Promoter polymorphism of TNF‑α (rs1800629) is associated with ischemic stroke susceptibility in a southern Thai population

Abstract

Stroke represents the leading cause of disability and mortality amongst the elderly worldwide. Multiple risk factors, including both genetic and non-genetic components, as well as their interactions, are proposed as etiological factors involved in the development of ischemic stroke (IS). Promoter polymorphisms of the IL-6-174G/C (rs1800795) and TNF-α-308G/A (rs1800629) genes have been considered as predictive risk factors of IS; however, these have not yet been evaluated in a Thai population. The aims of this study were to investigate the association of IL-6-174G/C and TNF-α-308G/A polymorphisms with IS. Genomic DNA from 200 patients with IS and 200 controls were genotyped for IL-6-174G/C and TNF-α-308G/A polymorphisms using TaqMan™ SNP genotyping and quantitative PCR-high resolution melting analysis, respectively. It was found that the TNF-α-308 A allele was significantly associated with an increased risk of IS development compared with the G allele [odds ratio (OR)=2.044; 95% CI=1.154-3.620; P=0.014]. Moreover, the IS risk was significantly higher in the presence of TNF-α-308 GA or AA genotypes compared with that in the presence of GG genotypes with a dominant inheritance (OR=1.971; 95% CI=1.080-3.599; P=0.027). However, there was no association between IL-6-174G/C and the risk of IS development. The interaction study demonstrated that IL-6-174 GG and TNF-α-308 GG genotypes enhanced IS susceptibility when combined with hypertension, hyperlipidemia and alcohol consumption. Hypertensive and hyperlipidemic subjects with the TNF-α-308 GA and AA genotypes were more likely to develop IS compared with those who did not have these two conditions and had the GG genotype. In a matched study design (1:1), the IL-6-174 GC genotype was associated with higher IL-6 levels in the control group. Collectively, the present results highlight the utility of the TNF-α-308G/A polymorphism as a predictive genetic risk factor for development of IS.

Genetic polymorphism in the tumour necrosis factor alpha gene (G‐308A) is associated with persistent apical periodontitis in Brazilians

“…González-Navarro et al, 2020), ischaemic heart disease (Kamdee et al, 2021) and diabetes (Shi et al, 2021). The literature highlights an association between the A allele in the rs1800629 variation in TNF-⍺ as a protective factor to diseases related to bone metabolism, such as acute AP, osteoporosis, and bone fracture risk (Amaya et al, 2013;de Sá et al, 2007;Jin et al, 2018;Kotrych et al, 2016;Moffett et al, 2005), data that corroborate with the results observed in the present study. Shi et al (2021) reported in a review article a higher risk for developing periodontal disease in Asian diabetic patients related to rs1800629 variation in TNF-⍺, which may be related to higher levels of TNF-⍺, although the study reports that such data are still inconclusive in the literature.…”

“…Thus, the gene for TNF-α is highly polymorphic with many polymorphisms. The rs1800629 gene polymorphism has already been evaluated in relation to bone diseases, temporomandibular disorders, periodontal diseases, autoimmune diseases (Jin et al, 2018;Kotrych et al, 2016;Moffett et al, 2005;Shi et al, 2021) and with Herpesviruses infection (Jakovljevic et al, 2020;Wu et al, 2002). It is important to emphasize here that TNF-⍺ is a well-known pleiotropic gene, in which the same gene or genetic variant has an effect in different traits.…”

“…The most common polymorphism studied in the endodontic research is the single-nucleotide polymorphism (SNP) at position 2308 (rs1800629, G-308A), which causes guanine (G) to adenosine (A) transition in the promoter region of the human TNF-a gene (Jakovljevic et al, 2020(Jakovljevic et al, , 2021(Jakovljevic et al, , 2022Salles et al, 2017). Although the A allele of this SNP is associated with significantly higher transcription and TNF-a production, and with increased risk of various oral diseases (Jakovljevic et al, 2020(Jakovljevic et al, , 2021, controversial results were observed in the scientific literature, as in other populations the A allele performs a protective role against diseases associated with bone metabolism (Jin et al, 2018;Kotrych et al, 2016;Moffett et al, 2005).…”

TNF-α (G-308A) Polymorphism, Circulating Levels of TNF-α and IGF-1: Risk Factors for Ischemic Stroke—An Updated Meta-Analysis

“…Strictly following the inclusion criteria, 47 properly controlled full-length studies, including 23 rs1800629 genotype-related studies ( Um et al, 2003 ; Balding et al, 2004 ; Lee et al, 2004 ; Um and Kim, 2004 ; Karahan et al, 2005 ; Rubattu et al, 2005 ; Harcos et al, 2006 ; Lalouschek et al, 2006 ; Llamas Sillero et al, 2007 ; Banerjee et al, 2008 ; Shi et al, 2009 ; Kim et al, 2010 ; Tong et al, 2010 ; Sultana et al, 2011 ; Cui et al, 2012 ; Tuttolomondo et al, 2012 ; Zhao et al, 2012 ; Djordjevic et al, 2013 ; Wawrzynek et al, 2014 ; Gu et al, 2015 ; Kumar et al, 2016 ; Palm et al, 2020 ; Kamdee et al, 2021 ) and 13 case reports ( Zaremba and Losy, 2001a , b ; Intiso et al, 2004 ; Domac et al, 2007 ; Jefferis et al, 2009 ; Cure et al, 2013 ; Bokhari et al, 2014 ; de Sousa Parreira et al, 2015 ; Wytrykowska et al, 2016 ; Billinger et al, 2017 ; Shishkova et al, 2018 ; Zhang Y. Y. et al, 2018 ; Ma et al, 2020 ) on the circulating level of TNF-α were finally selected for the meta-analysis ( Figure 1 ). Genotype-related literature included a total of 9,120 patients and 9,249 healthy controls (Caucasian, n = 10; Asian, n = 15).…”

Genetic, Cellular and Molecular Aspects involved in Apical Periodontitis

“…It is noteworthy that these studies are still controversial regarding methodological and sampling variables, from the point of view of disease, treatment, and ethnic and individual factors (14,130). The pleiotropic effect of genetic polymorphisms may explain part of the associations observed in epidemiological studies between AP and different systemic alterations, such as metabolic syndrome (131,132), ischemic heart disease (133) and diabetes (134). Additionally, a recent review emphasized the need for further studies within new cohorts of different populations and ethnicities to either confirm or refute the role of genetic polymorphisms in AP (135).…”