Chiea C. Khor

A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis.

Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4–6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 × 10−8). We found that the Mal S180L variant attenuated TLR2 signal transduction.

Leprosy and the adaptation of human toll-like receptor 1.

Leprosy is an infectious disease caused by the obligate intracellular pathogen Mycobacterium leprae and remains endemic in many parts of the world. Despite several major studies on susceptibility to leprosy, few genomic loci have been replicated independently. We have conducted an association analysis of more than 1,500 individuals from different case-control and family studies, and observed consistent associations between genetic variants in both TLR1 and the HLA-DRB1/DQA1 regions with susceptibility to leprosy (TLR1 I602S, case-control Pu200a=u200a5.7×10−8, ORu200a=u200a0.31, 95% CIu200a=u200a0.20–0.48, and HLA-DQA1 rs1071630, case-control Pu200a=u200a4.9×10−14, ORu200a=u200a0.43, 95% CIu200a=u200a0.35–0.54). The effect sizes of these associations suggest that TLR1 and HLA-DRB1/DQA1 are major susceptibility genes in susceptibility to leprosy. Further population differentiation analysis shows that the TLR1 locus is extremely differentiated. The protective dysfunctional 602S allele is rare in Africa but expands to become the dominant allele among individuals of European descent. This supports the hypothesis that this locus may be under selection from mycobacteria or other pathogens that are recognized by TLR1 and its co-receptors. These observations provide insight into the long standing host-pathogen relationship between human and mycobacteria and highlight the key role of the TLR pathway in infectious diseases.

CD209 Genetic Polymorphism and Tuberculosis Disease

Background Tuberculosis causes significant morbidity and mortality worldwide, especially in sub-Saharan Africa. DC-SIGN, encoded by CD209, is a receptor capable of binding and internalizing Mycobacterium tuberculosis. Previous studies have reported that the CD209 promoter single nucleotide polymorphism (SNP)-336A/G exerts an effect on CD209 expression and is associated with human susceptibility to dengue, HIV-1 and tuberculosis in humans. The present study investigates the role of the CD209 -336A/G variant in susceptibility to tuberculosis in a large sample of individuals from sub-Saharan Africa. Methods and Findings A total of 2,176 individuals enrolled in tuberculosis case-control studies from four sub-Saharan Africa countries were genotyped for the CD209 -336A/G SNP (rs4804803). Significant overall protection against pulmonary tuberculosis was observed with the -336G allele when the study groups were combined (nu200a=u200a914 controls vs. 1262 cases, Mantel-Haenszel 2x2 χ2u200a=u200a7.47, Pu200a=u200a0.006, odds ratiou200a=u200a0.86, 95%CI 0.77–0.96). In addition, the patients with -336GG were associated with a decreased risk of cavitory tuberculosis, a severe form of tuberculosis disease (nu200a=u200a557, Pearsons 2×2 χ2u200a=u200a17.34, Pu200a=u200a0.00003, odds ratiou200a=u200a0.42, 95%CI 0.27–0.65). This direction of association is opposite to a previously observed result in a smaller study of susceptibility to tuberculosis in a South African Coloured population, but entirely in keeping with the previously observed protective effect of the -336G allele. Conclusion This study finds that the CD209 -336G variant allele is associated with significant protection against tuberculosis in individuals from sub-Saharan Africa and, furthermore, cases with -336GG were significantly less likely to develop tuberculosis-induced lung cavitation. Previous in vitro work demonstrated that the promoter variant -336G allele causes down-regulation of CD209 mRNA expression. Our present work suggests that decreased levels of the DC-SIGN receptor may therefore be protective against both clinical tuberculosis in general and cavitory tuberculosis disease in particular. This is consistent with evidence that Mycobacteria can utilize DC-SIGN binding to suppress the protective pro-inflammatory immune response.

PTPN22 and invasive bacterial disease.

Vang et al.1 recently reported that the protein tyrosine phosphatase PTPN22 Trp620 variant is a gain-of-function mutant, resulting in increased PTPN22 phosphatase activity in T cells. This variant is associated with susceptibility to multiple autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and autoimmune thyroid disease2, 3, 4, 5, 6. Based on the observation that Trp620 downregulates T cell responses1, we hypothesized that the PTPN22 R620W polymorphism may be associated with susceptibility to invasive bacterial infection.

Common NFKBIL2 polymorphisms and susceptibility to pneumococcal disease: a genetic association study

