Meta-analysis of TNF-alpha promoter -308 A/G polymorphism and SLE susceptibility

Alleles of tumor necrosis factor-alpha (TNF-alpha) gene have been inconsistently associated with systemic lupus erythematosus (SLE), particularly the 308-A/G functional promoter polymorphism. To generate large-scale evidence on whether 308-A/G promoter polymorphism is associated with SLE susceptibility we have conducted a meta-analysis. We have identified 21 studies of this polymorphism and SLE using MEDLINE search. Meta-analysis was performed for genotypes A/A (recessive effect), A/A+A/G (dominant effect), and A allele in fixed or random effects models. All control samples were in Hardy-Weinberg proportion. The overall odds ratio (OR) of the A/A genotype was 3.2 (95% CI=2.0-5.3, P<0.001). Stratification by ethnicity indicated that the A/A genotype was associated with SLE in European-derived population (OR=4.0, CI=2.5-6.4, P<0.001). No association was detected in Asian-derived population (OR, 1.3, CI=0.3-6.3, P=0.76). The overall OR for the risk genotypes (A/A and A/G) was 2.0 (CI=1.3-3.1, P<0.001). Similar results were found between the risk allele A and SLE where a significant association was found in European population (OR=2.1, CI=1.6-2.7, P<0.001), but not in Asian (OR=1.4, CI=0.8-2.3, P=0.2) or African (OR=1.2, CI=0.6-2.5, P=0.59) populations. In summary, this meta-analysis demonstrates that the TNF-alpha promoter -308 A/G polymorphism may confer susceptibility to SLE, especially in European-derived population.     

TNF-alpha G-308A polymorphism is associated with rheumatic fever and correlates with increased TNF-alpha production

Previous studies suggested that abnormal regulation of TNF-alpha production may have a role in the pathogenesis of rheumatic fever (RF). Polymorphism at the promoter region of TNF-alpha gene (-308 A) has recently been shown to be associated with rheumatic heart disease (RHD) in Mexican patients. Although this polymorphism has long been shown to affect TNF-alpha gene expression in cell lines, its role in production of the cytokine in RF patients has not been studied. We therefore investigated TNF-alpha G-308A single nucleotide polymorphism and its effect on TNF-alpha production in 71 Turkish RF patients and 89 ethnically matched healthy controls. The TNF-alpha-308A allele frequency was found to be significantly higher in RF patients (RHD+arthritis) than in healthy controls [p<0.0032 Odds ratio (OR)=3.4, 95% confidence interval (CI) (1.5-7.7)]. When RHD patients were analyzed as a separate group, significant difference persisted [p<0.0055, OR=3.3, 95% CI (1.5-7.6)]. More importantly, ELISPOT analysis demonstrated that existence of A allele was associated with higher TNF-alpha production compared with G allele. Our data suggest that carrying a high responder TNF-alpha-308A allele may be a genetic factor in increasing the susceptibility to develop RF disease.     

Genetic polymorphism of p53, but not GSTP1, is association with susceptibility to esophageal cancer risk - A Meta-Analysis

A number of studies have evaluated two functional polymorphisms on p53 Arg72Pro and GSTP1 Ile105Val, in relation to esophageal cancer susceptibility. However, the results remain conflicting rather than conclusive. This meta-analysis on 2919 cases and 4074 controls for p53 Arg72Pro and 1885 cases and 2194 controls for GSTP1 Ile105Val from 13 published case-control studies showed that no significant general main effects for GSTP1 Ile105Val on esophageal cancer risk. However, we found that the p53 Arg72Pro was associated with an increased risk of esophageal cancer ((Pro/Arg +Pro/Pro) versus Arg/Arg: OR=1.20, 95%CI=1.06-1.36) without any between-study heterogeneity.In the stratified analysis by ethnicity, we found that the increased esophageal cancer risk associated with p53 Arg72Pro polymorphism was more evident in Asian group ((Pro/Arg +Pro/Pro) versus Arg/Arg: OR=1.35, 95%CI=1.14-1.60, P=0.09 for heterogeneity test), although we still failed to find any significant association between GSTP1 Ile105Val polymorphism and esophageal cancer risk in different ethnicity. These results suggest that p53 Arg72Pro polymorphism, but not GSTP1 Ile105Val, may contribute to esophageal cancer development, especially in Asian. Additional well-designed large studies were required for the validation of this association.     

