Lack of association between TNF-α gene promoter polymorphisms and pancreatitis: a meta-analysis

Background/Aims

Tumor necrosis factor alpha (TNF-α) is a major proinflammatory cytokine involved in the etiology of pancreatitis. The association between pancreatitis and the − 308G>A and − 238G>A polymorphisms in TNF-α gene has been analyzed in several studies, but results have been inconsistent. The purpose of this study was to integrate previous findings and explore whether these polymorphisms are associated with susceptibility and severity to pancreatitis.

Methods

A meta-analysis was performed by searching PubMed, Cochrane Library, and ScienceDirect databases. Data were extracted using predefined form and odds ratios (OR) with 95% confidence intervals (CI) were calculated.

Results

Our meta-analysis of a total of 1569 pancreatitis cases and 1330 control subjects from twelve published case–control studies for the − 308G>A polymorphism (OR 0.98; 95% CI 0.83–1.17), and of 480 cases and 302 controls from four studies for the − 238G>A polymorphism (OR 0.92; 95% CI 0.58–1.47) did not show any significant associations of susceptibility to pancreatitis with the variant GA+AA genotypes compared with the GG genotype. An association between severity of acute pancreatitis and − 308G>A polymorphism was not found either (OR 0.93; 95% CI 0.69–1.24).

Conclusion

Polymorphisms in two sites of TNF-α gene promoter do not alter the risk of pancreatitis.     

Lack of an association between -308G>A polymorphism of the TNF-α gene and liver cirrhosis risk based on a meta-analysis

TNF-α is a potential proinflammatory cytokine that plays an important role in the pathogenesis of liver cirrhosis. We investigated a possible association between TNF-α -308G>A polymorphism and liver cirrhosis risk by conducting a meta-analysis. Publications addressing the association between TNF-α -308G>A and liver cirrhosis risk were selected from the Pubmed and Embase databases. Data were extracted from the studies by two independent reviewers; odds ratio (OR) with a 95% confidence interval (CI) was calculated from these data. The meta-analysis was performed by Review Manager Version 5.0.24 and STATA Version 9.2. Eleven studies were retrieved, reporting a total of 1796 liver cirrhosis cases and 2113 healthy controls. A meta-analysis of these 11 studies identified no significant association between TNF-α -308G>A polymorphism and liver cirrhosis risk in all comparisons of G vs A allele; GG vs GA + AA; GG + GA vs AA; GG vs AA; GG vs GA (OR = 1.14, 95%CI = 0.85-1.55, P = 0.38; OR = 1.24, 95%CI = 0.87- 1.77, P = 0.24; OR = 0.90, 95%CI = 0.62-1.30, P = 0.57; OR = 1.03, 95%CI = 0.56-1.89, P = 0.92; OR = 1.30, 95%CI = 0.90-1.88, P = 0.17; respectively). In conclusion, we found no association between TNF-α -308G>A polymorphism and liver cirrhosis risk, both in Caucasian and Asian populations.     

Association between genome-wide association studies reported SNPs and pediatric-onset Crohn’s disease in Canadian children

A recent pediatric-focused genome-wide association study has implicated three novel susceptibility loci for Crohn’ disease (CD).We aimed to investigate whether the three recently reported and other previously reported genes/loci were also associated with CD in Canadian children. A case–control design was implemented at three pediatric gastroenterology clinics in Canada. Children <19 years of age with a confirmed diagnosis of CD were recruited along with controls. Single nucleotide polymorphisms (SNPs) in 19 reported genes/loci were genotyped. Associations between individual SNPs and CD were examined. A total of 563 cases and 553 controls were studied. The mean (±SD) age of the cases was 12.3 (±3.2) years. Most cases were male (56.0%), had ileo-colonic disease (L3 ± L4, 48.8%) and inflammatory behavior (B1 ± p, 87.9%) at diagnosis. Allelic association analysis (two-tailed) showed that 8 of the 19 targeted SNPs were significantly associated with overall susceptibility for CD. Associations with one additional SNP was borderline non-significant. Significantly associated SNPs included SNPs rs1250550 (p = 0.026) and rs8049439 (p = 0.04), recently reported to be specifically associated with pediatric-onset CD.Based on the results, we confirmed associations between two of the three novel pediatric-CD loci and other regions reported for associations with either pediatric and/or adult-onset CD.     

