Association of IL-10 genotype with sudden infant death syndrome

doi:10.1016/S0198-8859(00)00183-X

Human Immunology

Volume 61, Issue 12, December 2000, Pages 1270-1273

https://doi.org/10.1016/S0198-8859(00)00183-X Get rights and content

Abstract

Sudden infant death syndrome (SIDS) is a major cause of infant death of unknown etiology. We propose that SIDS results from a genetically determined imbalance in the production of inflammatory and anti-inflammatory cytokines in response to the infant’s microbial flora. We were especially interested to know the relationship between SIDS and genetically determined higher or lower production of IL-10, an anti-inflammatory cytokine. Biallelic polymorphisms in the promoter region of the IL-10 gene associated with higher or lower production of IL-10 were determined in a SIDS and in a control group using a sequence-specific oligonucleotide approach. One particular allele of the IL-10 gene, the IL-10-592∗A allele, was significantly associated with SIDS. Indeed, 70% of the SIDS babies carried the IL-10-592∗A allele (p = 0.007 compared with control). In addition, there was a significant reduction in the frequency of homozygosity for the allele IL-10-592∗C (p = 0.001 compared with control). Carrying the A allele (either A/A or A/C) had an odds ratio of 3.3 (95% confidence interval 1.4–8.0). In the same patients there was no association with other IL-10 gene polymorphisms nor with other cytokine (TNF-α, TGF-β1) genotypes, emphasizing the particular relationship between SIDS and the IL-10-592∗A allele.

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.

References (22)

A.N. Stanton
Over heating and cot death
Lancet
(1984)
J.A. Morris et al.
Hypothesiscommon bacterial toxins are a possible cause of the sudden infant death syndrome
Med Hypothesis
(1987)
N.M. Sayers et al.
Preliminary investigation of lethally toxic sera of sudden infant death syndrome victims and neutralisation by commercially available immunoglobulins and adult sera
FEMS Immunol Med Microbiol
(1999)
N.M. Sayers et al.
Cytokines may give insight into mechanisms of death in sudden infant death syndrome
Med Hypothesis
(1995)
I.V. Hutchinson et al.
Cytokine genotypes in allograft rejectionguidelines for immunosuppression
Trans Proc
(1998)
C. Perrey et al.
Genotyping for polymorphisms in interferon-γ, interleukin-10, transforming growth factor-b1 and tumour necrosis factora technical report
Transplant Immunol
(1998)
J.E. Smialek et al.
Investigation of sudden infant deaths
Paediatrician
(1988)
A.B. Bergman et al.
Sudden infant death syndrome
(1970)
S.R. Limerick
Sudden infant death in historical perspective
J Clin Pathol
(1992)
W.E. Parish et al.
The effect of anaesthesia on anaphylaxis in guinea-pigs
Clin Exp Immun
(1963)

P.J. Fleming et al.

Interaction between bedding and sleeping position in the Sudden Infant Death Syndromea population based case control study

Br Med J

(1990)

Cited by (71)

