = 0.003, respectively), while allele Met and genotype Met/Metwere associated with a lower risk (OR = 0.22, P = 0.003 and OR = 0.22, P = 0.003, respectively). The R335C polymorphism was not associated with atopic BA in Russians and was in Buryats. Allele Arg and homozygous genotype Arg/Arg suggested a higher risk of the disease (OR = 3.06, P = 0.030 and OR = 3.20, P = 0.027, respectively), while allele Cys and genotype Arg/Cys suggested a lower risk (OR = 0.33, P = 0.030 and OR = 0.31, P = 0.027, respectively). The results support the role of the IL8RA gene in atopic BA.     

Polymorphism of the Interleukin- and Interleukin Receptor Genes: Population Distribution and Association with Atopic Asthma

Population distribution and pathogenetic significance for bronchial asthma (BA) of the eight polymorphic variants of six interleukin- (IL) and interleukin receptor genes, C-589T, G/C 3"-UTRIL4, C-703T IL5 T113M IL9 Q551R, 150V IL4RA, G-80A IL5RA, and G1972A IL5RB, was examined. In the population samples of Russians, Tajiks, Buryats, and Tuvinians racial and ethnic specificity of these polymorphisms was established. These specific features were manifested as population-specific genetic portraits in respect of polymorphic allele frequencies. Analysis of the BA patients and their relatives from Tomsk by use of transmission/disequilibrium test (TDT) revealed the presence of a statistically significant association between the C-703 IL5 allele and the disease (P= 0.005). This is the first evidence of an association between the IL5 gene polymorphism and BA.     

<Emphasis Type="Italic">M31R</Emphasis> and <Emphasis Type="Italic">R335C</Emphasis> polymorphic variants of the <Emphasis Type="Italic">IL8RA</Emphasis> gene in Russian and Buryat patients with atopic bronchial asthma

To test the M31R and R335C polymorphisms of the Il8RA gene for association with atopic bronchial asthma (BA), the allele and genotype frequency distributions of the polymorphisms were studied in Russian patients from Moscow and Buryat patients from Ulan-Ude. The study involved two Russian groups, one including 291 DNA samples of patients with atopic BA, and the other, 266 DNA samples of healthy people. The two Buryat groups included 124 and 152 DNA samples from patients with atopic BA and healthy people, respectively. The M31R polymorphism proved to be associated with atopic BA in Russians. Allele Arg and genotype Met/Arg suggested a higher risk of BA (OR = 4.45, P = 0.003 and OR = 4.58, P = 0.003, respectively), while allele Met and genotype Met/Met were associated with a lower risk (OR = 0.22, P = 0.003 and OR = 0.22, P = 0.003, respectively). The R335C polymorphism was not associated with atopic BA in Russians and was in Buryats. Allele Arg and homozygous genotype Arg/Arg suggested a higher risk of the disease (OR = 3.06, P = 0.030 and OR = 3.20, P = 0.027, respectively), while allele Cys and genotype Arg/Cys suggested a lower risk (OR = 0.33, P = 0.030 and OR = 0.31, P = 0.027, respectively). The results support the role of the IL8RA gene in atopic BA.     

Association study on IL4, IL13 and IL4RA polymorphisms in mite-sensitized persistent allergic rhinitis in a Chinese population

Background

The IL4, IL13, and IL4 receptor α chain (IL4RA) genes are candidate genes for atopic diseases. We hypothesized that the polymorphisms in these genes are associated with persistent allergic rhinitis (PER).

Objective

To investigate the association of the potential functional polymorphisms in IL4, IL13, and IL4RA with PER induced by house dust mites in a Chinese population.

Methods

Using the TaqMan method, we genotyped six single nucleotide polymorphisms (SNPs) including C-590T in IL4, C-1055T and Arg130Gln in IL13, and Ile50Val, Ser478Pro and Gln551Arg in IL4RA, in a case-control study of 265 patients with PER and 275 healthy controls.

Results

We found that the CT/CC genotypes in IL4 C-590T were associated with a significantly decreased risk of mite-sensitized PER [adjusted odds ratio (OR)  = 0.64, 95% confidence interval (CI) 0.45–0.92], compared to the TT genotype. Furthermore, PER patients with CT/CC genotypes had significantly lower serum levels of total IgE than those with TT genotype (P = 0.001). However, there was no significant association of the IL13 and IL4RA polymorphisms with mite-sensitized PER (P>0.05).

