Gene Polymorphisms in the TNF Locus and the Risk of Myocardial Infarction

doi:10.1016/S0049-3848(00)00315-7

Thrombosis Research

Volume 100, Issue 4, 15 November 2000, Pages 263-269

https://doi.org/10.1016/S0049-3848(00)00315-7 Get rights and content

Abstract

We investigated two genetic polymorphisms in the tumor necrosis factor locus (TNF-α −308 G→A and LT-α +252 A→G) as risk factors for coronary atherothrombotic disease (CAD) by determining its prevalence in 148 survivors of myocardial infarction (MI) with angiographically-proven severe CAD, and in 148 age-, gender- and race-matched controls. The odds ratio (OR) for MI related to the mutant TNF-α and LT-α alleles was 0.8 (CI95: 0.4–1.3) and 1.3 (CI95: 0.8–2.0), respectively. We also sought interaction of smoking and metabolic risk factors for MI with each mutant genotype. Smokers not carrying the LT-α +252 A→G mutation had a risk of MI of 2.7 (CI95: 1.4–5.4) whereas in smoking carriers the risk was 6.9 (CI95: 3.4–14.1). An interactive effect of the LT-α mutation may also exist with dyslipidemia (OR for MI in non-carriers was 12 [CI95: 3.2–41.3] and in carriers the OR was 39, [CI95: 5.1–301] and with obesity (OR for MI was 2.7, [CI95: 1–7.2] in non-carriers and in carriers the OR was 6 [CI95: 2.1–16.8]). Lastly, the OR for MI in obese non-carriers of TNF-α −308 G→A was 2.8 (CI95: 1.3–6) and in obese carriers the OR was 14.5 (CI95: 1.8–113). Although significant interactive effects could not be detected, the findings suggest that interaction of polymorphisms in the TNF locus with major risk factors for CAD may exist, and should be explored in larger studies.

Section snippets

Patients and Controls

One hundred and sixty patients aged less than 55 years and with a diagnosis of MI were admitted for coronary angiography in the University Hospital of the School of Medicine of Ribeirão Preto, University of São Paulo, Brazil, between June 1996 and December 1997. Of these, DNA samples from 148 unrelated individuals (114 men [mean age 42 years; range 25–55 years] and 34 women [mean age 46 years; range 30–55 years]) were available for analysis in the present investigation. Myocardial infarction

TNF-α −308 G→A and LT-α +252 A→G and the Risk of MI

Similar frequencies of the two polymorphisms were found in patients and controls. The mutant TNF-α allele was found in 34 (1 homozygous and 33 heterozygous) out of 148 controls (allele frequency 11.8%, carrier frequency 22.9%) and in 28 (2 homozygous and 26 heterozygous) out of 148 patients with MI (allele frequency 10.1%, carrier frequency 18.9%). These data yield an overall OR for MI related to the TNF-α polymorphism of 0.8 (CI95: 0.4–1.4) (Table 2). The OR for heterozygous was 0.7 (CI95:

Discussion

The prevalence of LT-α and TNF-α was not significantly different between patients with MI and controls in the present study, suggesting that when isolated these mutations do not exert a major impact on the risk of atherothrombosis. When the OR for MI was recalculated by taking mutation combinations into account, still no increased risk for MI was verified. It must be emphasized, however, that the specific effect of the homozygous state for each mutation could not be fully addressed in our

Acknowledgments

J. Padovani was a recipient of a FAPESP Grant (98/10207-0). This research was supported by FAPESP (Grant 00/02623-5) and FUNDHERP.

