Association of IFNGR1 and IFNG genetic polymorphisms with the risk for pulmonary tuberculosis in the Chinese Tibetan population.
ABSTRACT: Interferon-gamma (IFNG) and its receptor (IFNGR1) are principal genes that associated with tuberculosis. In the current study we aimed to explore the genetic association of polymorphisms of IFNG and IFNGR1 with the risk of pulmonary tuberculosis (PTB) in the Chinese Tibetan population. We selected 467 PTB patients and 503 healthy controls to genotype 9 single nucleotide polymorphisms (SNPs). The unconditional logistic regression analysis was applied for assessing the associations, and the risk of PTB were evaluated by calculating the odds ratio (OR) and 95% confidence interval (CI). The results showed that mutants of rs9376268, rs1327475 and rs1327474 in IFNGR1 played a protective role in the PTB risk under genotype, dominant and additive model (P<0.05). On the contrary, minor allele "A" of rs2069705 in IFNG significantly increased the risk of PTB under genotype, dominant and additive model (P<0.05). However, after Bonferroni's multiple adjustment was applied to our data, which level of significant was set at P<0.0011 (0.05/45). Only variant of rs9376268 was significantly associated decrease the PTB susceptibility under additive model (OR=0.73, 95%CI=0.61-0.88, P<0.001). Furthermore, in the haplotype analysis, we found that the haplotypes "C-G-G-A-C", "C-G-A-G-T" and "T-A-G-G-T" of rs9376267-rs9376268-rs1327475-rs7749390-rs1327474 block were extremely decreased the PTB risk (P<0.01), however, the haplotypes "C-G-G-A-T", "T-G-G-G-T" and "C-G-G-G-T" of the block were extremely increased the PTB risk (P<0.01). These results suggested that variants of IFNGR1 may have a close relation with the PTB risk in Chinese Tibetan population.
Project description:Aim. The present study was undertaken to find out the possible association between interferon-gamma (IFN-?) receptor 1 (IFNGR1) gene polymorphisms and risk of pulmonary tuberculosis (PTB) in a sample of Iranian population. Methods. Polymorphisms of IFNGR1 rs1327474 (-611 A/G), rs11914 (+189 T/G), rs7749390 (+95 C/T), and rs137854905 (27-bp ins/del) were determined in 173 PTB patients and 164 healthy subjects. Results. Our findings showed that rs11914 TG genotypes decreased the risk of PTB in comparison with TT (OR = 0.36, 95% CI = 0.21-0.62, and p = 0.0002). The rs11914 G allele decreased the risk of PTB compared with T allele (OR = 0.41, 95% CI = 0.25-0.68, and p = 0.0006). IFNGR1 rs7749390 CT genotype decreased the risk of PTB in comparison with CC genotype (OR = 0.55, 95% CI = 0.32-0.95, and p = 0.038). No significant association was found between IFNGR1 rs1327474 A/G polymorphism and risk/protective of PTB. The rs137854905 (27-bp I/D) variant was not polymorphic in our population. Conclusion. Our findings showed that IFNGR1 rs11914 and rs7749390 variants decreased the risk of PTB susceptibility in our population.
Project description:Previous studies indicated that single-nucleotide polymorphisms (SNPs) of interferon gamma (IFNG) and IFNG receptor 1 (IFNGR1) may be involved in the pathogenesis of pulmonary tuberculosis (PTB) in different populations. In order to further explore the results in a Chinese Han population, this study was designed to investigate potential associations between the polymorphisms in IFNG and IFNGR1 and susceptibility to latent tuberculosis infection (LTBI) and/or PTB in a Chinese Han population. A total of 209 PTB, 173 LTBI, and 183 healthy control subjects (HCS) were enrolled in our study. Genotyping was conducted using an improved multiplex ligase detection reaction (iMLDR). We performed a logistic regression including sex and age as covariates to test the effect of alleles/genotypes on LTBI and/or TB. All six markers studied in IFNG and IFNGR1 conformed to the Hardy-Weinberg equilibrium (HWE). The IFNG rs1861494 was significantly associated with LTBI in recessive model, and the CC+CT genotype decreased risk of LTBI by 50% (P = 0.046, OR = 0.50, 95%CI: 0.25-0.99). The IFNGR1 rs2234711 was significantly associated with LTBI, and allele A increased the risk of LTBI by 55% (P = 0.047, OR = 1.55, 95%CI: 1.00-2.40). In the present study, we found that IFNG and IFNGR1 polymorphisms were associated with LTBI.