Conclusions

Our results suggest that the C-590T polymorphism in IL4 may contribute to the susceptibility to mite-sensitized PER in a Chinese population.     

The CTLA-4 +49 A/G and ?318 C/T polymorphisms and susceptibility to asthma: a meta-analysis

The aim of this study was to explore whether cytotoxic T lymphocyte antigen-4 (CTLA-4) +49 A/G, and -318 C/T polymorphisms confer susceptibility to asthma. A meta-analysis was conducted on the associations between the CTLA-4 +49 A/G, and -318 C/T polymorphisms and asthma using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. Eight studies on the CTLA-4 polymorphisms and asthma involving 2,330 patients with asthma and 1,743 control subjects were included in this meta-analysis. The meta-analysis revealed an association between asthma and the CTLA-4 +49 A/G polymorphism under the dominant model in Asians (OR = 0.758, 95 % CI = 0.599-0.958, p = 0.020). Stratification by age indicated an association between the CTLA-4 +49 GG+GA genotype and asthma in children (OR = 0.690, 95 % CI = 0.497-0.957, p = 0.026), but not in adults (OR = 0.837, 95 % CI = 0.598-1.172, p = 0.300). Furthermore, stratification by atopy status indicated an association between the CTLA-4 +49 G allele and atopic asthma (OR = 0.639, 95 % CI = 0.464-0.881, p = 0.006), but not non-atopic asthma (OR = 0.706, 95 % CI = 0.385-1.294, p = 0.266). There was no association between asthma and the CTLA-4 -318 C/T polymorphism for the whole population, or when stratified by ethnicity, age, or atopy status. This meta-analysis demonstrates that the CTLA-4 +49 A/G polymorphism confers susceptibility to asthma in Asians, children, patients with atopy status, but there was no association between the CTLA-4 -318 C/T polymorphism and asthma susceptibility.     

Association analysis of the common varieties of IL17A and IL17F genes with the risk of knee osteoarthritis

Osteoarthritis is mediated by various types of cytokines, growth factors, and inflammatory factors that the role of the interleukin-17 family in this disease is becoming increasingly apparent. The aim of this study is to determine the association between the common polymorphisms of IL17A (including rs2275913) and IL17F (including rs2397084 and rs763780) genes with the knee osteoarthritis risk which was followed by a bioinformatics approach. In a case-control study, 254 participants consisting of 127 healthy individuals and 127 subjects with knee osteoarthritis referring to Shahid Beheshti Hospital dependents on Kashan University of Medical Sciences (Kashan, Iran) were enrolled. After samples collection, the polymorphisms genotyping was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Finally, some bioinformatics tools were used to analyze the molecular effects of the three studied polymorphisms. Data analysis showed a significant association between rs2275913-GA genotype and the decreased risk of knee osteoarthritis (OR = 0.57, 95% CI = 0.33-0.97, P = .040). However, rs763780-AG genotype (OR = 2.29, 95%CI = 1.11-4.69, P = .024) and rs763780-G allele (OR = 2.01, 95% CI = 1.09-3.72, P = .026) were associated with an increased risk of knee osteoarthritis. However, no significant associations were found between the rs2397084 polymorphism and knee osteoarthritis risk. Our structural analysis revealed that the rs2275913 polymorphism could create a new binding site for TFII-I at the promoter region of IL17A. Also, rs2397084 and rs763780 could significantly affect the function and structure of IL17A. Based on our findings, rs2275913 and rs763780 could be considered as protective and risk factors for knee osteoarthritis, respectively. Therefore, these polymorphisms can be considered as biomarkers for the screening of knee osteoarthritis susceptible persons.     

Analysis of the association between the T113M polymorphism of the human il-9 gene and bronchial asthma

The T113M polymorphism resulting from the missense mutation in exon 5 of the human interleukin 9 (IL9) gene was tested for association with bronchial asthma (BA). The genotype frequency analysis did not reveal a deviation from the Hardy-Weinberg equilibrium. A comparison of the genotype frequency distributions in a control group of healthy individuals and in patients with BA suggested an association between T113M and the clinical phenotype. However, this association was not confirmed by the affected family-based association control (AFBAC) or the transmission/disequilibrium test (TDT).     