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Cited by (79)

Promoter variants of TNF-α rs1800629 and IL-10 rs1800871 are independently associated with the susceptibility of coronary artery disease in north Indian
2018, Cytokine
Citation Excerpt :
Vendrellet al. reported that the −308 (G/A) TNF-α gene polymorphism may contribute to the risk of developing CAD in women of European ancestry with type 2 diabetes; they also suggested that it might be a useful predictive marker for CAD in these patients [18]. Padovani et al. also noted that the −308 (G/A) polymorphism may be associated with atherothrombosis as it increases the risk conferred by particular major classical risk factors [21] On the other hand, IL-10 is an anti-inflammatory cytokine that may regulate the complex network of reactions that occur in acute cerebral ischemia.
Tumor necrosis factor-alpha (TNF-α) are considered as a pro inflammatory and interleukin-10 (IL-10) anti inflammatory have been shown to predict the risk of incident of coronary artery disease (CAD). The polymorphism at promoter of TNF-α and IL-10 has been shown to increase transcriptional activity of the gene and play a important role in patho physiology of CAD. Aim of present study is to examine the impact of the TNF-α and IL-10 variant allele on various markers of the CAD and to study its relation with circulating TNF-α and IL-10 levels.
The −308 G/A & −238 G/A of TNF-α and −1082 G/A & −819 C/T of IL-10 gene polymorphism has been studied in 301 diagnosed CAD subjects (Age 51.50 ± 9.28; BMI 25.30 ± 3.58) and 305 healthy controls (Age 51.57 ± 9.50; BMI 24.06 ± 7.26). These polymorphism of TNF-α and IL-10 were detected by real time PCR by using Taqman SNP genotyping assay. Furthermore serum TNF-alpha and IL-10 levels were also measured by ELISA.
Allelic and genotypic frequencies did not deviate from Hardy-Weinberg equilibrium in the controls (p > 0.05). On allele contrast, significant association with susceptibility to CAD was detected with polymorphisms in TNF-α -308 G/A, that variant genotype GA + AA (dominant model) (p = 0.030: OR = 1.61: 95% CI = 1.06–2.44) and variant allele (A) (p = 0.006: OR = 1.71: 95% CI = 1.17–2.51) of TNF-α 308 G/A gene was significant highly observed in the cases as compared to control group. Furthermore, variant genotype CT + TT (dominant model) (p = 0.004: OR = 1.62: 95% CI = 1.17–2.24) and variant allele (T) (p < 0.001: OR = 1.49: 95% CI = 1.17–1.89) of IL-10 −819 C/T gene was significant highly observed in the cases as compared to control group.
Our results suggest that the TNF-α G-308A polymorphism independently associated with DBP, cholesterol, triglyceride, LDL, TNF-α and IL-10 levels which may be leads to the development of coronary artery disease of North Indians.
Association of G308A and G238A Polymorphisms of the TNF-α Gene with Risk of Coronary Heart Disease: Systematic Review and Meta-analysis
2016, Archives of Medical Research
It is widely acknowledged that coronary heart disease (CHD) has a genetic influence. One of the most promising candidate genes is tumor necrosis factor-alpha (TNF-α). Although there have been several positive studies associating the TNF-α gene and CHD, the evidence is not entirely consistent. The aim of the study was to evaluate the role of the TNF-α gene in CHD using combined evidence by generating a meta-analysis and a systematic review of all published data.
Meta-analysis and systematic review were conducted using 27 articles of genetic association studies of the TNF-α gene variants (G308A and G238A) and CHD. To analyze the association we used allelic, additive, dominant and recessive models. Moreover, we conducted a subanalysis by populations using the same four models.
TNF-α variant G308A showed a significant association with CHD but only when the analysis comprised the whole population. In addition, the variant G238A yielded the same outcome in the Asian population.
Genetic polymorphisms at positions −308 and −238 in the promoter region of the TNF-α gene may be useful as predictive factors for CHD.
Association between maternal tumor necrosis factor-α G308A polymorphism and interferon-γ A874T polymorphism and risk of preterm birth: A meta-analysis
2015, European Journal of Obstetrics and Gynecology and Reproductive Biology