Macrophage migration inhibitory factor (MIF) gene polymorphism is associated with susceptibility to but not severity of inflammatory polyarthritis

The aim of the study was to investigate whether polymorphisms of macrophage migration inhibitory factor (MIF) determine susceptibility to or severity of inflammatory polyarthritis (IP). Genotypes for a single-nucleotide polymorphism (MIF-173*G/C) and a tetranucleotide (CATT)(n) repeat mapping to the promoter region of the MIF gene were compared between UK Caucasian IP cases (n=438) and controls (n=343). Both polymorphisms were also investigated for association with features of disease activity and severity at baseline and by 5 years. The MIF-173*C allele (OR 1.7, 95% CI 1.3-2.4, P=1.8 x 10(-4)) and the CATT(7) allele (OR 1.5, 95% CI 1.0-2.1, P=0.02) were found to be associated with increased susceptibility to IP. Furthermore, presence of the haplotype containing both associated polymorphisms was associated with a three-fold increase risk of developing IP. No association with disease severity or activity either at baseline or by 5 years was detected for either of the promoter polymorphisms studied. In conclusion, MIF is a susceptibility gene for the development of IP. The same alleles previously reported to be associated with susceptibility to juvenile idiopathic arthritis account for the increased risk. The promoter polymorphisms of MIF, investigated in this study, do not influence the severity of disease outcome by 5 years.     

Alleles -308A and -1031C in the TNF-alpha gene promoter do not increase the risk but associated with circulating levels of TNF-alpha and clinical features of vivax malaria in Indian patients

The biological significance of TNF promoter polymorphism and infectious disease association prompted us to investigate whether TNF-alpha -308 G/A and -1031 T/C promoter polymorphisms are associated with Plasmodium vivax infection, cellular TNF-alpha level and possibly with clinical symptoms by employing PCR-RFLP methods. An overall significant elevation of serum TNF-alpha, IL-6 content (p=0.0002, p=0.002, respectively), whereas highly significant depletion of IL-10 content (p=0.0001) was observed in vivax patients. In addition, TNF-alpha concentration in patients with and without fever were found to be significant (p=0.0001, p=0.0004, respectively). The genotypic distribution for -308 G/A and -1031 T/C positions were found non significant, but it was clinically potent to observe statistically significant distribution of genotypes (p=0.032) in patients with and without fever. Furthermore, the TNF-alpha level in TNF1 and TNF2 genotype for -308 position was significantly higher (p=0.010, p=0.006 respectively). In case of -1031 position TNF-alpha level was significant in ancestral (TT) genotype (p=0.0007) in patients compared to healthy subjects and significantly higher in rare (CC) genotype (p=0.021) as compared to ancestral genotype. In addition, the two polymorphisms 308G/A and -1031T/C were in highly significant LD (D'=0.7992, r(2)=0.6005, p=0.0001) in the patients as well as it is interesting to report that the distribution of novel 308A: 1031C alleles associated haplotypes are nearly the same in patients (0.2610) and in healthy subjects (0.2636). In view of present observation of promoter polymorphism with TNF-alpha level and other clinical parameters of vivax infection, we suggest that evaluation of TNF level and its polymorphisms in the promoter region may be considered to be reliable molecular and immunological markers, possess promising rational for diagnostic potential and immunotherapeutic interventions in clinical vivax malaria. Genetic variation in the promoter region is of biological significance and may play important roles in host defense mechanisms against vivax infection by enhancing cell-mediated immunity and stimulating the protective immunological cascade.     