CARD15 and TLR4 genes polymorphisms in atopic bronchial asthma

In order to investigate whether single nucleotide polymorphisms G(+2722)C and 3020insC in CARD15 gene and Asp299Gly in TLR4 gene contribute to atopic bronchial asthma we performed a comparative analysis of alleles and genotypes frequencies of these polymorphisms in Russian patients from Moscow. DNA samples from 283 patients with atopic bronchial asthma and 227 healthy donors were genotyped. There were associations neither of G(+2722)C and 3020insC in CARD15 gene and Asp299Gly in TLR4 gene with asthma nor of markers of CARD15 gene with asthma severity. Haplotype frequency analysis of CARD15 gene polymorphisms did not reveal significant difference between groups. However, a strong association was found between Asp299Gly and asthma severity. Allele Asp of this marker showed association with mild atopic bronchial asthma and allele Gl--with moderate/severe asthma = 0.47, 95% CI [0.24-0.93] i OR = 2.12, 95% CI [1.08-4.18] respectively).     

Gene-Gene Interaction in Asthma: IL4RA and IL13 in a Dutch Population with Asthma

Asthma is a common respiratory disease that is characterized by variable airways obstruction caused by acute and chronic bronchial inflammation; associated phenotypes include bronchial hyperresponsiveness (BHR), elevated total serum immunoglobulin E (IgE) levels, and skin tests positive to common allergens. Binding of interleukin-13 (IL13) or interleukin-4 (IL4) to the IL4 receptor (IL4R) induces the initial response for Th2 lymphocyte polarization. Both IL13 and IL4 are produced by Th2 cells and are capable of inducing isotype class-switching of B-cells to produce IgE after allergen exposure. These cytokines also share a common receptor component, IL4R alpha. We have investigated five IL4RA single-nucleotide polymorphisms in a population of Dutch families ascertained through a proband with asthma. By considering the probands and their spouses as an unrelated sample, we observed significant associations of atopy and asthma-related phenotypes with several IL4RA polymorphisms, including S478P and total serum IgE levels (P=.0007). A significant gene-gene interaction between S478P in IL4RA and the -1111 promoter variation in IL13, previously shown to be associated with BHR (P=.003), was detected. Individuals with the risk genotype for both genes were at almost five times greater risk for the development of asthma compared to individuals with both non-risk genotypes (P=.0004). These data suggest that variations in IL4RA contribute to elevated total serum IgE levels, and interaction between IL4RA and IL13 markedly increases an individual's susceptibility to asthma.     

Interactions between IL17A, IL23R, and STAT4 polymorphisms confer susceptibility to intestinal Behcet's disease in Korean population

AimsAlthough polymorphisms in IL23R have recently been proposed to predispose to Behcet's disease (BD), associations between IL23R polymorphisms and intestinal BD have yet to be elucidated. We therefore performed a study to evaluate whether IL17A, IL23R, and STAT4 polymorphisms are associated with susceptibility to intestinal BD in the Korean population.Main methodsSingle nucleotide polymorphisms (SNP) in the IL17A, IL23R, and STAT4 genes were analyzed using DNA sequencing, denaturing high performance liquid chromatography, and TaqMan genotyping assays.Key findingsIndividual polymorphism analysis revealed that the TT genotype of IL17A rs8193036 (odds ratio (OR) 2.10, 95% confidence interval (CI) (1.12–3.92), p = 0.021), and GG + GT genotype of IL23R rs1884444 (OR 1.92, 95% CI (1.03–3.57), p = 0.034) was associated with the development of intestinal BD. When these two genotypes were combined, the risk of BD increased compared to that of patients with no-risk or one-risk genotype (OR 2.21, 95% CI (1.13–4.34), p = 0.021). Furthermore, statistically significant gene–gene interactions were observed between G149R in IL23R vs. rs11685878 in STAT4, rs2275913 in IL17A vs. rs7574865 in STAT4, and rs11889341 in STAT4 vs. rs2275913 in IL17A. The haplotypes of IL17A had a positive association with intestinal BD risks, whereas those of IL23R were protective for disease development.SignificanceOur results indicate that the interaction of specific IL17A, IL23R, and STAT4 SNPs modulate susceptibility to intestinal BD in the Korean population, suggesting that the IL-17/23 axis plays a significant role in disease pathogenesis.     