This article was undertaken to investigate the association between tumor necrosis factor-α (TNF-α) G308A polymorphism and interferon-γ (INF-γ) A874T polymorphism and risk of preterm birth (PTB) by performing a meta-analysis of available studies.
Articles were chosen based on PubMed, EMBASE, Web of science, and China Biology Medicine (CBM) databases with no language restriction from their inceptions to 1 March, 2014. Specific inclusion criteria were used to evaluate articles. Meta-analysis was performed by using a random or fixed effect model with STATA 11.0 software. We estimated the summary odds ratios (ORs) with its corresponding 95% confidence interval (95%CI) to assess the association.
21 eligible case–control studies with a total of 2103 cases and 5070 controls were finally included into this meta-analysis. Pooled analysis showed that A allele of TNF-α G308A was not associated with increased PTB risk (OR = 0.84, 95%CI: 0.65–1.07, p = 0.167 for G vs. A). Stratifying analysis for ethnicity and different definition of PTB also indicated that A allele was not associated with increased PTB risk. However, the meta-analysis showed that INF-γ A874T polymorphism was associated with the increased risk of PTB (OR = 1.14, 95%CI: 1.11–1.73, p = 0.004 for A vs. T). Stratifying analysis was not performed due to the small sample size.
TNF-α G308A polymorphism was not associated with an increased risk of PTB, but INF-γ A874T polymorphism may contribute to increasing susceptibility to PTB. Detection of polymorphism of INF-γ A874T might be a promising biomarker for the diagnosis and prognosis of preterm delivery.
Synergistic effect of anti and pro-inflammatory cytokine genes and their promoter polymorphism with ST-elevation of myocardial infarction
2014, Gene
The single-gene approach in association studies of polygenic diseases such as acute myocardial infarction (AMI) is likely to provide limited value. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) plasma levels may be genetically influenced.
We evaluate the impact of single nucleotide polymorphism of the promoter region of these genes, as well as reciprocal interaction of these genes with ST-elevation of myocardial infarction (STEMI).
In a case–control study 500 STEMI patients and 500 age- and sex-matched controls were studied. Three single-nucleotide polymorphism genotypes were evaluated by polymerase chain reaction and restriction enzyme analysis and assessed their association with STEMI. The synergistic effects of IL-6, TNF-α and IL-10 gene polymorphisms were evaluated by using logistic regression analysis.
We found that IL-6 and TNF-α concentrations of studied population were significantly different (p < 0.0001) in each genotype of IL-6 − 174G>C and TNF-α − 308G>A gene polymorphisms respectively. A significant association was found in multivariate analysis for the IL-6 − 174G>C [odds ratio (OR): 0.390; 95% confidence interval (CI): 0.176–0.865, p = 0.020] and TNF-α − 308G>A [OR: 0.372; 95% CI: 0.171–808, p = 0.012] gene polymorphisms with STEMI. In contrast, IL-10 − 592C>A gene polymorphism was no longer significant in the multivariate model (OR: 0.678; 95% CI: 0.288 to 1.594, p = 0.373) whereas significant in univariate analysis (OR: 0.697; 95% CI: 0.523–0.929, p = 0.014).
Our findings suggest that IL-6, TNF-α and IL-10 gene polymorphisms all contribute in the association with STEMI whereas the association persisted only for IL-6 and TNF-α but not for IL-10 gene polymorphism with this disease in the multivariate analysis.
TNF-α polymorphisms and coronary artery disease: Association study in the Korean population
2013, Cytokine
Coronary artery disease (CAD) results from atherosclerosis, a chronic inflammatory disease mediated in part by proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α), which is expressed by atherosclerotic plaques. In this study, we investigated whether TNF-α gene promoter polymorphisms affect the incidence of CAD in Koreans by genotyping. 