PADI4 gene polymorphism is not associated with ankylosing spondylitis in Chinese Han population

The cause of ankylosing spondylitis (AS) remains unelucidated. Both genetic and environmental factors are suspected playing an important role in AS development. Peptidyl arginine deiminase type IV (PADI4) is a member of gene family that encodes enzymes responsible for the conversion of arginine to citrulline residues. A strong linkage between PADI4 polymorphism and rheumatoid arthritis has been found in Japanese and Korean patients, but there is no association study about PADI4 in AS. We speculated that PADI4 may be a pivotal gene for AS development. So we investigated the PADI4 polymorphisms in AS in Chinese Han population. A total of 316 Chinese AS patients of Han nationality and 439 healthy controls were recruited. Five single-nucleotide polymorphisms (SNP), PADI4-89 (rs11203366), PADI4-90 (rs11203367), PADI4-92 (rs874881) PADI4-94 (rs2240340) and PADI4-104 (rs1748033), of PADI4 gene were selected, and the major allele frequencies between cases and controls were assessed as 0.571 versus 0.597, 0.565 versus 0.585, 0.565 versus 0.574, 0.446 versus 0.421 and 0.614 versus 620, respectively. No significant differences in the frequency of PADI4 alleles and genotypes between the cases and controls were observed. Two haplotypes ACGGC and GTCGC were significant with AS even after Bonferroni's correction but were with a tiny frequency in AS cases as 1.0% and 1.2%, respectively. These results indicate that PADI4 polymorphisms may not play an important role in the development of AS in Chinese Han population.     

TNF-alpha −308G>A polymorphism is associated with suicide attempts in major depressive disorder

Background

Despite the substantial role of the cytokine network in depression and suicide, few studies have investigated the role of genetic polymorphisms of pro- and anti-inflammatory cytokines in suicide in major depressive disorder (MDD). The aim of this study was to investigate whether tumor necrosis factor-alpha (TNF-alpha) −308G>A, interferon-gamma (IFN-gamma) +874A>T, and interleukin-10 (IL-10) −1082A>G are associated with increased risk for suicide attempts in MDD.

Methods

Among patients with MDD, 204 patients who had attempted suicide and 97 control patients who had not attempted suicide were recruited. A chi-square test was used to identify a possible risk genotype or allele type for suicide. A subsequent multivariate logistic regression analysis was conducted to investigate the influence of a risk genotype or allele type adjusted for other environmental factors. The lethality of the suicide attempt was also tested between genotype and allele types among suicidal patients with MDD.

Results

The GG genotype of the TNF-alpha −308G>A polymorphism was found to significantly increase risk for suicide attempt (adjusted OR=2.630, 95% CI=1.206 to 5.734). IFN-gamma +874A>T and IL-10 −1082A>G were not associated with risk for suicide. Lethality of the suicide attempt was not associated with any of the three cytokine genotypes or allele types.

Limitations

Limitations include a relatively small sample size and a cross-sectional design.

Conclusions

TNF-alpha −308G>A polymorphism is an independent risk factor for suicide attempts in MDD. Future studies should clarify the neural mechanisms by which the GG genotype of TNF-alpha −308G>A influences suicide in MDD.     

Interleukin-17A gene polymorphism is associated with susceptibility to gastric cancer

We conducted a study to investigate the role of three common SNPs in the IL-17A and IL-17F genes (rs2275913G>A, rs3748067C>T and rs763780T>C) in the development of gastric cancer, and their interaction with H.pylori infection. A total of 326 patients with gastric cancer and 326 control subjects were consecutively recruited between May 2012 and May 2014. Genotyping of IL-17A rs2275913G>A and rs3748067C>T and IL-17F rs763780T>C was performed in a 384-well plate format on the Sequenom MassARRAY platform. By logistic regression analysis, individuals carrying the GA and AA genotypes of IL-17 rs2275913G>A were significantly associated with an increased risk of gastric cancer when compared with GG genotype, and the adjusted Ors (95% CI) were 1.46 (1.03-2.06) for GA genotype and 2.57 (1.51-4.43) for AA genotype. We observed that the GA+AA genotype of rs2275913 was associated with an increased risk of gastric cancer among H.pylori infection subjects (OR=2.21, 95% CI=1.29-3.79). In conclusion, we found that there was a significant association between L-17A rs2275913G>A polymorphism and increased gastric cancer risk, especially in H.pylori infection subjects.     

