Elsevier

Human Immunology

Volume 69, Issue 6, June 2008, Pages 368-373
Human Immunology

TNF-α promoter polymorphisms in sudden infant death

https://doi.org/10.1016/j.humimm.2008.04.006Get rights and content

Summary

Several studies indicate that the immune system is stimulated in sudden infant death syndrome (SIDS). Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine that strongly affects the cytokine cascade. A genetic variant associated with high production of TNF-α may thus be of significance in the pathogenesis of SIDS. The purpose of the current study was to investigate possible relationships among the promoter polymorphisms −1031T/C, −857C/T, −308G/A, −244G/A, and −238G/A in the TNF-α gene and SIDS. The subjects investigated consisted of 148 SIDS cases, 56 borderline SIDS cases, 41 cases of infectious death, and 131 adult controls. When investigating each single nuclear polymorphism (SNP) separately, associations between −238GG and SIDS (p = 0.022) and between −308GA and borderline SIDS (p = 0.005) were found. There were no associations between any of the other SNPs investigated. Furthermore, a SNP profile was constructed by creating a genotype pattern from the investigated SNPs. Fifteen gene combinations were obtained, and 4 profiles had significantly different frequencies in SIDS cases and controls. The two SNP profiles −1031CT, −238GG, −857CC, −308GG and −1031TT, −238GG, −857CC, −308AA were found more often in SIDS and may thus be unfavorable. The findings add evidence to the theory that an unfavorable genetic profile in the TNF-α gene may be involved in SIDS by exposing the infant to both a high level of and prolonged exposure to TNF-α.

Introduction

Sudden infant death syndrome (SIDS) is defined as the sudden unexpected death of an infant under 1 year of age, with onset of the fatal episode apparently occurring during sleep, that remains unexplained after a thorough investigation that includes carrying out a complete autopsy and review of the circumstances of death and the clinical history [1]. Several studies indicate that the immune system is stimulated in SIDS victims [2], [3], [4], [5], [6]. Previously, we reported elevated levels of interleukin-6 (IL-6) in the cerebrospinal fluid of SIDS cases [7]. Furthermore, the SIDS cases with the highest IL-6 cerebrospinal fluid levels also had an increased number of immunoglobulin A cells and epithelial human leukocyte antigen (HLA)-DR expression in the laryngeal mucosa, as well as symptoms of slight infection prior to death [8]. These observations may indicate that a significant proportion of the infants who die from SIDS have an increased vulnerability to infection resulting from disturbed immunologic homeostasis. In accordance with the concept of the fatal triangle [9] of SIDS, a genetic predisposition, a vulnerable developmental stage, and a trigger event may induce a disturbed immunologic homeostasis. Such a disturbed homeostasis may induce a toxic shock-like reaction, similar to that seen in infectious death [10].

Several attempts have been made to disclose an association between SIDS and different polymorphisms in the interleukin genes [11], [12], [13], [14], [15], [16]. In the IL-10 gene, the ATA haplotype and the ATA/ATA genotype of the IL-10 gene are claimed to be associated both with infectious death and with SIDS [11], [12]. Two common polymorphisms of importance for IL-1β levels are the −511C/T polymorphism in the IL-1β gene and the 2018T/C polymorphism in the IL-1RN gene. These genes have been studied in SIDS, but no association to SIDS has so far been established [13]. A study of 25 British SIDS cases included common polymorphisms in the IL genes IL-4, IL-6, interferon-γ, transforming growth factor, and vascular endothelial growth factor [14]. Significant differences existed for IL-6 and VEGF: the genotypes −174GG and −1154AA were more frequent in SIDS cases than in controls. The findings regarding IL-6 were confirmed in a study of Australian SIDS cases [15], but not in a Norwegian study [16].

Tumor necrosis factor-α (TNF-α) is a multifunctional proinflammatory cytokine produced by different cell types, but mainly by macrophages and monocytes. TNF-α is involved in the regulation of biological processes, including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. The synthesis of TNF-α is activated by many different proteins, depending on the cell type, but IL-1 and bacterial endotoxins are the most important. TNF-α expression is regulated at multiple levels, with transcriptional control of the gene promoter as the first step of regulation. This implies that the single nuclear polymorphisms (SNPs) in the promoter region are of special importance. Previous studies described nine different SNPs in the promoter region [17]. In the current study, we aimed at genotyping the TNF-α promoter SNPs −1031 T/C, −857 C/T, −308 G/A, −244 G/A, and −238 G/A (see Figure 1). Interest in these particular SNPs is a result of their effect on the promoter activity. Thus, they may influence the TNF-α level and, furthermore, they have the potential to cause disrupted immunologic homeostasis. We propose that imbalance in the cytokine network is involved in SIDS and that TNF-α is of special interest in this respect. The purpose of the current study was to investigate functional polymorphisms in the promoter of the TNF-α gene in cases of SIDS, infections death, and controls.

Section snippets

Subjects

The subjects investigated in this study included 148 SIDS cases, 56 borderlines SIDS cases, 41 cases of infectious death, and 131 controls (Table 1). Samples from all individuals were collected during autopsy in the period 1988–2006 at the Institute of Forensic Medicine, University of Oslo, using standard protocols. The protocols included evaluation of the circumstances of death, review of medical and family history, radiographic examination, toxicology, and a thorough autopsy with extensive

Results

In the five polymorphic sites within the TNF-α promoter region, an association existed between the SNP in bp −238 and SIDS because the −238 GG genotype was s more frequent in the SIDS cases than in controls (p = 0.022) (Table 3). Furthermore, for the SNP in bp −308, significant differences existed in genotype frequency between borderline SIDS cases and controls: the borderline SIDS cases more often demonstrated the −308GA genotype (p = 0.005) and less often demonstrated the −308GG genotype (p =

Discussion

The main finding of this study is the association between two SNP profiles in the TNF-α promoter region and SIDS. This new observation supports the theory that genetic risk factors for SIDS may exist, SNP profiles −1031CT, 238GG, 857CC, 308GG (No. 3, Table 5) and −1031TT, 238GG, 857CC, 308AA (No. 4, Table 5), representing an unfavorable genetic make-up. Interestingly, four of the five infants with the latter gene combination had fever prior to death.

There is evidence to support the importance

Acknowledgment

The study was supported by the Unexpected Child Death Society of Norway.

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