Control of Salmonella enterica serovar Typhimurium (S. typhimurium) infection in the mouse model of typhoid fever is critically dependent on the natural resistance–associated macrophage protein 1 (Nramp1). In this study, we examined the role of genetic polymorphisms in the human homologue, NRAMP1 in resistance to typhoid fever in southern Vietnam. Patients with blood-culture–confirmed typhoid fever and healthy control subjects were genotyped for 6 polymorphic markers within and near NRAMP1 on chromosome 2q35. Four single base-pair polymorphisms (274 C/T, 469+14 G/C, 1465−85 G/A, and D543N), a (GT)n repeat in the promoter region of NRAMP1 and D2S1471, and a microsatellite marker ∼130-kb downstream of NRAMP1 were examined. The allelic and genotypic frequencies for each polymorphism were compared in case patients and control subjects. No allelic association was identified between the NRAMP1 alleles and typhoid fever susceptibility. In addition, neither homozygotes nor heterozygotes for any NRAMP1 variants were at increased risk of typhoid fever
On the basis of population genomic and phylogeographic analyses of 1669 Mycobacterium tuberculosis lineage 4 (L4) genomes, we find that dispersal of L4 has been completely dominated by historical migrations out of Europe. We demonstrate an intimate temporal relationship between European colonial expansion into Africa and the Americas and the spread of L4 tuberculosis (TB). Markedly, in the age of antibiotics, mutations conferring antimicrobial resistance overwhelmingly emerged locally (at the level of nations), with minimal cross-border transmission of resistance. The latter finding was found to reflect the relatively recent emergence of these mutations, as a similar degree of local restriction was observed for susceptible variants emerging on comparable time scales. The restricted international transmission of drug-resistant TB suggests that containment efforts at the level of individual countries could be successful.
Abstract Tuberculosis (TB) continues to be a leading cause of morbidity and mortality worldwide. Past genome-wide association studies (GWAS) have explored TB susceptibility across various ethnic groups, yet a significant portion of TB heritability remains unexplained. In this study, we conducted GWAS in the Singapore Chinese and Vietnamese, followed by a comprehensive meta-analysis incorporating independent East Asian data, and identified a novel pulmonary TB (PTB) susceptibility locus at 22q12.2 [rs6006426, OR(95%Cl)=1.097(1.066, 1.130), P meta =3.31×10 -10 ]. Our lead SNP was found to affect the expression of SF3A1 in various immune-related cells ( P ranging from 1.48×10 -9 to 6.17×10 - 18 ). Furthermore, a significant association was observed between rs6006426 and cigarette smoking ( P <0.044). When exploring the interplay between genetic marker, smoking and TB, our findings indicated that smoking status significantly mediated the effect of rs6006426 on PTB (β indirect-effect =-0.004, P indirect-effect =0.020). Our findings offer novel insights into the genetic factors underlying TB and reveals new avenues for understanding its etiology.
ABSTRACT Rationale Lung mucins are an understudied component of the mucosal immune response and may influence tuberculosis pathogenesis and outcomes. Objectives To assess if variants in lung mucins MUC5B and MUC5AC are associated with Mycobacterium tuberculosis immune responses, susceptibility, and outcomes. Methods We characterized four haplotype tagging single nucleotide polymorphisms (SNPs) in MUC5B and MUC5AC for association with log 2 TNF concentrations in cerebral spinal fluid (CSF) from TBM patients. SNPs associated with CSF TNF concentrations were carried forward for analyses of pulmonary and meningeal TB susceptibility and TBM mortality. Measurements and Main Results MUC5AC SNP rs28737416 T allele was associated with lower CSF concentrations of TNF(p=1.8*10 −8 ) and IFNγ(p=2.3*10 −6 ), and higher TBM, but not pulmonary TB, susceptibility (OR 1.24, 95% confidence interval 1.03, 1.49; p=0.021). Mortality from TBM was higher among participants with the rs28737416 T/T and T/C genotype (35/119, 30.4%) versus the C/C genotype (11/89, 12.4%; log-rank p=0.005) in a Vietnamese cohort (N=211). This finding was confirmed in an independent Vietnamese validation cohort (N=87; 9/87, 19.1% vs 1/20, 2.5%; log-rank p=0.02) and an Indonesian validation cohort (N=468, 127/287, 44.3% vs 65/181, 35.9%, log-rank p=0.06). Conclusions The MUC5AC rs28737416 T/T and T/C genotypes were associated with higher susceptibility and mortality from TBM and lower CSF concentrations of TNF and IFNγ compared to the C/C genotype, suggesting that MUC5AC contributes to immune changes that influence TBM outcomes.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effect has proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum infection.Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multicentre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual's level of enzyme activity from their genotype.Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia.Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations.
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