Type 1 diabetes (T1D) is a long-term autoimmune condition characterised by the destruction of insulin-producing beta cells in the pancreas, resulting in an insufficiency of insulin and inadequate control of blood glucose levels [1]. The beginning of Type 1 Diabetes (T1D) often occurs suddenly, especially in children and teenagers, with the main clinical signs consisting of frequent urination, excessive thirst, unexplained weight loss, tiredness, and blurred eyesight [2]. Individuals may also demonstrate a higher vulnerability to infections and face the possibility of developing diabetic ketoacidosis (DKA), a serious and potentially fatal complication. The presence of islet cell autoantibodies, insulin autoantibodies, or other specific autoantibodies in the blood is a characteristic feature of T1D [3]. Due to complete insulin deficiency, people with T1D require insulin therapy for their entire lives to regulate blood glucose levels. The worldwide occurrence of T1D is rising rapidly. In 2021, around 8.4 million people were affected by T1D globally [4]. This number is expected to rise to between 13.5 and 17.4 million by 2040, indicating an increase of 60 to 107 % compared to 2021 [4]. The incidence of T1D among adolescents and young adults increased from 7.78 per 100,000 in 1990 to 11.07 per 100,000 in 2019 [5]. Significant disparities exist in T1D outcomes between high-income and low-income countries. The life expectancy for a 10-year-old with T1D is just 13 years in low-income nations, whereas it is 65 years in high-income nations [4]. In China, T1D has historically been relatively uncommon compared to Western countries. However, the incidence is rising rapidly in China. A study estimated that over 13,000 new T1D cases occur annually in China [6]. The total number of individuals with T1D in China is estimated to exceed 1 million [7].

Inflammatory molecules are crucial in the development of Type 1 Diabetes (T1D). Pro-inflammatory cytokines like interleukin-1α (IL-1α), IL-1β, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-6, and IL-17 play a role in the onset and advancement of T1D by facilitating the differentiation and function of immune cells that promote diabetes and creating a setting that hastens the destruction of β-cells [8,9]. The cytokines involved may promote the upregulation of inducible nitric oxide synthase (iNOS) in pancreatic β-cells, possibly contributing to their destruction [10]. On the other hand, anti-inflammatory cytokines like IL-10, TGF-β, and IL-33 are believed to promote the re-establishment of immune tolerance and protect β-cells from damage [9]. The interplay between pro-inflammatory and anti-inflammatory cytokines is complex, with some cytokines exhibiting context-dependent functions [9]. Chronic inflammation in T1D is associated with elevated levels of circulating immune cells and inflammatory markers, which may contribute to disease progression and complications [10]. Elucidating these inflammatory mechanisms has led to the investigation of cytokine-targeted therapies as potential immunotherapeutic approaches for T1D. Nevertheless, outcomes have varied due to the complex roles cytokines play in the disease process [9].

TNF-α is a key factor in the development of T1D. Individuals with T1D exhibit higher serum TNF-α levels than healthy individuals [11]. This pro-inflammatory cytokine plays a role in autoimmune-mediated damage to pancreatic β-cells by enhancing antigen presentation and facilitating β-cell destruction by CD8+ T cells [12]. TNF-α, working with other inflammatory cytokines such as IFN-γ and IL-1β, can directly damage pancreatic β-cells and facilitate the maturation of dendritic cells that trigger islet-specific T cells in the pancreatic lymph nodes [13]. Notably, TNF-α plays a dual role, with potential immunosuppressive effects depending on the timing and context of its expression [14]. This complex role has rendered TNF-α a target for therapeutic interventions [15]. The TNF-α gene promoter contains several polymorphisms that can significantly affect TNF-α expression levels as they are close to the transcription initiation site. The −308 G/A (rs1800629) variant is the most thoroughly studied polymorphism, with the less common TNF2 allele (A allele) linked to increased TNF-alpha production in both in vitro and in vivo settings compared with the more prevalent TNF1 allele (G allele) [16]. The region around G-308 A in the TNF2 allele interacts more strongly with nuclear factors than the TNF1 allele, leading to a 2-fold increase in the activity of a heterologous promoter [17]. Likewise, several reports emphasised the link between TNF-α promoter variations and TNF-α levels [18,19]. Importantly, various polymorphisms in the TNF-α promoter can interact to influence overall gene activity, as demonstrated by the in vitro interactions among the -308G/A, -857C/T, and -1031 T/C polymorphisms. Details of the SNPs are documented in Supplementary Table 1. Given the functional significance of TNF-α promoter polymorphisms, numerous studies have been conducted across diverse populations to investigate potential associations with T1D susceptibility. Nonetheless, the findings have been inconsistent.

A meta-analysis of common TNF-α promoter polymorphisms in T1D aims to resolve inconsistent findings across individual studies. By combining data from multiple studies, a meta-analysis increases statistical power and provides a more reliable estimate of the actual effect sizes. This approach can clarify the role of these polymorphisms [G-238 A(rs361525), G-308 A (rs1800629), C-587 T (rs1700724), and T-1031C (rs1799964)] in T1D susceptibility across populations, assess association strengths, identify sources of heterogeneity, and guide future research, potentially informing targeted prevention or treatment strategies.