404 Control subjects and 197 patients who previously received a coronary artery stent for the G/A, C/T, and C/A polymorphisms at position −238, −857 and −863, respectively. The G/G, G/A and A/A genotypes at position −238 occurred in 85.8%, 14.2% and 0% CAD patients and 91.8%, 7.9% and 0.3% control subjects, respectively. The G/A polymorphisms at position −238 were significantly associated with CAD when assuming a dominant model of inheritance (OR = 1.87; 95% CI = 1.10–3.20; P = 0.02), and A allele carriers had a significantly increased risk of developing CAD relative to the G allele (OR = 1.74; 95% CI = 1.04–2.92; P = 0.03). However, the polymorphisms at positions −857 and −863 were not associated with CAD. Haplotype-based analysis revealed the CAD and control groups differed significantly in the frequencies of haplotype ACC at positions −238, −857 and −863 (OR = 1.77; 95% CI = 1.05–2.98; P = 0.03). This was confirmed by multivariate analysis after adjusting body mass index and the presence of diabetes and hypertension (OR = 2.06; 95% CI = 1.15–3.68; P = 0.015). Thus, the −238A allele of TNF-α is associated with an increased risk of CAD and could be used as predictor for CAD in Koreans. Further studies are needed to elucidate the clinical implications of these findings.
Pro-inflammatory cytokine gene polymorphisms and threat for coronary heart disease in a North Indian Agrawal population
2013, Gene
Citation Excerpt :
Thus, our findings suggest IFN-γ 874 A/T polymorphism to be a strong determinant of CHD among the studied population and a threshold is surpassed in individuals with high diastolic blood pressure. Genotypic distribution of TNF-α − 308 G/A was not significantly different between the patients and controls in the present study which is concordant with findings of (Banerjee et al., 2009; Padovani et al., 1999), and many others (Allen et al., 2001; Elghannam et al., 2000; Ghazouani et al., 2009; Herrmann et al., 1998; Keso et al., 2001; Koch et al., 2003; Martin et al., 2004; Porto et al., 2005; Tiroch et al., 2005; Vendrell et al., 2003; Yamada et al., 2002) as against the findings of (Cesari et al., 2003; Dedoussis et al., 2005; Dennsem et al., 2002; Masood, 1999). OR revealed no risk associated with this polymorphism.
The association of IFN-γ (+ 874 A/T; rs2430561), TNF-α (− 308 G/A; rs1800629) and TNF-β (+ 252 A/G; rs909253) with Coronary Heart Disease (CHD) has not been rigorously tested in Indian population. In the present study we sought to examine the role of these cytokines in the causation of CHD and their association with conventional CHD risk factors. A total of 138 case and 187 unrelated healthy controls aged 35 to 80 years, matched on ethnicity and geography were collected from North Indian Agrawal population. Single nucleotide polymorphisms at the promoter TNF-α − 308 G/A and the intronic IFN-γ + 874 A/T were analyzed by allele-specific PCR, and the intronic TNF-β + 252 A/G was analyzed by RFLP. Of the three selected polymorphisms, genotypic distribution of IFN-γ + 874 A/T and TNF-β + 252 A/G polymorphisms was significantly different between patients and controls in the present study. OR revealed statistically significant risk for CHD with respect to IFN-γ + 874 T allele, whereas OR for TNF-β + 252 A/G showed three fold risk in homozygous condition though not significant. No such trend could be observed for TNF-α − 308 G/A polymorphism. Multivariate logistic regression after adjusting for all the confounders showed significant risk for CHD with the genotypes and genotypic combinations of all the three markers (albeit not significant with TNF-α). Increased risk for CHD was likely to be associated with interaction of IFN-γ with diastolic hypertension, TNF-α with diabetes and BMI, and TNF-β with serum triglyceride and very low density lipoprotein (VLDL) levels. The results suggest that these selected cytokine polymorphisms could possibly serve as potential bio-markers for CHD in conjunction with specific conventional risk factors.

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Original articleGene Polymorphisms in the TNF Locus and the Risk of Myocardial Infarction

Abstract

Section snippets

Patients and Controls

TNF-α −308 G→A and LT-α +252 A→G and the Risk of MI

Discussion

Acknowledgments

Am J Cardiol

Am J Cardiol

Blood

J Reprod Immunol

Atherosclerosis—an inflammatory disease

N Engl J Med

Expression of inflammatory mediators and adhesion molecules in human atherosclerotic plaque

Neurology

Original article
Gene Polymorphisms in the TNF Locus and the Risk of Myocardial Infarction