TIRAP (MAL) S180L polymorphism is a common protective factor against developing tuberculosis and systemic lupus erythematosus
Introduction
The involvement of Toll-like receptors (TLRs)-mediated pathways in infectious, autoimmune and inflammatory disease has been shown (Mansell et al., 2004, Takeda, 2005). TLRs are pattern recognition receptors of the innate immune system that recognize a wide variety of molecules which lead to the transcription of proinflammatory genes through a complex signaling cascade (Horng et al., 2001). Thus, activation of TLRs pathways may control not only host defense against pathogens but also autoimmune responses.
The MyD88 adaptor-like (Mal), also known as TIR domain-containing adaptor protein (TIRAP), is a cytoplasmic structure of 221 amino acids in length encoded by a gene holding the same name at chromosome 11q24.2. Functionally, TIRAP is implicated in the TLR2- and TLR4-mediated MyD88-dependent signaling pathway. The MyD88 was the first adapter in the family of the TIR domain-containing adaptor proteins to be described (Janssens and Beyaert, 2002). TIRAP resembles MyD88 in that it is involved in the early activation of NFκB and MAP kinases, but its use is essential and restricted to TLR2 and TLR4 (Mansell et al., 2004). Heterozygous carriage of the TIRAP single nucleotide polymorphism (SNP) rs8177374 (C/T), which encodes a leucine substitution at serine 180 of Mal (S180L) was showed to be associated with a decreased risk against pneumococcal disease, bacteremia, malaria and tuberculosis (TB) in English and African populations (Khor et al., 2007). Since S180L leads to an amino acid substitution in which Mal attenuates TLR2 and TLR4 signaling and thereby protects against excessive inflammation (Mansell et al., 2004), we hypothesized that variations at this TIRAP rs8177374 SNP might influence the susceptibility not only to common infectious diseases but also to autoimmune diseases. Therefore, we underwent the current study to examine the effect of TIRAP (MAL) polymorphism S180L in patients with TB and autoimmune diseases from a Colombian population (Latin American individuals).
TB is a contagious and potentially fatal disease caused by Mycobacterium tuberculosis that affects almost any part of the body but manifests mainly as an infection of the lungs. Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies, B-cell hyperactivation, and defective clearance of immune complexes, affecting several organs (Tan et al., 1982). Primary Sjögren's syndrome (pSS) is a late-onset autoimmune disease characterized by lymphocytic and plasma cell infiltration of the salivary and lachrymal glands, as well as by the production of autoantibodies leading to dryness of mucosa, mainly oral and lachrymal (Vitali et al., 2002). Rheumatoid arthritis (RA) is characterized by an autoimmune polyarthritis with progressive damage of diarthrodial joints leading to disability, increased comorbidity and premature mortality (Arnett et al., 1988). Type 1 diabetes mellitus (T1D) is an organ-specific autoimmune disease resulting from the damage of insulin-producing pancreatic β cells (Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 1997).
Section snippets
Methods
The whole sample was constituted by 1325 individuals, of whom 976 were included in a case–control study. The rest of individuals were T1D affected probands (n = 68) and their relatives (n = 281) who were included in a family based study (n = 65). They belonged to a well defined and homogeneous northwestern Colombian population with a low rate of admixture (Bravo et al., 1996), with a calculated ancestral ethnic component of 85% Caucasian and 15% Amerindian (Correa et al., 2002, Bedoya et al., 2006).
Results
All patient and control groups fulfilled the Hardy–Weinberg proportions for the polymorphism S180L. As expected, the population involved in this study was not stratified (Fst = 0.01). Differences in the allelic frequencies according to gender were not observed. The Leu180 allele was associated with a decrease of 73% in the risk of SLE and a decrease of 50% in the risk of TB (Table 1). The calculated false-positive report probability for the Leu180 allele was 0.02–0.013 in SLE, while for TB was
Discussion
Replication of promising initial results is a necessary step to assess the genetic contribution to human disease. With this goal, the present study was conducted to confirm earlier findings in TB, and to explore a possible influence of TIRAP (MAL) polymorphism on autoimmune diseases. When data are interpreted in the context of earlier results (Khor et al., 2007), association between TIRAP (MAL) S180L and TB was reproduced and confirmed to be true (Manly, 2005). Nevertheless, as for many
Acknowledgements
We thank all patients and participants in this study and to Juan G. McEwen for his support. This study was granted by the “Comité para el Desarrollo de la Investigación” of the Universidad de Antioquia (Sostenibilidad 2007–2008), Medellin, Colombia, and the Rosario University, Bogotá, Colombia.
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