Association of interleukin (IL)-12 and IL-27 gene polymorphisms with chronic obstructive pulmonary disease in a Chinese population

The pathogenesis of chronic obstructive pulmonary disease (COPD) is not fully understood, and environment and genetic factors have been investigated. Moreover, cytokine genes play an important role in COPD pathogenesis. However, the molecular mechanism of COPD induced by the factors is still unknown. The present study was undertaken to clarify a role of interleukin (IL)-12 16974A/C and IL-27 4730T/C, -964A/G, and 2905T/G polymorphisms in Chinese subjects with COPD. Polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) and sequence analyses were used to type IL-12 and IL-27 polymorphisms in 120 patients with COPD and 100 healthy controls. There were significant differences in the genotype and allele distribution of -964A/G and 2905T/G polymorphisms of the IL-27 gene among cases and controls in a Chinese population. When compared with the control group, subjects with AG genotype of the IL-27 -964A/G had a 2.22-fold decreased risk of COPD (odds ratio [OR] = 0.450, 95% confidence interval [CI]: 0.245-0.826; p = 0.009), and subjects with TG genotype of the IL-27 2905T/G had a 2.85-fold decreased risk of COPD (OR = 0.351, 95% CI: 0.137-0.899; p = 0.024). Compared with the TAT haplotype, the TGG haplotype was associated with a significantly decreased risk of COPD (OR = 0.29, 95% CI: 0.108-0.784; p = 0.010). Even after Bonferroni corrections, significant associations with COPD were observed for the AG genotype of the IL-27 -964A/G and the TGG haplotype of the IL-27 gene. Our data suggest that polymorphisms in the IL-27 gene may play a role in the development of COPD in Chinese population.     

Association of interleukin-13 gene polymorphisms with atopic bronchial asthma

A comparative analysis of allele and genotype distribution of C(−1055)T and R130Q IL13 gene polymorphisms has been performed in Russian patients from the Moscow region. In the study, 283 DNA specimens of atopic bronchial asthma (BA) patients and 227 DNA specimens of healthy donors were used. No association of these markers with atopic BA development as well as with total IgE concentration has been found. Haplotype frequency analysis did not reveal significant difference between samples. However, significant association of C(−1055)T polymorphism with the disease severity has been revealed (OR = 2.39, 95% confidence interval 1.44–3.98, p = 0.001). Therefore, C(−1055)T polymorphism was shown to be associated with atopic BA progression.     

Association and interaction of the IL4R,IL4, and IL13 loci with type 1 diabetes among Filipinos

In the search for genes involved in type 1 diabetes (T1D), other than the well-established risk alleles at the human leukocyte antigen loci, we have investigated the association and interaction of polymorphisms in genes involved in the IL4/IL13 pathway in a sample of 90 Filipino patients with T1D and 94 controls. Ten single-nucleotide polymorphisms (SNPs), including two promoter SNPs in the IL4R locus on chromosome 16p11, one promoter SNP in the IL4 locus on chromosome 5q31, and four SNPs--including two promoter SNPs--in the IL13 locus on chromosome 5q31 were examined for association, linkage disequilibrium, and interaction. We found that both individual SNPs (IL4R L389L; odds ratio [OR] 0.34; 95% confidence interval [CI] 0.17-0.67; P=.001) and specific haplotypes both in IL4R (OR 0.10; 95% CI 0-0.5; P=.001) and for the five linked IL4 and IL13 SNPs (OR 3.47; P=.004) were strongly associated with susceptibility to T1D. Since IL4 and IL13 both serve as ligands for a receptor composed, in part, of the IL4R alpha chain, we looked for potential epistasis between polymorphisms in the IL4R locus on chromosome 16p11 and the five SNPs in the IL4 and IL13 loci on chromosome 5q31 and found, through use of a logistic-regression model, significant gene-gene interactions (P=.045, corrected for multiple comparisons by permutation analysis). Our data suggest that the risk for T1D is determined, in part, by polymorphisms within the IL4R locus, including promoter and coding-sequence variants, and by specific combinations of genotypes at the IL4R and the IL4 and IL13 loci.     

CARD15 and TLR4 polymorphisms in atopic bronchial asthma

In order to investigate whether single nucleotide polymorphisms G(+2722)C and 3020insC of CARD15 and Asp299Gly of TLR4 contribute to atopic bronchial asthma, we performed a comparative analysis of allele and genotype frequencies of these polymorphisms in Russian patients from Moscow. DNA specimens obtained from 283 patients with atopic bronchial asthma and 227 healthy donors were genotyped. Neither G(+2722)C or 3020insC in CARD15 nor Asp299Gly in TLR4 were associated with asthma; CARD15 polymorphisms were not also associated with asthma severity. A haplotype frequency analysis of CARD15 polymorphisms did not detect significant differences between the groups studied. However, a strong association was found between Asp299Gly and asthma course: the Asp allele was associated with mild disease, while the minor Gly allele was associated with moderate/severe asthma (OR = 0.47, 95% CI [0.24–0.93] and OR = 2.12, 95% CI [1.08–4.18], respectively).     

