Journal Article

Influence of Polymorphisms in Innate Immunity Genes on Susceptibility to Invasive Aspergillosis after Stem Cell Transplantation

Jolink, Hetty, van der Heiden, Pim L. J., Kremer, Dennis, van Dissel, Jaap T., de Boer, Mark G. J., Halkes, Constantijn J. M., Falkenburg, J. H. Frederik, van de Vosse, Esther

2011

Overview

The innate immune system plays a pivotal role in the primary defence against invasive fungal infection. Genetic variation in genes that regulate this response, initiated by pulmonary macrophages, may influence susceptibility to invasive aspergillosis in patients at risk. We investigated in a clinical setting whether common polymorphisms in Toll-like receptor (TLR) and cytokine genes involved in macrophage regulation are associated with susceptibility to invasive aspergillosis. Forty-four allogeneic stem cell transplantation recipients diagnosed with probable or proven IA according to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group, were enrolled. The control group consisted of 64 allogeneic stem cell transplantation recipients without invasive aspergillosis. The TLR4 1063A>G single nucleotide polymorphism was associated with invasive aspergillosis when present in donors of allogeneic stem cell transplantation recipients (unadjusted OR 3.77 95%CI 1.08-13.2, p = 0.03). In a multivariate analysis, adjusted for occurrence of graft-versus-host-disease, Cytomegalovirus serostatus and duration of neutropenia, paired presence of the TLR4 1063A>G and IFNG 874T>A single nucleotide polymorphisms showed a trend towards increased susceptibility to invasive aspergillosis (p = 0.04). These findings point to the relevant immunological pathway involved in resistance to invasive aspergillosis and warrant further study of the effects of TLR and cytokine polymorphisms and their interaction, which may occur on different levels of the complex biological interplay between the immunocompromised host and Aspergillus sp.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Analysis / Aspergillosis / Aspergillosis - etiology / Aspergillosis - genetics / Aspergillus / Binding sites / Biology / Bone marrow / Cancer / Cytokines / Cytomegalovirus / Deoxyribonucleic acid / Disease susceptibility / DNA / Epidemiology / Female / Fungal infections / Gene expression / Gene Frequency / Gene regulation / Genes / Genetic aspects / Genetic diversity / Genetic Predisposition to Disease - genetics / Haplotypes / Health aspects / Hematology / Humans / Immune system / Immunity / Immunity, Innate - genetics / Immunology / Infectious diseases / Innate immunity / Interferon-gamma - genetics / Interleukin-12 - genetics / Invasiveness / Leukemia / Lymphoma / Macrophages / Macrophages - immunology / Macrophages - metabolism / Male / Medical research / Medicine / Middle Aged / Multivariate analysis / Neutropenia / Nucleotides / Pathogenesis / Polymorphism / Polymorphism, Single Nucleotide / Proteins / Risk factors / Single nucleotide polymorphisms / Single-nucleotide polymorphism / Stem cell transplantation / Stem Cell Transplantation - adverse effects / Stem cells / TLR4 protein / Toll-like receptors / Toll-Like Receptors - genetics / Transplantation / Transplants & implants / Tuberculosis