HLA-DR mediated cell death is associated with, but not induced by TNF-alpha secretion in APC

Tumor necrosis factor alpha (TNFalpha) is a pleiotropic cytokine involved in inflammatory responses which can trigger both cell apoptosis and cell activation. In antigen presenting cells (APC), TNFalpha increased antigen presentation, notably by up-regulation of HLA class II expression. In addition to their role in antigen presentation, HLA-DR molecules transduce intracellular signals which lead to cytokine up-regulation or cell death. We have previously observed that the susceptibility of APC to HLA-DR mediated apoptosis increase throughout their maturation. We therefore investigated the relationship between TNFalpha production and susceptibility to HLA-DR-mediated apoptosis of different APC. The hematopoietic progenitor cell line (KG1), monocytic cell line (THP-1), monocyte-derived dendritic cell (DC), and B-lymphoid cell line (Raji) have been studied. We report that apoptosis susceptibility and spontaneous TNFalpha release are correlated in these different cells. However, while autocrine TNFalpha production was critical for DC maturation, upregulation of TNFalpha release after HLA-DR crosslinking was not observed and neutralization of endogenous TNFalpha did not modify HLA-DR-mediated apoptosis. These data reveal that HLA-DR mediated apoptosis susceptibility and spontaneous TNFalpha release are regulated in a parallel manner and that while TNFalpha may induce maturation of APC to an "apoptosis sensitive" stage, there is no direct role for TNFalpha in HLA-DR-mediated apoptosis of APC.     

MASP2 gene polymorphism is associated with susceptibility to hepatitis C virus infection

Hepatitis C virus (HCV) has become a major public health issue and is prevalent in most countries. We examined several MASP2 functional polymorphisms in 104 Brazilian patients with moderate and severe chronic hepatitis C using the primers set to amplify the region encoding the first domain (CUB1), a critical region for the formation of functional mannan-binding lectin (MBL)/MBL-associated serine proteases (MASP)-2 complexes, and the fifth domain (CCP2), which is essential for C4 cleavage of the MASP2 gene. We identified five single nucleotide polymorphisms in patients and controls: p. R99Q, p. D120G, p.P126L, p.D371Y, and p.V377A. Our results show that the p.D371Y variant (c.1111 G > T) is associated with susceptibility to HCV infection (p = 0.003, odds ratio = 6.33, 95% confidence interval = 1.85-21.70). Considered as a dominant function for the T allele, this variant is associated with high plasma levels of the MASP-2 in hepatitis C patients (p < 0.001). However, further functional investigations are necessary to understand the degree of involvement between MASP2 and the HCV susceptibility.     

Deletion polymorphism in the angiotensin-converting enzyme gene is not associated with hypertension in a Gulf Arab population

We have studied an insertion/deletion dimorphism in the human angiotensin-converting enzyme gene amongst UAE nationals from the Abu Dhabi Emirate. Our findings show lack of association between the I/D allele marker system and clinical diagnosis of essential hypertension, suggesting that variations of the angiotensin-converting enzyme gene do not play a major role in the determination of elevated blood pressure in this Arab population. This agrees with results reported on other ethnic groups.     

CT60 single nucleotide polymorphism of the CTLA-4 gene is associated with susceptibility to Graves' disease in the Taiwanese population

Graves' disease (GD) is an autoimmune disease but the underlying etiology has not been completely elucidated. Genetic susceptibility has been believed to play a major role. Recent studies showed that the CT60 single nucleotide polymorphism (SNP), which is in the 3'-noncoding region of the CTLA-4 gene, is strongly associated with some immune-mediated diseases. The aim of this study was to test for association between GD susceptibility and polymorphisms of CTLA-4 (ie, the CT60 SNP and the exon 1 +49 SNP) in the Taiwanese population. Our results demonstrate significant differences in the frequencies of the genotypes and alleles between 107 GD patients and 101 control subjects in the CT60 and exon 1 +49 SNPs (p <0.05). Significant differences in phenotypes were only found for CT60 SNP (78.4% vs 67.8% between patients and controls; chi2 = 3.93, p = 0.047). Furthermore, we found that the G/G genotype of both CT60 and exon 1 +49 was associated with increased risk for GD (p = 0.022, OR = 1.97). Significant linkage disequilibrium was found between the CT60 SNP and the exon 1 +49 SNP in both GD patients and control subjects (D' = 1.00). Because of tight linkage disequilibrium, a combination of these SNPs enhanced the role of the CTLA-4 gene in GD. The frequency of the disease-susceptible G allele of CT60 was comparable to that in Japanese and higher than in Caucasians. In conclusion, we provide evidence that CT60 SNP is associated with susceptibility to GD in the Taiwanese population.     

