Association of common single-nucleotide polymorphisms in innate immune genes with differences in TLR-induced cytokine production in neonates

Abstract

Significant variability in cytokine and chemokine expression after Toll-like receptor (TLR) stimulation has been observed between individuals. In this study, we determined the immunophenotypic variation in a cohort of 152 neonates associated with specific single-nucleotide polymorphisms (SNPs). We identified 23 SNPs in 12 genes of the innate immune system to be significantly associated with differential cytokine and chemokine production. SNPs in three gene families, namely STAT, IRF and SYK, accounted for most associations. These gene families are important signaling components of the innate anti-viral response. A potentially damaging non-synonymous SNP in the TLR3 gene (rs3775291) associated with significant differences in expression of interferon-γ after stimulation with the synthetic TLR3 ligand, poly (I:C). Additionally, a general increase in cytokine production was observed in subjects of Asian descent. This observation could be associated with differences in SNP genotype distribution between racial groups in our cohort. Taken together, our data suggest that particular aspects of the newborn innate response to TLR stimulation are closely associated with genetic variation. These findings provide the basis for detailed molecular dissection of cause-effect relationships between genotype and immune responses, and may account for inter-individual differences in response to vaccination and risk for infection and autoimmune disease.

Pattern recognition receptor-mediated cytokine response in infants across 4 continents⋆

“…We have recently shown that variation in innate immune responses can be influenced by single nucleotide polymorphisms within the PRR pathways and that the prevalence of these single nucleotide polymorphisms varies within different racial backgrounds 39 . It is thus entirely possible that genetic differences (including variation in HLA) between our populations contributed to the differences in functional responses we measured between sites.…”

Adjuvants in the Driver’s Seat: How Magnitude, Type, Fine Specificity and Longevity of Immune Responses Are Driven by Distinct Classes of Immune Potentiators

“…Responses to adjuvanted vaccines are also significantly affected by polymorphisms in innate immune receptors (e.g., TLR [ 200 ]) and/or other immune factors [ 200 , 201 ] and have not only been linked to autoimmunity (reviewed in [ 202 ]) but also been blamed for the failure of certain vaccines [ 203 ]. Cytokine expression levels are controlled by polymorphisms and for example in the case of IL-10, these polymorphisms have been shown to correlate with disease susceptibility (and likely also responsiveness to vaccines) when modeled in humanized mice [ 204 ].…”

p.Glu477Lys mutation in keratin 5 is not necessarily mortal in generalized severe epidermolysis bullosa simplex

“…1 A cohort study suggested that single nucleotide polymorphisms in Toll-like receptor response pathways are associated with the general increase in inflammatory cytokine production in subjects of Asian descent. 4 In summary, daily intensive dressing care has prevented our infant patient with KRT5 p.Glu477Lys mutation from developing lethal complications. Our case therefore offers hope to all GS-EBS patients with the same mutation and their caregivers.…”