Genetic and Environmental Factors Affecting TNF-α Responses in Relation to Sudden Infant Death Syndrome.

Sophia M Moscovis,Ann E Gordon,Christine Burns,Maree Gleeson,Rodney J Scott,Osama M Al Madani,Caroline Blackwell,Sharron T Hall

doi:10.3389/fimmu.2015.00374

Abstract

Dysregulation of the inflammatory responses has been suggested to contribute to the events leading to sudden infant deaths. Our objectives were (1) to analyze a single nucleotide polymorphism (SNP) associated with high levels of tumor necrosis factor-α (TNF-α) responses, TNF G-308A, in sudden infant death syndrome (SIDS) infants, SIDS and control parents, and ethnic groups with different incidences of SIDS; (2) the effects of two risk factors for SIDS, cigarette smoke and virus infection, on TNF-α responses; and (3) to assess effects of genotype, cigarette smoke, and gender on TNF-α responses to bacterial toxins identified in SIDS infants. TNF G-308A genotypes were determined by real-time polymerase chain reaction for SIDS infants from Australia, Germany, and Hungary; parents of SIDS infants and their controls; and populations with high (Aboriginal Australian), medium (Caucasian), and low (Bangladeshi) SIDS incidences. Leukocytes from Caucasian donors were stimulated in vitro with endotoxin or toxic shock syndrome toxin-1 (TSST-1). TNF-α responses were measured by L929 bioassay (IU/ml) and assessed in relation to genotype, smoking status, and gender. There was a significantly higher proportion of the minor allele AA genotype among Australian SIDS infants (6/24, 24%) compared to 3/62 (4.8%) controls (p = 0.03). There were no significant differences in TNF-α responses by TNF G-308A genotypes when assessed in relation to smoking status or gender. Given the rarity of the TNF G-308A A allele in Caucasian populations, the finding that 24% of the Australian SIDS infants tested had this genotype requires further investigation and cautious interpretation. Although non-smokers with the AA genotype had higher TNFα responses to both TSST-1 and endotoxin, there were too few subjects with this rare allele to obtain statistically valid results. No effects of genotype, smoking, or gender were observed for TNF-α responses to these toxins.

Highlights

Tumor necrosis factor-α (TNF-α) is a key pro-inflammatory cytokine which could play a role in several of the mechanisms proposed to explain sudden infant death syndrome (SIDS)
Distribution of TNF G-308A among SIDS Infants The majority of each SIDS group possessed the GG genotype; Australian SIDS infants had a significant increase in proportion with the AA genotype (6/25, 24%) compared to the Hungarian (0/18, 0%) (p = 0.09) and German (0/46, 0%) (p < 0.01) SIDS infants
The distribution of allele frequencies for the Australian control population differed significantly from that observed for Australian SIDS infants (p = 0.02)

Summary

Introduction

Tumor necrosis factor-α (TNF-α) is a key pro-inflammatory cytokine which could play a role in several of the mechanisms proposed to explain sudden infant death syndrome (SIDS). TNF-α induces fever and affects respiration [1] and can affect myocardial function. TNF and SIDS [2, 3]. One of its single nucleotide polymorphisms (SNPs), TNF G-308A, has been associated with severe responses to infection. Cytokine gene polymorphisms can significantly affect the level of these substances produced in response to infection [4]. In vitro studies found that the A allele was associated with increased responses [5] and individuals homozygous for the A allele had higher levels of circulating TNF-α [6]. The molecular basis for the A allele being a more powerful transcriptional activator is not clear; the region −323 to −285 has been found to bind nuclear factors differently compared with the corresponding G allele [7]

Objectives

Methods

Results