IntroductionStreptococcus pneumoniae remains a major global health problem and a leading cause of death in children worldwide. The factors that influence development of pneumococcal sepsis remain poorly understood, although increasing evidence points towards a role for genetic variation in the hosts immune response. Recent insights from the study of animal models, rare human primary immunodeficiency states, and population-based genetic epidemiology have focused attention on the role of the proinflammatory transcription factor NF-κB in pneumococcal disease pathogenesis. The possible role of genetic variation in the atypical NF-κB inhibitor IκB-R, encoded by NFKBIL2, in susceptibility to invasive pneumococcal disease has not, to our knowledge, previously been reported upon.MethodsAn association study was performed examining the frequencies of nine common NFKBIL2 polymorphisms in two invasive pneumococcal disease case-control groups: European individuals from hospitals in Oxfordshire, UK (275 patients and 733 controls), and African individuals from Kilifi District Hospital, Kenya (687 patients with bacteraemia, of which 173 patients had pneumococcal disease, together with 550 controls).ResultsFive polymorphisms significantly associated with invasive pneumococcal disease susceptibility in the European study, of which two polymorphisms also associated with disease in African individuals. Heterozygosity at these loci was associated with protection from invasive pneumococcal disease (rs760477, Mantel-Haenszel 2 × 2 χ2 = 11.797, P = 0.0006, odds ratio = 0.67, 95% confidence interval = 0.53 to 0.84; rs4925858, Mantel-Haenszel 2 × 2 χ2 = 9.104, P = 0.003, odds ratio = 0.70, 95% confidence interval = 0.55 to 0.88). Linkage disequilibrium was more extensive in European individuals than in Kenyans.ConclusionsCommon NFKBIL2 polymorphisms are associated with susceptibility to invasive pneumococcal disease in European and African populations. These findings further highlight the importance of control of NF-κB in host defence against pneumococcal disease.

Positive replication and linkage disequilibrium mapping of the Chromosome 21q22.1 malaria susceptibility locus

Four cytokine receptor genes are located on Chr21q22.11, encoding the α and β subunits of the interferon-α receptor (IFNAR1 and IFNAR2), the β subunit of the interleukin 10 receptor (IL10RB) and the second subunit of the interferon-γ receptor (IFNGR2). We previously reported that two variants in IFNAR1 were associated with susceptibility to malaria in Gambians. We now present an extensive fine-scale mapping of the associated region utilizing 45 additional genetic markers obtained from public databases and by sequencing a 44u2009kb region in and around the IFNAR1 gene in 24 Gambian children (12 cases/12 controls). Within the IFNAR1 gene, a newly studied C → G single-nucleotide polymorphism (IFNAR1 272354c-g) at position −576 relative to the transcription start was found to be more strongly associated with susceptibility to severe malaria. Association was observed in three populations: in Gambian (P=0.002), Kenyan (P=0.022) and Vietnamese (P=0.005) case–control studies. When all three studies were combined, using the Mantel–Haenszel test, the presence of IFNAR1 −576G was associated with a substantially elevated risk of severe malaria (N=2444, OR=1.38, 95% CI: 1.17–1.64; P=1.7 × 10−4). This study builds on previous work to further highlight the importance of the type-I interferon pathway in malaria susceptibility and illustrates the utility of typing SNPs within regions of high linkage disequilibrium in multiple populations to confirm initial positive associations.

Mannose-binding lectin genotypes: lack of association with susceptibility to thoracic empyema

BackgroundThe role of the innate immune protein mannose-binding lectin (MBL) in host defence against severe respiratory infection remains controversial. Thoracic empyema is a suppurative lung infection that arises as a major complication of pneumonia and is associated with a significant mortality. Although the pathogenesis of thoracic empyema is poorly understood, genetic susceptibility loci for this condition have recently been identified. The possible role of MBL genotypic deficiency in susceptibility to thoracic empyema has not previously been reported.MethodsTo investigate this further we compared the frequencies of the six functional MBL polymorphisms in 170 European individuals with thoracic empyema and 225 healthy control individuals.ResultsNo overall association was observed between MBL genotypic deficiency and susceptibility to thoracic empyema (2 × 2 Chi square = 0.02, P = 0.87). Furthermore, no association was seen between MBL deficiency and susceptibility to the Gram-positive or pneumococcal empyema subgroups. MBL genotypic deficiency did not associate with progression to death or requirement for surgery.ConclusionsOur results suggest that MBL genotypic deficiency does not associate with susceptibility to thoracic empyema in humans.

Reply to ”Analysis of association of the TIRAP (MAL) S180L variant and tuberculosis in three populations”

of rs8177374 with all four infectious diseases jointly and used a combined statistic (P = 9.6 × 10−8) as evidence of association for each of them. However, tuberculosis, invasive pneumococcal disease, malaria and bacteremia (with various Gram-positive or Gram-negative bacteria) are rather different infections, comprising multiple specific pathways of infection and host defense. Consequently, even if TIRAP protein was involved in each of these diseases, the relative contribution of its S180L variant to the etiology of each disease would be expected to vary. Combining, in one association test, disease A, in which a genetic variant has an effect, and disease B, in which the same variant has no effect reduces the overall power of the test to detect association with disease A and may lead to false conclusions about the association with disease B. If adopted by the research community, this approach may lead to false association reports, based on combinations of small cohorts from various diseases. Although it is conceivable that immunity against different infectious diseases involves common pathways, and some genetic variants in these pathways may predispose to multiple diseases, we suggest that datasets for distinct diseases should not be combined in the same association test, and convincing evidence of genetic association must be established for each disease individually. We have no statistically powerful sample collections to address association of rs8177374 with invasive pneumococcal disease, bacteremia and malaria. However, lack of support for an association of rs8177374 with tuberculosis in our study undermines results of the ‘multiple diseases test’ done by Khor et al. and the credibility of association between rs8177374 and the three other diseases.