TNF-α promoter polymorphisms in sudden infant death
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.
References (40)
- et al.
Sudden infant death syndrome, infection and inflammatory responses
FEMS Immunol Med Microbiol
(2004) SIDS pathogenesis: pathological findings indicate infection and inflammatory responses are involved
FEMS Immunol Med Microbiol
(2004)- et al.
IL-10 gene polymorphisms are associated with infectious cause of sudden infant death
Hum Immunol
(2003) - et al.
Association of IL-10 genotype with sudden infant death syndrome
Hum Immunol
(2000) - et al.
Interleukin 1-beta responses to bacterial toxins and sudden infant death syndrome
FEMS Immunol Med Microbiol
(2004) - et al.
Association of sudden infant death syndrome with VEGF and IL-6 gene polymorphisms
Hum Immunol
(2006) - et al.
IL6 G-174C associated with sudden infant death syndrome in a Caucasian Australian cohort
Hum Immunol
(2006) - et al.
The IL6 −174G/C polymorphism and sudden infant death syndrome
Hum Immunol
(2007) - et al.
ARMS-PCR methodologies to determine IL-10, TNF-alpha, TNF-beta and TGF-beta 1 gene polymorphisms
Transpl Immunol
(1999) - et al.
The −308 tumor necrosis factor-alpha promoter polymorphism effects transcription
Mol Immunol
(1997)
Functional analysis of linker-scan mutants spanning the −376, −308, −244, and −238 polymorphic sites of the TNF-alpha promoter
Cytokine
Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis
Hepatology
Different transcriptional activity and in vitro TNF-alpha production in psoriasis patients carrying the TNF-alpha 238A promoter polymorphism
J Invest Dermatol
Sudden infant death syndrome and unclassified sudden infant deaths: a definitional and diagnostic approach
Pediatrics
Sudden infant death syndrome, etiology and epidermiology
Sudden infant death syndrome victims show local immunoglobulin M response in tracheal wall and immunoglobulin A response in duodenal mucosa
Pediatr Res
Changes in the concentration and distribution of immunoglobulin-producing cells in SIDS palatine tonsils
Pediatr Allergy Immunol
Up-regulated epithelial expression of HLA-DR and secretory component in salivary glands: reflection of mucosal immunostimulation in sudden infant death syndrome
Pediatr Res
SIDS cases have increased levels of interleukin-6 in cerebrospinal fluid
Acta Paediatr
IL-6 cerebrospinal fluid levels are related to laryngeal IgA and epithelial HLA-DR response in sudden infant death syndrome
Pediatr Res
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