Clinical and experimental aspects of breathing modulation by inflammation
2019, Autonomic Neuroscience: Basic and Clinical
Neuroinflammation is produced by local or systemic alterations and mediated mainly by glia, affecting the activity of various neural circuits including those involved in breathing rhythm generation and control. Several pathological conditions, such as sudden infant death syndrome, obstructive sleep apnea and asthma exert an inflammatory influence on breathing-related circuits. Consequently breathing (both resting and ventilatory responses to physiological challenges), is affected; e.g., responses to hypoxia and hypercapnia are compromised. Moreover, inflammation can induce long-lasting changes in breathing and affect adaptive plasticity; e.g., hypoxic acclimatization or long-term facilitation. Mediators of the influences of inflammation on breathing are most likely proinflammatory molecules such as cytokines and prostaglandins. The focus of this review is to summarize the available information concerning the modulation of the breathing function by inflammation and the cellular and molecular aspects of this process. I will consider: 1) some clinical and experimental conditions in which inflammation influences breathing; 2) the variety of experimental approaches used to understand this inflammatory modulation; 3) the likely cellular and molecular mechanisms.
A systematic review exploring the relationship between infection and sudden unexpected death between 2000 and 2016: A forensic perspective
2018, Forensic Science International
Death due to infectious diseases is a major health concern worldwide. This is of particular concern in developing countries where poor-socio economic status and a lack of healthcare resources contribute to the high burden of disease. In some cases death due to infection can be acute and aggressive, and death may occur without a diagnosis whilst the person is still alive. These deaths may ultimately lead to a medico-legal autopsy being performed. There are various mechanisms by which sudden death due to infection may occur. In addition, there are many risk factors associated with sudden death due to infection, which differ between infants and older individuals. However, it is unclear which pathogens and risk factors are most frequently associated with sudden death due to infection. Therefore a systematic review of articles and case reports published between 1 January 2000 and 30 June 2016 was undertaken in order to (1) explore the relationship between pathogens and their causative role and (2) identify the relationship between predisposing and/or risk factors associated with sudden death due to infection. Major databases were searched and after critical appraisal 143 articles were identified. It was found that respiratory infections and deaths involving bacterial pathogens were most commonly associated with these deaths. In addition the most common risk factors in infants were exposure to tobacco smoke and co-sleeping. In adults the most common risk factors were co-morbid conditions and illnesses. This information aids in a better understanding of these deaths and highlights the need for more research in this field, particularly in developing countries
Ion channelopathies associated genetic variants as the culprit for sudden unexplained death
2017, Forensic Science International
Citation Excerpt :
Coincidentally, immune dysfunctions were also frequently reported in SIDS. Several studies about various genes that encode proteins involved in modulating immune function, such as IL-6, IL-10 and TNF, have validated that polymorphisms in these genes are responsible for perturbed immune responses, and thus be of significance in the pathogenesis of SIDS [149–151]. It is worth mentioning that megalothymus, which was earlier defined as status thymico-lymphaticus, is often described as a symbolic feature appeared in SIDS [152,153].
Forensic identification of sudden unexplained death (SUD) has always been a ticklish issue because it used to be defined as sudden death without a conclusive diagnosis after autopsy. However, benefiting from the developments in genome research, a growing body of evidence points to the importance of ion channelopathies associated genetic variants in the pathogenesis of SUD. Genetic diagnosis of the deceased is also a new trend in epidemiological studies, for it enables the undertaking for preventive approach in individuals with high risks. In this review, we briefly discuss the molecular structure of ion channels and the role of genetic variants in regulating their functions as well as the diverse mechanisms underlying the ion channelopathies at gene level.
Autopsy Findings: Sudden Infant Death Syndrome - Epidemiology and Etiology
2015, Encyclopedia of Forensic and Legal Medicine: Second Edition
Over the past two decades there have been dramatic developments in sudden infant death syndrome (SIDS) with numbers of deaths falling, once the risk factors of prone sleeping position and cigarette smoke exposure in particular, were identified. Deaths due to unsafe sleeping environments that had been previously misdiagnosed were also being separated out from under the umbrella of ‘SIDS.’ Of equal significance, the promulgation of the triple risk model that integrated a vulnerable age with external risk factors and internal deficiencies provided a framework for understanding the complex interactions that contributed to these unexpected and tragic infant deaths.
Gut microbiome in sudden infant death syndrome (SIDS) differs from that in healthy comparison babies and offers an explanation for the risk factor of prone position
2014, International Journal of Medical Microbiology