Association between TNF-α promoter G-308A and G-238A polymorphisms and obesity

Tumor necrosis factor-α (TNF-α), an adipokine, is produced in adipocytes, and the elevation of its levels has been linked to obesity and insulin resistance in some population. In this study the relationship between TNF-α promoter gene polymorphism and obesity in an Iranian population has been studied. Subjects were randomly selected from Tehran Cohort Lipid and Glucose Study. Adult participants placed in three groups according to their body mass index (BMI): BMI < 25, 25 ≤ BMI < 30, BMI ≥ 30 and under-18 subjects placed in two groups, under 85th percentile BMI and above 85th percentile. Finally, 244 persons were selected for G-308A and G-238A polymorphisms analysis. The FBS, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride, cholesterol levels and blood pressure and HOMA of all subjects were measured. The polymorphism −308 and −238 were revealed by restriction fragment length polymorphism (RFLP; NCOI and MSPI) after the promoter site was amplified by PCR. The allele frequency of TNF-α polymorphism was in the Hardy–Weinberg equilibrium. There was no relation between BMI and the frequency of this allele. The fact that there is no association between G-308A and G-238A TNF-α promoter polymorphisms and obesity probably shows that it is not an important risk factor for obesity and consequently for cardiovascular disease.     

A comparative analysis of the molecular genetic processes in the pathogenesis of psoriasis and Crohn’s disease

Molecular Biology - A comparative bioinformatics analysis of the molecular genetic processes in the pathogenesis of multifactorial diseases—psoriasis and Crohn’s disease—was...     

Cohen’s h for detection of disease association with rare genetic variants

Background

The power of the genome wide association studies starts to go down when the minor allele frequency (MAF) is below 0.05. Here, we proposed the use of Cohen’s h in detecting disease associated rare variants. The variance stabilizing effect based on the arcsine square root transformation of MAFs to generate Cohen’s h contributed to the statistical power for rare variants analysis. We re-analyzed published datasets, one microarray and one sequencing based, and used simulation to compare the performance of Cohen’s h with the risk difference (RD) and odds ratio (OR).

Results

The analysis showed that the type 1 error rate of Cohen’s h was as expected and Cohen’s h and RD were both less biased and had higher power than OR. The advantage of Cohen’s h was more obvious when MAF was less than 0.01.

Conclusions

Cohen’s h can increase the power to find genetic association of rare variants and diseases, especially when MAF is less than 0.01.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-875) contains supplementary material, which is available to authorized users.     

A review of major Crohn’s disease susceptibility genes and their role in disease pathogenesis

Crohn’s disease (CD) is a chronic inflammatory bowel disease whose relevance is increasing in industrialized society. Recent genome wide association studies revealed over seventy one loci associated with disease penetrance. Several variants that increase disease risk encode for altered proteins that diminish bacterial host defense. NOD2 alters intracellular bacterial sensing while ATG16L1 is thought to diminish bacterial clearance by impairing autophagy. Additionally, changes in the IBD5 locus are thought to diminish barrier function. Alternatively, recent data indicate a gain of function genetic variant of IL23R is protective amongst European CD patients. These recent genetic discoveries contradict historical theories that Crohn’s disease results from overactive auto-aggressive responses. Rather, new genetic data suggest disease-associated variants encode for dysfunctional proteins that diminish essential innate immune responses against commensal organisms. This review provides an overview of these critical discoveries and places them in their biological context.     