Project description:In this study, we aim to explore the correlation between single nucleotide polymorphisms (SNPs) in the P2X7R gene and pulmonary tuberculosis (PTB) susceptibility in the Tibetan Chinese population in China. We examined 467 patients with active PTB and 504 healthy controls living in Xi'an and the surrounding area. Eight P2X7R SNPs were genotyped, and association analysis was performed. Odds ratios (ORs) and 95% confidence intervals (CIs) were tested by unconditional logistic regression analysis to evaluate the effects of the polymorphisms on PTB risk. P2X7R SNP association analyses were performed using SPSS 17.0 statistical packages and Microsoft Excel, SNP statistics software, Haploview software package (version 4.2), and SHEsis software platform. The results show that the "C" allele of rs656612 in the P2X7R gene was associated with an increased PTB risk by the additive model (OR = 1.307, 95% CI = 1.088-1.570, P = 0.004) and dominant model (rs656612, OR = 1.490, 95% CI = 1.153-1.926, P = 0.002). The "A" allele of rs208290 showed an increased PTB risk by the additive model (OR = 1.418, 95% CI = 1.179-1.706, P < 0.001) and dominant model (OR = 1.680, 95% CI = 1.297-2.177, P < 0.001), whereas the "A" allele of rs7958311 showed an increased risk by the additive model (rs7958311, OR = 1.260, 95% CI = 1.055-1.505, P = 0.011) and recessive model (OR = 1.609, 95% CI = 1.200-2.158, P = 0.001). After Bonferroni correction, rs208290 was found to be associated with PTB in the allele, dominant, and genotype models. In conclusion, our study revealed a significant association between three P2X7R gene polymorphisms (rs656612, rs208290, and rs7958311) and PTB in a Tibetan Chinese population.
Project description:Tuberculosis (TB) has substantial mortality worldwide with 5-10% of those exposed progressing to active TB disease. Studies in mice and humans indicate that the inducible nitric oxide synthase (iNOS) molecule plays an important role in immune response to TB. A mixed case-control association study of individuals with TB, relatives, or close contact controls was performed in 726 individuals (279 case and 166 control African-Americans; 198 case and 123 control Caucasians). Thirty-nine single nucleotide polymorphisms (SNPs) were selected from the NOS2A gene for single SNP, haplotype, and multilocus interaction analyses with other typed candidate genes using generalized estimating equations. In African-Americans, ten NOS2A SNPs were associated with TB. The strongest associations were observed at rs2274894 (odds ratio (OR) = 1.84, 95% confidence interval (CI) [1.23-2.77], p = 0.003) and rs7215373 (OR = 1.67, 95% CI [1.17-2.37], p = 0.004), both of which passed a false discovery rate correction for multiple comparisons (q* = 0.20). The strongest gene-gene interactions were observed between NOS2A rs2248814 and IFNGR1 rs1327474 (p = 0.0004) and NOS2A rs944722 and IFNGR1 rs1327474 (p = 0.0006). Three other SNPs in NOS2A interacted with TLR4 rs5030729 and five other NOS2A SNPs interacted with IFNGR1 rs1327474. No significant associations were observed in Caucasians. These results suggest that NOS2A variants may contribute to TB susceptibility, particularly in individuals of African descent, and may act synergistically with SNPs in TLR4 and IFNGR1.