Citation Excerpt :
Based on this work we published an hypothesis (Highet et al., 2009) similar to that of Morris et al. (2007) proposing that a brief bacteraemia occurred prior to death. The hypothesis included pathogen recognition defectiveness supported by the finding of immune response gene defects, e.g. IL-10 low-producer polymorphism (Summers et al., 2000). Bacteraemic episodes are common (Kuppermann, 1999) and we presume that “normal” babies (who lack genetic immune response defects) would be better able to cope with these events and deal with the bacteraemia without an adverse outcome (bearing in mind that the peak of SIDS occurs when maternal antibodies have declined significantly and thus leaving the genetically susceptible baby less able to cope with a bacteraemic episode).
The role of bacteria in the causation of sudden infant death syndrome (SIDS) is gaining acceptance. Mainstream research favouring respiratory compromise has failed to provide a plausible pathogenetic mechanism despite many years of investigation and thousands of research papers. Bacterial colonisation of the colon of the human infant is influenced by many factors including age, mode of delivery, diet, environment, and antibiotic exposure. The gut microbiome influences development of the immune system. The gut microflora could be important in protection against the bacteria and/or their toxins purportedly involved in SIDS pathogenesis. The aim was to perform a preliminary investigation of the gut microflora in sudden infant death syndrome (SIDS) compared with live comparison babies. The intestinal contents from 52 SIDS, and 102 faecal samples from age-matched live comparison infants were screened by PCR to target 16s RNA genes of Clostridium innocuum, Cl. Perfringens, Cl. difficile, Bacteroides thetaiotaomicron and Staphylococcus aureus. Gut colonisation of the babies with these bacteria was analysed in relation to age, gender and type of feeding; and for SIDS babies sleeping position. Cl. difficile, Cl. innocuum and B. thetaiotaomicron were significantly associated with SIDS with 25%, 46% and 30% of cases PCR positive for these respective bacteria compared with only 6%, 23% and 8.8% respectively in the comparison group. SIDS babies had dual colonisation by both Cl. perfringens and Cl. difficile significantly more often than comparison babies and also with triple colonisation by Cl. perfringens, Cl. difficile and Cl. innocuum. SIDS babies were more often colonised by S. aureus than comparison babies. In addition, SIDS babies found prone were significantly more likely to be colonised by S. aureus than for other positions recorded (OR = ∞; CI = 2·04 - ∞). No significant differences between breast and bottle-fed SIDS babies was observed in regard to each clostridial bacterium, or S. aureus, however Cl. innocuum was found to be significantly associated with formula feeding in the comparison cohort. Comparison of breast and formula feeding of SIDS babies with live comparison babies revealed significant differences with regards to some of the clostridial bacteria. Age-specific differences in gut bacterial microbiome were observed in both SIDS and comparison healthy babies. This study gives an insight into differences in the gut bacterial microbiome of SIDS babies compared with healthy babies. These differences could be important in contributing to a baby's susceptibility to infection and therefore to SIDS. The association of S. aureus colonisation with prone sleep position supports the hypothesis that prone sleep position could increase the risk of ingestion/inhalation of bacteria contaminating the sleeping surface and could account for the increased risk of SIDS in babies who are put to sleep prone. The study provides impetus for broader studies into the gut microbiome of babies and could lead to effective approaches to SIDS prevention.
Serotonin gene variants are unlikely to play a significant role in the pathogenesis of the sudden infant death syndrome
2013, Respiratory Physiology and Neurobiology
Sudden infant death syndrome (SIDS) is defined as the sudden and unexpected death of an infant less than 12 months of age that is related to a sleep period and remains unexplained after a complete autopsy, death scene investigation, and review of the clinical history. The cause of SIDS is unknown, but a major subset of SIDS is proposed to result from abnormalities in serotonin (5-HT) and related neurotransmitters in regions of the lower brainstem that result in failure of protective homeostatic responses to life-threatening challenges during sleep. Multiple studies have implicated gene variants that affect different elements of 5-HT neurotransmission in the pathogenesis of these abnormalities in SIDS. In this review I discuss the data from these studies together with some new data correlating genotype with brainstem 5-HT neurochemistry in the same SIDS cases and conclude that these gene variants are unlikely to play a major role in the pathogenesis of the medullary 5-HT abnormalities observed in SIDS.

View all citing articles on Scopus

View full text

Association of IL-10 genotype with sudden infant death syndrome

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

Lancet

Med Hypothesis

FEMS Immunol Med Microbiol

Med Hypothesis

Trans Proc

Transplant Immunol

Investigation of sudden infant deaths

Paediatrician

Sudden infant death syndrome

Sudden infant death in historical perspective

J Clin Pathol

The effect of anaesthesia on anaphylaxis in guinea-pigs

Clin Exp Immun

Interaction between bedding and sleeping position in the Sudden Infant Death Syndromea population based case control study

Br Med J