Association of IL1R polymorphism with HLA-B27 positive in Iranian patients with ankylosing spondylitis

Ankylosing spondylitis (AS) is one of the most common causes of inflammatory arthritis, with an estimated prevalence of 0.1-0.9%. Genetic factors have been strongly implicated in its aetiology, and heritability as assessed by twin studies has been estimated to be >90%. HLA- B27 is almost essential for inheritance of AS; it is not merely sufficient for explaining the pattern of familial recurrence of the disease. This study's purpose is to investigate the association of ankylosing spondylitis with single-nucleotide polymorphisms (SNPs) in the IL-1 family: IL-1a (-889C/T) rs1800587, IL-1b (-511C/T) rs16944, IL-1b (+3962C/T) rs1143634, IL-1R (Pst-1 1970C/T) rs2234650 and IL-1RA (Mspa-1 11100C/T) rs315952. 99 unrelated Iranian AS patients and 217 healthy control subjects were selected. Cytokine typing was performed by the polymerase chain reaction with sequence-specific primers assay. The allele and genotype frequencies of the polymorphisms were determined: The IL1α rs1800587, IL1β rs16944 and IL1β rs1143634 were not significantly associated with AS. Genotype frequencies at IL1R rs2234650 differed between cases and controls (χ(2)=8.85; p=0.01); the IL1R rs2234650 C/T and T/T genotypes were less common in AS patients than controls. The IL1R rs2234650 C/T genotype was inversely associated with AS comparing with the IL1R rs2234650 C/C genotype (OR=0.48; p=0.005). IL1R rs2234650 C/T genotype was less common in patients than controls (OR=0.37; p=0.02).Furthermore IL1R rs2234650 T allele was strongly associated with HLA-B2702 patients rather than HLA-B2705 but was not associated with HLA-B27 negative patients (OR=0.33; p=0.01). Polymorphisms of IL1α rs1800587, IL1β rs16944 and IL1β rs1143634 were not significantly associated with ankylosing spondylitis but inversely in this study IL1R rs2234650 was significantly associated and carriage of T allele in IL1R rs2234650 seems to be protective, while carriage of C allele result in two fold higher risk of developing AS.     

Association between single-nucleotide polymorphisms in pre-miRNAs and the risk of asthma in a Chinese population

Single-nucleotide polymorphisms (SNPs) in pre-miRNAs may alter microRNA (miRNA) expression levels or processing and contribute to susceptibility to a wide range of diseases. We investigated the correlation between four SNPs (rs11614913, rs3746444, rs2910164, and rs229283) in pre-miRNAs and the risk of asthma in 220 asthma patients and 540 controls using polymerase chain reaction-restriction fragment length polymorphism methodology and DNA-sequencing. There were significant differences in the genotype and allelic distribution of rs2910164G/C and rs2292832C/T polymorphisms among cases and controls. The CC genotype and C allele of rs2910164G/C were significantly associated with a decreased risk of asthma (CC vs. GG, odds ratio [OR]?= 0.51, 95% confidence interval [CI]: 0.31-0.82; C vs. G, OR = 0.74, 95% CI: 0.59-0.93). Similarly, the TT genotype and T allele of rs2292832C/T were significantly associated with a decreased risk of asthma (TT vs. CC, OR = 0.56, 95% CI: 0.33-0.95; T vs. C, OR = 0.71, 95% CI: 0.53-0.95). However, no significant association between the other two polymorphisms (i.e., rs11614913C/T and rs3746444C/T) and the risk of asthma was observed. Our data indicate that rs2910164G/C and rs2292832C/T may play a role in the development of asthma.     

