Association of IL-10 genotype with sudden infant death syndrome
Introduction
Sudden infant death syndrome (SIDS) is a major cause of post-perinatal mortality in the UK [1] with a rate of 0.62 per 1000 live births (in 1997). SIDS is defined as “the sudden death of an infant or young child, which is unexpected by history, and in which a thorough postmortem examination fails to demonstrate an adequate cause of death” [2].
Several epidemiological characteristics have been established [3]. In particular, the age distribution peaks at around 4 months. Several etiological mechanisms have been implicated 4, 5, 6, 7, including the common bacterial toxin hypothesis 7, 8, 9. The latter hypothesis states that toxins produced by commonly occurring bacteria, especially if following a viral respiratory infection, may cause SIDS in infants who are hypoimmune. The incidence of SIDS peaks at an age when there is a nadir in the infant’s humoral immunity, between the phase of declining transplacental maternal antibodies and the development of acquired immunity to environmental antigens. This lack of neutralizing immunity leaves the baby poorly protected from microbial toxins, which elicit cytokine release and symptoms akin to those of toxic shock syndrome [10]. Cytokines are essential in the regulation of responses to immune challenge, but aberrant cytokine production contributes to pathological processes. Recent research has shown elevated levels of the pro-inflammatory and inflammatory cytokines interleukin-1 (IL-1), interleukin-2 (IL-2), and interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) 11, 12, 13, 14 in SIDS postmortem samples, a cytokine profile that may provide insight into the mechanism of death in SIDS.
Variations (polymorphisms) in the genes encoding IL-10 correlate with levels of IL-10 cytokine production [15]. Moreover, these polymorphisms have been shown to be associated with certain diseases such as autoimmune disease [16] and inflammatory bowel disease [17].
The aim of this study was to analyse the distribution of polymorphisms in the IL-10 gene in SIDS and control populations. As a further comparison we also determined the genotypes of the same patients for TNF-α (an inflammatory cytokine) and TGF-β1 (an anti-inflammatory cytokine). The objective was to further our understanding of the abnormal regulation of inflammatory responses in SIDS.
Section snippets
Materials and methods
Typing for IL-10 gene polymorphisms was carried out on DNA extracted from spleen and liver samples of SIDS victims. Polymerase chain reactions (PCR) and sequence specific oligonucleotide probing (SSOP) analysis were carried out as described by Perrey et al. [18]. The biallelic polymorphisms investigated were IL-10–1082 (G or A) and IL-10–592 (A or C). The IL-10–819 alleles were inferred because they are invariably linked to the −592 alleles. In addition, the samples were typed for the TNF-α
Results
The IL-10 polymorphisms at positions −1082, −819, and −592 from the transcription start site on the same strand of DNA segregate as haplotypes. The IL-10 low producer haplotype, −1082∗A −819∗T −592∗A (or ATA for short), was more frequent in the SIDS group and this distortion of the distribution of haplotypes was significant (p = 0.003), as shown in Table 1. It appeared to be the presence of the A allele at position −592 that was responsible for this association, since the −1082 alleles were
Discussion
Sudden infant death is strongly associated with IL-10 genotype, both with the ATA haplotype and with the presence of the −592∗A allele. There is a threefold increase in the risk of SIDS with the IL-10–592∗A genotype compared with the normal population. This compares with risk factors associated with passive smoking (two- to threefold) and sleeping position (three- to eightfold). The specificity of IL-10–592∗A association is remarkable because an adjacent polymorphism, the IL-10–1082
Acknowledgements
We wish to thank Dr. Vera Pravica and Mr. Chris Perrey for their technical advice and support.
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