The study of the association between genotype and phenotypic manifestations of the Huntington’s chorea pathogenesis

Direct molecular-genetic analysis of the region containing CAG and CCG repeats of the IT15 gene from 37 patients with the clinical diagnosis of Huntington’s chorea was carried out. The allele with the expansion of CAG repeats in the state of heterozygosity was found in 33 patients; DNA analysis did not confirm a clinical diagnosis in four cases. Twenty probable asymptomatic carriers were examined; 11 of them inherited a mutant chromosome. A disequilibrium in the linkage between the (CGG)₁₀ allele and the alleles with the expansion of CAG repeats in the IT15 gene in a group of patients from Ukraine was found. Significant differences in character of instability of CAG repeats that depends on paternal or maternal inheritance were revealed. The genetic factors that are associated with age variability of onset of the disease were studied.     

Genome-wide pathway analysis of a genome-wide association study on psoriasis and Behcet’s disease

The aim of this study was to identify candidate causal single nucleotide polymorphisms (SNPs) and candidate causal mechanisms of psoriasis and Behcets’s disease (BD) and to generate an SNP → gene → pathway hypothesis. A psoriasis genome-wide association study (GWAS) dataset that included 436,192 SNPs in 1,409 psoriasis cases and 1,436 controls of European descent and a BD GWAS dataset that contained 310,324 SNPs in 1,215 BD cases and 1,278 controls were used in this study. Identify candidate causal SNPs and pathways (ICSNPathway) analysis was applied to the GWAS datasets. ICSNPathway analysis identified 15 candidate causal SNPs and 28 candidate causal pathways. The top five candidate causal SNPs were rs1063478 (P = 1.45E−10), rs8084 (P = 2.20E−08), rs7192 (P = 5.18E−08), rs20541 (P = 5.30E−06), and rs1130838 (P = 5.65E−06), which with the exception of rs20541 [interleukin (IL)-13] are at human leukocyte antigen (HLA) loci. These candidate causal SNPs and pathways provided ten hypothetical biological mechanisms. The most strongly associated pathway concerned HLA. When HLA loci were excluded, ICSNPathway analysis provided one hypothetical biological mechanism. rs20541 (non_synonymous_coding) → IL-13 → dendritic cell involvement in the regulation of Th1 and Th2 development, and the GATA3 pathway. ICSNPathway analysis identified four candidate causal SNPs, eleven candidate causal pathways, and three hypothetical biological mechanisms. One of them was as follows: rs2072895 (non_synonymous_coding & splice-site) and rs2735059 (non_synonymous_coding) → HLA-F → type I diabetes mellitus, antigen processing and presentation, and autoimmune thyroid disease. The application of ICSNPathway analysis to GWAS dataset of psoriasis and BD resulted in the identification of candidate causal SNPs and candidate pathways that might contribute to psoriasis susceptibility.     

Association between TNF-α polymorphisms and cervical cancer risk: a meta-analysis

Tumor necrosis factor alpha (TNF-α) is a vital cytokine involved in inflammation, immunity, and cellular organization. The TNFA-308G/A (rs1800629) and -238G/A (rs361525) polymorphisms are two widely investigated variants for their associations with risk of cervical cancer, but the results are conflicting. Here, we performed a meta-analysis to pool the data and evaluate the between-studies heterogeneity. All the case–control studies published from January 1989 to October 2010 on the association between the two polymorphisms of TNFA and cervical cancer risk were identified by searching the electronic literature Medline. The cervical cancer risk associated with the two polymorphisms of TNFA gene was estimated for each study by OR together with its 95% CI, respectively, by using the Review Manager 4.2 software. It was showed that the variant homozygote -308AA was associated with a significantly increased risk of cervical cancer (AA vs. GG: OR = 1.41, 95% CI = 1.03–1.92, P = 0.033; AA vs. GA/GG: OR = 1.39, 95% CI = 1.02–1.90, P = 0.036), and the effect was more evident among Asians (AA vs. GA/GG: OR = 3.67, 95% CI = 1.25–10.81, P = 0.018). We also found that the variant genotypes -238GA/AA was associated with a significantly decreased risk of cervical cancer (GA/AA vs. GG: OR = 0.55, 95% CI = 0.41–0.74, P < 0.001). The results suggested that TNFA-308G/A and -238G/A may contribute to cervical cancer susceptibility.     

