ABSTRACT
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 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction.
Subject(s)
Bacteremia/genetics , Malaria/genetics , Membrane Transport Proteins/genetics , Myelin Proteins/genetics , Pneumococcal Infections/genetics , Polymorphism, Single Nucleotide , Proteolipids/genetics , Tuberculosis/genetics , Africa , Case-Control Studies , Genetic Predisposition to Disease , Humans , Linkage Disequilibrium , Membrane Glycoproteins/genetics , Membrane Transport Proteins/physiology , Models, Molecular , Myelin Proteins/physiology , Myelin and Lymphocyte-Associated Proteolipid Proteins , Polymorphism, Single Nucleotide/physiology , Proteolipids/physiology , Receptors, Interleukin-1/genetics , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 4/metabolism , United Kingdom , VietnamABSTRACT
Interleukin-1 (IL1) is a potent endogenous pyrogen and inducer of the acute phase response, and these innate immune responses are an important part of the human host's initial reaction to infection by the malaria parasite. In addition, several single-nucleotide polymorphisms (SNPs) in this region have previously been demonstrated to be associated with susceptibility to infectious disease. Therefore, a possible association with malaria susceptibility was investigated. A total of 13 polymorphic markers were used in a two-stage screening strategy to genotype a Gambian case-control study group by either restriction endonuclease digestion or the Sequenom MassARRAY assay. This involved an initial screen of 188 severe cases and 188 mild controls, and if there was a significant association with a malaria phenotype (P<0.05); this was followed by screening of the remaining 1044 samples. Two markers showed significant association with malaria: interleukin-1 alpha +4845 G --> T (P=0.035 for mild malaria versus controls) and interleukin-1 beta +3953 C --> T (P=0.030 for mild malaria versus severe malaria). Haplotypes constructed using the SNPHAP programme were not associated with any of the malaria phenotypes investigated. In summary, if IL1 variants are involved in malaria susceptibility in the Gambia at all, then the effects are small.
Subject(s)
Genetic Predisposition to Disease , Interleukin-1/genetics , Malaria/genetics , Multigene Family , Polymorphism, Single Nucleotide , Case-Control Studies , Gambia , HumansABSTRACT
Malaria continues to claim the lives of more children worldwide than any other infectious disease, and improved understanding of disease immunology is a priority for the development of new therapeutic and vaccination strategies. FcgammaRIIa (CD32) contains a polymorphic variant (H/R131) that has been associated with variability in susceptibility to both bacterial diseases and Plasmodium falciparum parasitemia. We investigated the role of this polymorphism in West Africans with mild and severe malarial disease. The HH131 genotype was significantly associated with susceptibility to severe malaria (P = 0.03, odds ratio = 1.40, 95% confidence interval = 1.02-1.91). In contrast to studies of parasitemia, the presence of the R131 allele, rather than the RR131 genotype, appeared to be the important factor in protection from disease. This is the first evidence for an association between CD32 polymorphism and severe malaria and provides an example of balancing selective pressures from different infectious diseases operating at the same genetic locus.
Subject(s)
Antigens, CD/genetics , Genetic Predisposition to Disease , Malaria, Cerebral/genetics , Receptors, IgG/genetics , Animals , Case-Control Studies , Child , Child, Preschool , Female , Gambia , Humans , Infant , Infant, Newborn , Malaria, Cerebral/pathology , Malaria, Cerebral/prevention & control , Male , Plasmodium falciparum , Polymorphism, Genetic , Severity of Illness IndexABSTRACT
The influence of haptoglobin polymorphisms on severe malaria occurrence was assessed in 1183 individuals from The Gambia. No significant association was found between severe malaria and either haptoglobin genotypes or phenotypes. The advantages of using a deoxyribonucleic acid-based haptoglobin typing method are discussed.
Subject(s)
Haptoglobins/genetics , Malaria, Falciparum/genetics , Polymorphism, Genetic , Case-Control Studies , Gambia , Gene Frequency , Genetic Predisposition to Disease , Genotype , Humans , Immunity, Innate/genetics , Malaria, Falciparum/immunologyABSTRACT
BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a fatal, untreatable prion encephalopathy. Previous studies showed that doxycycline is effective in in-vitro and in-vivo models of disease, and patients with CJD who received compassionate treatment with doxycycline showed increased survival time compared with historical series. We therefore did a randomised, double-blind study of doxycycline versus placebo in CJD. METHODS: We recruited patients older than 18 years old who had a diagnosis of definite or probable sporadic CJD or genetic forms of the disease via Italian reference centres and the French national referral system. Patients were randomly assigned (ratio 1:1) to receive oral doxycycline (100 mg daily) or placebo under double-blind conditions from the day of randomisation to death. Centralised randomisation was done independently of enrolment or evaluation of patients using a minimisation method in Italy and a simple randomisation in France. Participants, caregivers, and clinicians were masked to group assignment. The primary efficacy variable was the survival time from randomisation. Interim analyses were planned to detect a significant effect of treatment as early as possible. This trial is registered with EudraCT, 2006-001858-27 for the Italian study and 2007-005553-34 for the French study. FINDINGS: From April 12, 2007, to Aug 19, 2010, in Italy, and from Jan 30, 2009, to Jan 10, 2012, in France, 121 patients with CJD were enrolled in the study, 62 of whom were randomly assigned to the treatment group and 59 to the placebo group. The first interim analysis showed absence of superiority of doxycycline compared with placebo, and the trial was stopped for futility. Efficacy analyses did not show significant differences between patients treated with doxycycline and placebo with regard to survival times (HR 1.1, 95% CI 0.8-1.7, p=0.50). Serious adverse events were judged not to be related to treatment, whereas a relation was deemed probable or possible for five non-serious adverse events that occurred in each treatment group. INTERPRETATION: Doxycycline at a dose of 100 mg per day was well tolerated but did not significantly affect the course of CJD, at variance with the results of previous observational studies. Our experience could be useful in the design of large multinational controlled trials of potential anti-prion molecules in this rare disease. FUNDING: Agenzia Italiana Farmaco, Italian Ministry of Health, AIEnP, and French Ministry of Health.