Genome-wide association study of leprosy in Malawi and Mali

Leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae. Despite recent improvements in disease control, leprosy remains an important cause of infectious disability globally. Large-scale genetic association studies in Chinese, Vietnamese and Indian populations have identified over 30 susceptibility loci for leprosy. There is a significant burden of leprosy in Africa, however it is uncertain whether the findings of published genetic association studies are generalizable to African populations. To address this, we conducted a genome-wide association study (GWAS) of leprosy in Malawian (327 cases, 436 controls) and Malian (247 cases, 368 controls) individuals. In that analysis, we replicated four risk loci previously reported in China, Vietnam and India; MHC Class I and II, LACC1 and SLC29A3. We further identified a novel leprosy susceptibility locus at 10q24 (rs2015583; combined p = 8.81 × 10-9; OR = 0.51 [95% CI 0.40 - 0.64]). Using publicly-available data we characterise regulatory activity at this locus, identifying ACTR1A as a candidate mediator of leprosy risk. This locus shows evidence of recent positive selection and demonstrates pleiotropy with established risk loci for inflammatory bowel disease and childhood-onset asthma. A shared genetic architecture for leprosy and inflammatory bowel disease has been previously described. We expand on this, strengthening the hypothesis that selection pressure driven by leprosy has shaped the evolution of autoimmune and atopic disease in modern populations. More broadly, our data highlights the importance of defining the genetic architecture of disease across genetically diverse populations, and that disease insights derived from GWAS in one population may not translate to all affected populations

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Taha Toros Arşivi, Dosya No: 220-Kaptanzade Ali Rıza Be

Candidate polymorphisms and severe malaria in a Malian population.

Malaria is a major health burden in sub-Saharan African countries, including Mali. The disease is complex, with multiple genetic determinants influencing the observed variation in response to infection, progression, and severity. We assess the influence of sixty-four candidate loci, including the sickle cell polymorphism (HbS), on severe malaria in a case-control study consisting of over 900 individuals from Bamako, Mali. We confirm the known protective effects of the blood group O and the HbS AS genotype on life-threatening malaria. In addition, our analysis revealed a marginal susceptibility effect for the CD40 ligand (CD40L)+220C allele. The lack of statistical evidence for other candidates may demonstrate the need for large-scale genome-wide association studies in malaria to discover new polymorphisms. It also demonstrates the need for establishing the region-specific repertoire of functional variation in important genes, including the glucose-6-phosphatase deficiency gene, before embarking on focused genotyping

Safety of epoietin beta-quinine drug combination in children with cerebral malaria in Mali

cerebral malaria in Mal

Protection of Malian children from clinical malaria is associated with recognition of multiple antigens

Contains fulltext : 153754.pdf (publisher's version ) (Open Access)BACKGROUND: Naturally acquired immunity to clinical malaria is thought to be mainly antibody-mediated, but reports on antigen targets are contradictory. Recognition of multiple antigens may be crucial for protection. In this study, the magnitude of antibody responses and their temporal stability was assessed for a panel of malaria antigens in relation to protection against clinical Plasmodium falciparum malaria. METHODS: Malian children aged two to 14 years were enrolled in a longitudinal study and followed up by passive and active case detection for seven months. Plasma was collected at enrolment and at the beginning, in the middle and after the end of the transmission season. Antibody titres to the P. falciparum-antigens apical membrane protein (AMA)-1, merozoite surface protein (MSP)-1(1)(9), MSP-3, glutamine-rich protein (GLURP-R0) and circumsporozoite antigen (CSP) were assessed by enzyme-linked immunosorbent assay (ELISA) for 99 children with plasma available at all time points. Parasite carriage was determined by microscopy and nested PCR. RESULTS: Antibody titres to all antigens, except MSP-1(1)(9), and the number of antigens recognized increased with age. After malaria exposure, antibody titres increased in children that had low titres at baseline, but decreased in those with high baseline responses. No significant differences were found between antibody titers for individual antigens between children remaining symptomatic or asymptomatic after exposure, after adjustment for age. Instead, children remaining asymptomatic following parasite exposure had a broader repertoire of antigen recognition. CONCLUSIONS: The present study provides immune-epidemiological evidence from a limited cohort of Malian children that strong recognition of multiple antigens, rather than antibody titres for individual antigens, is associated with protection from clinical malaria

Description of Acinetobacter ihumii sp. nov., Microbacterium ihumii sp. nov., and Gulosibacter massiliensis sp. nov., three new bacteria isolated from human blood

International audienceAbstract Blood is precious tissue that is normally sterile. With the aim of diagnosing the cause of bacteremia, three bacterial strains were isolated from three different individuals. Strains Marseille-P7157T and Marseille-Q2854T are Gram-stain positive, non-spore-forming rod-shaped bacteria, while strain Marseille-P8049T is a Gram-stain negative, motile, non-spore-forming and rod-shaped bacterium. The major fatty acids found (>30%) were hexadecanoic acid for strain Marseille-P8049T and 12-methyl tetradecanoic acid for both strains Marseille-P7157T and Marseille-P2854T. The 16S rRNA gene sequence analysis shows that strains Marseille-P8049 and Marseille-Q2854T have sequence similarity of 96.8%, 99.04%, and 98.3% with Acinetobacter ursingii strain LUH3792 (NR_025392.1), Gulosibacter faecalis strain B187 (NR_041812.1), and Schaalia canis strain CCUG 41706 (NR_025366.1), respectively. In addition, strains Marseille-Q2854T, Marseille-P8049T and Marseille-P7157T shared with their closely related species cited above the following DDH values: 19.5%, 24.4%, and 20.2%, respectively. Based on these phenotypic and genomic findings, we consider that strains Marseille-P8049T (= CSUR P8049 = CECT 30350), Marseille-P2854T ( = CSUR Q2854 = CECT 30120) and Marseille-P7157T ( = CSUR P7157 = CECT 30048) are new bacterial species, for which the names Acinetobacter ihumii sp. nov., Microbacterium ihumii sp. nov., and Gulosibacter massiliensis sp. nov., are proposed

Minimum p-values from tests of association for the autosomal SNPs ^*.

<p>^*Genotypic tests of dominant, recessive, general, heterozygous advantage, and additive models, adjusted for HbS and ethnicity; in this analysis controls include uncomplicated malaria cases; the dashed line represents a p-value of 0.002.</p

Single nucleotide polymorphisms.

<p>MinA = minor allele, MajA = major allele, MAF = overall minor allele frequency, HWE P is the Hardy-Weinberg p-value, OR = odds ratio, 95% Confidence interval (LCL, UCL), P = P-value; rs8176746 and rs8176719 are used to infer ABO blood groups; for X chromosome SNPs (rs3092945 (CD40), rs1126535 (CD40), rs1050829 (G6PD-376), rs1050828 (G6PD-202/A-), analyses are presented for separately for females (F) and males (M) and pooled to obtain overall results (Ov), NA not applicable; rs33950507, rs5743611, rs2814778, rs2227478, rs2535611 and rs1801274 did not pass quality control filters and are not presented.</p

99% credible set SNPs for leprosy association at chromosome 10q24

99% credible set SNPs for leprosy association at chromosome 10q24