Effect of TNF-α and IL-1β genetic variants on the development of myocardial infarction in Turkish population

Tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β) genetic variants which resulting in TNF-α and IL-1 overproduction may increase susceptibility to autoimmune diseases such as atherosclerosis. We have studied the association of TNF-α G308A and IL-1β (+3953) C/T polymorphism with myocardial infarction in Turkish population. 143 patients with myocardial infarction and 213 age-matched healthy controls were included in the study. In univariant analysis, the frequencies of IL-1β, TNF-α genotype or allele, and haplotype of C:A and T:A were significantly elevated in patients when compared with those of controls. GA genotype of TNF-α, T allele of IL-1β and A of TNF-α allele seem to be risk factors for myocardial infarction. In contrast, CC genotype of IL-1β and GG genotype of TNF-α have protective effect against myocardial infarction. In multivariate logistic regression analysis, TNF-α A allele, gender and smoking were associated with myocardial infarction. In conclusion, we can state that TNF-α A allele might be associated with myocardial infarction.     

A genome-wide association study of Alzheimer’s disease using random forests and enrichment analysis

Alzheimer??s disease (AD) is a serious neurodegenerative disorder and its cause remains largely elusive. In past years, genome-wide association (GWA) studies have provided an effective means for AD research. However, the univariate method that is commonly used in GWA studies cannot effectively detect the biological mechanisms associated with this disease. In this study, we propose a new strategy for the GWA analysis of AD that combines random forests with enrichment analysis. First, backward feature selection using random forests was performed on a GWA dataset of AD patients carrying the apolipoprotein gene (APOE?4) and 1058 susceptible single nucleotide polymorphisms (SNPs) were detected, including several known AD-associated SNPs. Next, the susceptible SNPs were investigated by enrichment analysis and significantly-associated gene functional annotations, such as ??alternative splicing??, ??glycoprotein??, and ??neuron development??, were successfully discovered, indicating that these biological mechanisms play important roles in the development of AD in APOE?4 carriers. These findings may provide insights into the pathogenesis of AD and helpful guidance for further studies. Furthermore, this strategy can easily be modified and applied to GWA studies of other complex diseases.     

Association between α1-antichymotrypsin signal peptide −15A/T polymorphism and the risk of Alzheimer’s disease: a meta-analysis

No consensus has been recently reached at the relationship between the α1-antichymotrypsin (ACT) signal peptide −15A/T polymorphism and Alzheimer’s disease (AD) risk. Thus, our study aimed to better assess this association by performing a meta-analysis, including 4,212 cases and 4,039 controls from 29 studies. Odds ratios (ORs) with the 95% confidence interval (CI) were used to assess the strength of relationship between ACT −15A/T polymorphism and AD risk. Overall, a borderline statistically significant association was detected under recessive model comparison in all subjects (AA vs. AT+TT: OR 1.12, 95% CI 1.01–1.25, P = 0.04). But in subgroup analysis by ethnicity, no significant association was found in Caucasians, Asians, or Africans. Moreover, after exclusion of one study which affect the heterogeneity, the ACT A allele and AA genotype were statistically associated with late-onset AD (LOAD) risk (AA vs. TT: OR 1.25, 95% CI 1.06–1.48, P = 0.007, A vs. T: OR 1.12, 95% CI 1.03–1.21, P = 0.008), especially in Caucasians. In conclusion, our study suggests that the common α1-antichymotrypsin signal peptide −15A/T polymorphism may not be a major risk factor for AD. However, the polymorphism is capable of increasing LOAD risk.     