Project description:<h4>Background</h4>Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) refers to a common disorder with unclear etiology and unsatisfactory treatment, which reduces the male's quality of life.<h4>Objective</h4>To examine the effects of genetic polymorphisms of <i>IFNG</i>, <i>IFNGR1</i>, and androgen receptor (<i>AR</i>) on CP/CPPS.<h4>Methods</h4>The single nucleotide polymorphisms (SNPs) of <i>IFNG</i>, <i>IFNGR1</i>, and <i>AR</i> were genotyped with the improved multiplex ligation detection reaction. The GTEx, RegulomeDB, HaploReg, and 3DSNP databases were adopted to predict the regulatory functions of the genotyped SNPs. The correlation between SNPs and CP/CPPS was analyzed with the <i>χ</i> <sup>2</sup> test, logistic regression, and two genetic models (codominant and log-additive models). The nomogram was built to predict the risk of CP/CPPS occurrence.<h4>Results</h4>On the whole, 130 CP/CPPS patients and 125 healthy controls were recruited in the study, and 18 SNPs of <i>IFNG</i>, <i>IFNGR1</i>, and <i>AR</i> were genotyped. The results of functional annotation indicated that the 18 genotyped SNPs might have regulatory effects in the whole blood. The rs144488434 was correlated with the elevated CP/CPPS risk (odds ratio (OR): 2.40, 95% confidence interval (CI): 1.12-5.13, <i>χ</i> <sup>2</sup> = 5.37, and <i>P</i> = 0.021) by the <i>χ</i> <sup>2</sup> test. In the built genetic models, rs10457655 was correlated with the elevated National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) scores (codominant model: GA/GG: crude mean difference (MD) = 0.98, 95% CI: -1.71-3.67 and AA/GG: crude MD = 9.10, 95% CI: 0.58-17.62, <i>P</i> = 0.10). In subgroup analysis, rs2069718 was correlated with the elevated CP/CPPS risk (log-additive model: crude OR = 2.18, 95% CI: 1.03-4.64, and <i>P</i> = 0.034) in patients ≥ 35 years. The nomogram integrating age, rs2069718, rs10457655, and rs144488434 showed good performance to predict the risk of CP/CPPS.<h4>Conclusions</h4>Genetic polymorphisms of <i>IFNG</i>, <i>IFNGR1</i>, and <i>AR</i> might act as the genetic factors for CP/CPPS susceptibility, which deserved further explorations.
Project description:BACKGROUND & OBJECTIVES: Tuberculosis is (TB) responsible for high morbidity and mortality worldwide. Cytokines play a major role in defense against Mycobacterium tuberculosis infection. Polymorphisms in the genes encoding the various pro- and anti-inflammatory cytokines have been associated with tuberculosis susceptibility. In this study we examined association of 25 sequence polymorphisms in six candidate cytokine genes namely IFNG, TNFB, IL4, IL1RA, IL1B and IL12 and their related haplotypes with risk of developing pulmonary tuberculosis (PTB) among north Indians. METHODS: Pulmonary TB (n=110) patients and 215 healthy controls (HC) from north India were genotyped. Purified multiplex PCR products were subjected to mass spectrometry using Sequenom MassARRAY platform to generate the genotypes in a population-based case-control study. RESULTS: Using multiple corrections, significant overall risk against PTB was observed at seven loci which included variants in IFNG at rs1861493 and rs1861494; IL1RA at rs4252019, IL4 variant rs2070874, IL12 variants rs3212220, rs2853694 and TNFB variant rs1041981. Analysis of gene structure revealed two haplotype blocks formed by IFNG variants rs1861493 and rs1861494. The TA haplotype was significantly over-represented (P=0.011) in the cases showing a two-fold risk in the current population (Odds ratio=1.59 CI=1.101 to 2.297) and TNFB variants at rs2229094 and rs1041981 contributed to two haplotypes which were in strong linkage disequilibrium (LD) with AT haplotype showing a three-fold risk (P=0.0011, Odds ratio=3, CI=0.1939 to 0.7445) of developing PTB in north Indians. INTERPRETATION & CONCLUSIONS: Our study showed six novel associations of cytokine gene variants with susceptibility to PTB in north Indians. Variants of IFNG and TNFB emerged as factors imposing a significant risk of developing PTB in north Indians apart from risk indicated by IL1RA, IL4 and IL12.