Interaction of HLA-DRB1*1501 allele and TNF-alpha -308 G/A single nucleotide polymorphism in the susceptibility to multiple sclerosis

Multiple sclerosis is a multifactorial disorder with complex genetic basis. It is believed that genes encoding HLA molecule and cytokines are involved in the pathogenesis of MS. In this study, we have evaluated the impact of HLA-DRB1*1501 allele and TNF-alpha -308 G/A single nucleotide polymorphism, and their interaction, in the susceptibility to MS in Iranian population. Genomic DNA samples were prepared from whole blood of 366 MS Patients and 414 control subjects. The genotypes were determined by SSP-PCR method. Frequency of alleles and genotypes were compared between the two groups by using Fisher's exact test. HLA-DRB1*1501 allele was more frequent among patients (OR=1.57, P=0.0026). TNF-α -308 G allele and G/G genotype had higher frequency among MS patients than control subjects (G vs. A: OR=1.26, P<0.05); G/G vs. A/A: OR=4.59, P=0.0003). The odds ratio was higher among HLA-DRB1*1501 positive individuals. Co-existence of TNF G and HLA-DRB1*1501 alleles showed higher prevalence among MS patients (OR=7.07, P=0.0007). Our results have shown that HLA-DRB1*1501 allele and TNF-α -308 G/A polymorphism are associated with the risk of multiple sclerosis in Iranian population. We also observed an interaction between these two loci that support the role of HLA alleles and cytokine genes and gene-gene interaction in the development and pathogenesis of MS.     

PITX3 polymorphism is not associated with Parkinson's disease in a Chinese population

Several studies have indicated that three PITX3 single nucleotide polymorphisms (SNPs), rs2281983, rs4919621 and rs3758549, are likely to be associated with Parkinson's disease (PD) in Caucasians. Some studies also suggested an age-of-onset effect. We recently reported that allele and genotype frequencies did not differ between late-onset PD (LOPD) patients and controls for all three SNPs. To extend the analysis to early-onset PD (EOPD) patients, and to test whether an age-of-onset effect exists in Chinese, we genotyped these SNPs in 290 Chinese EOPD patients using a ligase detection reaction (LDR). For all three SNPs, allele and genotype frequencies did not differ between total PD patients and controls, between LOPD patients and controls, between EOPD patients and controls, or between LOPD and EOPD patients. Our results suggest that these PITX3 SNPs do not contribute to the risk of developing PD in EOPD or LOPD in Chinese.     

NLRC5 polymorphism is associated with susceptibility to chronic periodontitis

Periodontitis is a chronic oral pathology caused by impaired immune response against oral bacteria resulting in tissue inflammation and damage. Among the members of innate immune response, the first line of defence against pathogens, inflammasomes are macro-molecular protein complexes that can be activated by different stimuli, comprised bacteria infections. Different proteins are involved in inflammasoma formation; the most important are molecules belonging from the family of nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs).In this study, polymorphisms within 20 NLRs related genes were analysed in order to investigate their possible association with periodontitis susceptibility in a population from North-East Italy.One polymorphism, namely rs289723, in NLRC5 gene resulted associated with chronic slight and chronic localized periodontitis susceptibility, specifically A/A genotype was correlated with increased risk of disease development.Our study, for the first time, identified the possible involvement of a polymorphism within NLRC5 gene as a possible biomarker for periodontitis condition susceptibility among Italian individuals from genetic isolates.