Associations between TNF-α Polymorphisms and Pneumonia: A Meta-Analysis

Background

Several studies evaluated the associations of tumor necrosis factor-α (TNF-α) polymorphisms with pneumonia in different populations. However, the results were conflicting and controversial.

Methods

Databases including PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI) were searched to find relevant studies. Data were extracted independently by two investigators. Crude odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated.

Results

Twelve case-control studies and one cohort study were included. Overall, no association between TNF-α −308A/G polymorphism and pneumonia risk was observed for AA +AG vs. GG (OR = 1.13; 95% CI 0.99–1.30; P = 0.07). In addition, TNF-α −308A/G polymorphism was not associated with pneumonia mortality (OR = 1.96; 95% CI 0.94–4.09; P = 0.07). Furthermore, there was no association of TNF-α −238A/G polymorphism with the risk of pneumonia (OR = 1.38; 95% CI 0.84–2.28; P = 0.20).

Conclusions

TNF-α −308A/G, −238A/G polymorphisms were not associated with pneumonia risk. Moreover, TNF-α −308A/G polymorphism did not play a role in the pneumonia mortality risk.     

Identifying candidate genes for discrimination of ulcerative colitis and Crohn’s disease

In this study we aimed to screen effective biomarkers for differential diagnosis of ulcerative colitis (UC) and Crohn’s disease (CD). By using the gene expression profile dataset GSE24287 including 47 ileal CD, 27 UC and 25 non-inflammatory bowel diseases control downloaded from Gene Expression Omnibus database, we identified the differentially expressed genes (DEGs) between UC patients and controls as well as between CD patients and controls (|log₂FC(fold change)| > 1 and p < 0.05). Then Gene Ontology (GO) functional enrichment analyses were performed for these DEGs in two groups, followed by the construction of weight PPI (protein–protein interaction) networks. Subnets enriched for the PPIs and differentially expressed genes were constructed based on the weight PPI networks. The overlapping genes between the genes in the top 10 subnets with smallest p value and the DEGs were selected as the candidate genes of disease. A total of 75 DEGs were identified in UC group and 87 ones in CD group. There were 69 and 57 specific DEGs in CD group and UC group, respectively. The DEGs in CD group were mainly enriched in “inflammatory response” and “defense response”, while the most significantly enriched GO terms in UC group were “anion transport” and “chemotaxis”. FOS and SOCS3 were identified as candidate genes for CD and other three genes HELB, ZBTB16 and FAM107A were candidate genes for UC. In conclusion, there were distinct genetic alterations between UC and CD. The candidate genes identified in current study may be used as biomarkers for differential diagnosis of CD and UC.     

Psychiatric disorders and SLC6A4 gene variants: possible effects on alcohol dependence and alzheimer’s disease

Molecular Biology Reports - Serotoninergic system is one of the most important neurotransmission systems investigated in the field of psychiatry. Extensive evidence reveals how alterations of this...     

Predictive association of copper metabolism proteins with Alzheimer’s disease and Parkinson’s disease: a preliminary perspective

Neurodegenerative diseases, Alzheimer’s disease (AD) and Parkinson’s disease (PD), constitute a major worldwide health problem. Several hypothesis have been put forth to elucidate the basis of onset and pathogenesis of AD and PD; however, till date, none of these seems to clearly elucidate the complex pathoetiology of these disorders. Notably, copper dyshomeostasis has been shown to underlie the pathophysiology of several neurodegenerative diseases including AD and PD. Numerous studies have concluded beyond doubt that imbalance in copper homeostatic mechanisms in conjunction with aging causes an acceleration in the copper toxicity elicited oxidative stress, which is detrimental to the central nervous system. Amyloid precursor protein and α-synuclein protein involved in AD and PD are copper binding proteins, respectively. In this review, we have discussed the possible association of copper metabolism proteins with AD and PD along with briefly outlining the expanding proportion of “copper interactome” in human biology. Using network biology, we found that copper metabolism proteins, superoxide dismutase 1 and ceruloplasmin may represent direct and indirect link with AD and PD, respectively.