Project description:A subset of atopic dermatitis is associated with increased susceptibility to eczema herpeticum (ADEH+). We previously reported that common single nucleotide polymorphisms (SNPs) in the IFN-? (IFNG) and IFN-? receptor 1 (IFNGR1) genes were associated with the ADEH+ phenotype.We sought to interrogate the role of rare variants in interferon pathway genes for the risk of ADEH+.We performed targeted sequencing of interferon pathway genes (IFNG, IFNGR1, IFNAR1, and IL12RB1) in 228 European American patients with AD selected according to their eczema herpeticum status, and severity was measured by using the Eczema Area and Severity Index. Replication genotyping was performed in independent samples of 219 European American and 333 African American subjects. Functional investigation of loss-of-function variants was conducted by using site-directed mutagenesis.We identified 494 single nucleotide variants encompassing 105 kb of sequence, including 145 common, 349 (70.6%) rare (minor allele frequency <5%), and 86 (17.4%) novel variants, of which 2.8% were coding synonymous, 93.3% were noncoding (64.6% intronic), and 3.8% were missense. We identified 6 rare IFNGR1 missense variants, including 3 damaging variants (Val14Met [V14M], Val61Ile, and Tyr397Cys [Y397C]) conferring a higher risk for ADEH+ (P = .031). Variants V14M and Y397C were confirmed to be deleterious, leading to partial IFNGR1 deficiency. Seven common IFNGR1 SNPs, along with common protective haplotypes (2-7 SNPs), conferred a reduced risk of ADEH+ (P = .015-.002 and P = .0015-.0004, respectively), and both SNP and haplotype associations were replicated in an independent African American sample (P = .004-.0001 and P = .001-.0001, respectively).Our results provide evidence that both genetic variants in the gene encoding IFNGR1 are implicated in susceptibility to the ADEH+ phenotype.
Project description:Post-kala-azar dermal leishmanaisis (PKDL) in Sudan is associated with elevated interferon-gamma (IFN-gamma). To study interferon-gamma pathways in PKDL, we genotyped 80 trios from the Masalit ethnic group for polymorphisms at -470 ins/delTT, -270T/C, -56T/C and +95T/C in IFNGR1 and at -179G/A and +874T/A in IFNG. No associations occurred at IFNG. Global association with haplotypes comprising all four markers at IFNGR1 (chi(2)(10df)=21.97, P=0.015) was observed, associated with a significant (chi(2)(1df)=4.54, P=0.033) bias in transmission of the haplotype insTT T T T and less (chi(2)(1df)=5.59, P=0.018) than expected transmission of insTT C C C. When compared with data on malaria associations from Gambia, the results suggest a complex pattern of haplotypic variation at the IFNGR1 promoter locus associated with different infectious disease in African populations that reflect the complex roles of IFN-gamma in parasite killing versus inflammation and pathogenesis.
Project description:AIM:Pulmonary tuberculosis (PTB) is an infectious disease with a high incidence worldwide. Previous genome-wide association studies have identified multiple susceptibility loci for pulmonary tuberculosis (PTB); however, validation of these findings is still needed. METHODS:For this study, we recruited 300 subjects with PTB and 300 healthy subjects from a Tibetan population living in near or in Xi'an, China. Association analyses of single-nucleotide polymorphisms (SNPs) in TAP2 and SEC14L2 were performed with SPSS Statistics (version 17.0), SNPStats, Haploview (version 4.2), and SHEsis software. RESULTS:We found a correction between one SNP (rs1061660) and PTB based on Chi-square or Fisher's exact tests. In the allelic model analysis, the SNPs rs1061660 in SEC14L2 gene increased PTB 1.32-fold risk (OR = 1.32, CI = 1.05-1.66, P = 0.017). In the genetic model analysis, the rs3819721 in TAP2 gene was associated with increased 1.65-fold risk in the co-dominant model and 1.67-fold risk in the over-dominant model, respectively. For the rs1061660 in SEC14L2 gene, we found it was associated with a 1.49-fold increase the risk of PTB in the dominant model and a 1.37-fold increase the risk of PTB in the log-additive model, respectively. CONCLUSION:We found that two SNPs are associated with increased PTB risk in the Chinese Tibetan population.
Project description:The vitamin D receptor (VDR) is an important factor in activating immune response in different infectious diseases. The aim of the present study was to investigate the association between the VDR gene polymorphisms and pulmonary tuberculosis (PTB). The case control study was performed on 120 PTB patients and 131 healthy controls. Genetic analysis was performed by polymerase chain reaction and the restriction fragment length polymorphism method. The VDR Fok1 Ff genotype was associated with TB and the risk of PTB was two times higher in individuals with the Ff genotype. A higher frequency of f allele was observed in PTB patients and therefore, the f allele may be a risk factor for PTB susceptibility. There were no associations between the Taq1 and Bsm1 polymorphisms and PTB. In addition, haplotype analysis showed that the f-T-B and f-t-b haplotypes (Fok1, Taq1 and Bsm1) may have the potential to increase PTB susceptibility. In conclusion, the Ff genotype and f allele of the VDR Fok1 polymorphism were associated with PTB susceptibility. In addition, the f-T-B and f-t-b haplotypes may be the susceptible haplotypes for PTB.