Single Nucleotide Polymorphisms in IL17A and IL6 Are Associated with Decreased Risk for Pulmonary Tuberculosis in Southern Brazilian Population

In Mycobacterium tuberculosis (MTB) infection, the complex interaction of host immune system and the mycobacteria is associated with levels of cytokines production that play a major role in determining the outcome of the disease. Several single-nucleotide polymorphisms (SNPs) in cytokine genes have been associated with tuberculosis (TB) outcome. The aim of this study was to evaluate the association between previously reported SNPs IL2–330 T>G (rs2069762); IL4–590 C>T (rs2243250); IL6–174 G>C (rs1800795); IL10–592 A>C (rs1800872); IL10–1082 G>A (rs1800896); IL17A -692 C>T (rs8193036); IL17A -197 G>A (rs2275913); TNF -238 G>A (rs361525); TNF -308 G>A (rs1800629) and IFNG +874 T>A (rs2430561) and pulmonary TB (PTB) susceptibility. We conducted a case-control study in individuals from Southern Brazil who were recruited between February 2012 and October 2013 in a high incidence TB city. We performed a multiplex genotyping assay in 191 patients with PTB and 175 healthy subjects. Our results suggest a decreased risk for PTB development associated with the IL17A -197A allele (OR = 0.29; p = 0.04), AA genotype (OR = 0.12; p = 0.04) and A carrier (AG/AA) (OR = 0.29; p = 0.004) and IL6 -174C carrier (CC/CG) (OR = 0.46; p = 0.04). We could not properly analyze IL17A -692 C>T (rs8193036) and IFNG +874T>A due to genotypic inconsistencies and found no evidence of association for the IL2, IL4, IL10 and TNF polymorphisms and PTB. In conclusion, our results show a protective effect of IL17 and IL6 polymorphisms on PTB outcome in Southern Brazilian population.     

Toll-like receptor 2 and Toll-like receptor 4 polymorphisms and susceptibility to asthma and allergic rhinitis: a case-control analysis

The aim of the study was to investigate whether polymorphisms in genes encoding Toll-like receptors (TLR2 and TLR4) may modify relative risk for development of asthma or allergic rhinitis. The results showed that the genotype and allele frequencies of the TLR2 Arg753Gln and TLR4 Asp299Gly polymorphisms were not significantly different between asthmatic children or allergic rhinitis when compared to controls (p>0.05 for each) or even when compared further with IgE level. However, it was shown that the mutant allele of TLR2 or TLR4 polymorphisms were significantly associated with the moderate-severe group compared to the mild group in both atopic asthmatics and allergic rhinitis group (p>0.001 for each). In conclusion, our study demonstrates a lack of association of TLR2 and TLR4 polymorphisms with asthma and allergic rhinitis but suggests significant association between these genetic variants and the disease severity.     

TNF,IL6, and IL1B Polymorphisms Are Associated with Severe Influenza A (H1N1) Virus Infection in the Mexican Population

Background

Hypercytokinemia is the main immunopathological mechanism contributing to a more severe clinical course in influenza A (H1N1) virus infections. Most patients infected with the influenza A (H1N1) pdm09 virus had increased systemic levels of pro-inflammatory cytokines; including interleukin IL-6, IL-8, and tumor necrosis factor-alpha (TNF-α). We propose that single-nucleotide polymorphisms (SNPs) in the promoter regions of pro-inflammatory genes are associated with the severity of influenza A (H1N1) pdm09 virus infection.

Methods

145 patients with influenza A (H1N1) (pA/H1N1), 133 patients with influenza-like illness (ILI), and 360 asymptomatic healthy contacts (AHCs) were included. Eleven SNPs were genotyped in six genes (TNF, LT, IL1B, IL6, CCL1, and IL8) using real-time PCR; the ancestral genotype was used for comparison. Genotypes were correlated with 27 clinical severity variables. Ten cytokines (GM-CSF, TNF-α, IL-2, IL-1β, IL-6, IL-8, IFN-γ, IL-10, IL-5, and IL-4) were measured on a Luminex 100.

Results

The IL6 rs1818879 (GA) heterozygous genotype was associated with severe influenza A (H1N1) virus infection (odds ratio [OR] = 5.94, 95% confidence interval [CI] 3.05–11.56), and two IL1B SNPs, rs16944 AG and rs3136558 TC, were associated with a decreased risk of infection (OR = 0.52 and OR = 0.51, respectively). Genetic susceptibility was determined (pA/H1N1 vs. AHC): the LTA rs909253 TC heterozygous genotype conferred greater risk (OR = 1.9), and a similar association was observed with the IL1B rs3136558 CC genotype (OR = 1.89). Additionally, severely ill patients were compared with moderately ill patients. The TNF-238 GA genotype was associated with an increased risk of disease severity (OR = 16.06, p = 0.007). Compared with ILIs, patients with severe pA/H1N1 infections exhibited increased serum IL-5 (p <0.001) and IL-6 (p  =  0.007) levels.

Conclusions

The TNF gene was associated with disease severity, whereas IL1B and IL6 SNPs were associated with influenza A (H1N1) virus infection.