title: USP38, FREM3, SDC1, DDC, and LOC727982 Gene Polymorphisms and Differential Susceptibility to Severe Malaria in Tanzania.
abstract: Populations exposed to Plasmodium falciparum infection develop genetic mechanisms of protection against severe malarial disease. Despite decades of genetic epidemiological research, the sickle cell trait (HbAS) sickle cell polymorphism, ABO blood group, and other hemoglobinopathies remain the few major determinants in severe malaria to be replicated across different African populations and study designs. Within a case-control study in a region of high transmission in Tanzania (n = 983), we investigated the role of 40 new loci identified in recent genome-wide studies. In 32 loci passing quality control procedures, we found polymorphisms in USP38, FREM3, SDC1, DDC, and LOC727982 genes to be putatively associated with differential susceptibility to severe malaria. Established candidates explained 7.4% of variation in severe malaria risk (HbAS polymorphism, 6.3%; α-thalassemia, 0.3%; ABO group, 0.3%; and glucose-6-phosphate dehydrogenase deficiency, 0.5%) and the new polymorphisms, another 4.3%. The regions encompassing the loci identified are promising targets for the design of future treatment and control interventions.
authors: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi National Institute for Medical Research, Dar es Salaam, Tanzania.
authors: Alphaxard
authors: A
authors: Manjurano
authors: Departments of Immunology and Infection Centre of Statistics and Applications, University of Lisbon, Portugal.
authors: Nuno
authors: N
authors: Sepúlveda
authors: Clinical Research.
authors: Behzad
authors: B
authors: Nadjm
authors: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi National Institute for Medical Research, Dar es Salaam, Tanzania.
authors: George
authors: G
authors: Mtove
authors: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi.
authors: Hannah
authors: H
authors: Wangai
authors: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi.
authors: Caroline
authors: C
authors: Maxwell
authors: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi.
authors: Raimos
authors: R
authors: Olomi
authors: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi Departments of Immunology and Infection.
authors: Hugh
authors: H
authors: Reyburn
authors: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi Departments of Immunology and Infection.
authors: Christopher J
authors: CJ
authors: Drakeley
authors: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi Departments of Immunology and Infection.
authors: Eleanor M
authors: EM
authors: Riley
authors: Pathogen Molecular Biology Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom.
authors: Taane G
authors: TG
authors: Clark
mesh_terms: D000017:ABO Blood-Group System / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000235:genetics; D006239:Haplotypes; D006441:Hemoglobin A / Q000235:genetics; D006453:Hemoglobinopathies / Q000097:blood / Q000235:genetics; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D012805:Sickle Cell Trait / Q000235:genetics; D053668:Syndecan-1 / Q000235:genetics*; D013636:Tanzania; D064570:Ubiquitin-Specific Proteases / Q000235:genetics*
chemical_list: D000017:ABO Blood-Group System; C514425:CCDC30 protein, human; D002352:Carrier Proteins; D016326:Extracellular Matrix Proteins; C575351:FREM3 protein, human; D009419:Nerve Tissue Proteins; C508241:SDC1 protein, human; D053668:Syndecan-1; D006441:Hemoglobin A; C000601043:USP38 protein, human; D064570:Ubiquitin-Specific Proteases
keywords: Plasmodium falciparum; Tanzania; genetic association study; host susceptibility; severe malaria