Genes and Immunity (2000) 1, 435–441  2000 Macmillan Publishers Ltd All rights reserved 1466-4879/00 $15.00 www.nature.com/gene Human genetic factors related to susceptibility to mild malaria in Gabon F Migot-Nabias 1 , LE Mombo 1 , AJF Luty 1,2 , B Dubois 3 , R Nabias 1 , C Bisseye 1 , P Millet 1,4 , CY Lu 1,5 and P Deloron 1 1 Centre International de Recherches Me ´dicales de Franceville (CIRMF), Gabon; 3 Institut National de la Sante ´ et de la Recherche Me ´dicale (INSERM), Unite ´ 13 and Institut de Me ´decine et d’Epide ´miologie Africaines (IMEA), CHU Bichat, Paris, France Several human genetic factors, including red blood cell polymorphisms (ABO blood group, sickle-cell trait, G6PD deficiency) as well as point mutations in the mannose binding protein (MBP) and in the promoter regions of both the TNF-  and NOS2 genes, influence the severity of disease due to infection with Plasmodium falciparum. We assessed their impact on mild P. falciparum malaria, as part of a longitudinal investigation of clinical, parasitological and immunological parameters in a cohort of 300 Gabonese schoolchildren. We found the following frequencies: blood group O (0.54), sickle- cell trait (0.23), G6PD deficiency (0.09), MBP gene mutations (0.34), TNF- promoter mutations (at positions -238: 0.17 and -308: 0.22) and NOS2 promoter mutation (0.18). Blood group O or hemoglobin AA were associated with protection against higher parasitemia. Girls with normal G6PD enzyme activity were protected against clinical malaria attacks. In addition, we demonstrated for the first time that the mutation at position -238 of the gene coding for the promoter region of TNF- was positively correlated with the level of the antibody response specific for epitopes of the antigens MSA-2 and RAP-1 of P. falciparum. Genes and Immunity (2000) 1, 435–441. Keywords: Gabon; genetic polymorphisms; immunity; malaria; Plasmodium falciparum Introduction For some years it has been clear that the genetic determi- nation of malaria susceptibility in humans is highly poly- genic, as it is for many infectious diseases. Genetic poly- morphisms of the innate immune system and of the erythrocyte have namely been proposed as factors pro- tecting against severe malaria. 1 A better knowledge of the polymorphic host genes associated with resistance to clinical malaria and/or with high parasite densities might provide new insights into disease mechanisms, and suggest new approaches for prophylactic or thera- peutic interventions. 2 Although several host genetic fac- tors related to resistance to severe malaria (cerebral malaria, severe anemia) have convincingly been listed, 3 the same is not the case for the mild expression of the disease. 4 Indeed, concerning red blood cell polymor- phisms for example, no study has revealed any influence of ABO blood groups on the susceptibility to mild Correspondence: Florence Migot-Nabias, CIRMF, BP 769, Franceville, Gabon. E-mail: migot nabiasyahoo.com 2 Present address: Institut fu ¨ r Tropenmedizin, Wilhelmstrasse 27, 72074 Tu ¨ bingen, Germany 4 Present address: University Bordeaux 2, 146 rue Le ´o Saignat, 33076 Bordeaux Cedex, France 5 Present address: Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA This study was partially supported by an INSERM North-South Network grant (No. 94/NS01). The Centre International de Recherches Me ´dicales de Franceville is financially supported by the government of Gabon, Elf Gabon and the Ministe `re Franc ¸ais des Affaires Etrange `res. Received 7 March 2000; revised and accepted 21 June 2000 malaria 5 nor on the delay of reinfection after curative anti-malarial treatment. 6 Although sickle-cell trait pro- tects against severe malaria and reduces susceptibility to mild malaria, 7 it does not appear to prevent Plasmodium falciparum infection. Lastly, the geographical overlap between the distribution of G6PD deficiency and the endemicity of malaria has suggested that G6PD deficient subjects might be protected against malaria, but field studies have yielded conflicting results. 8–10 Polymor- phisms of components of the inflammatory response have been investigated more recently, and among them, polymorphisms in the promoter region of the TNF- gene are the most widely studied. Results from different study sites have varied in their ability to demonstrate an impact on the clinical outcome of P. falciparum infec- tion. 11–13 In all these studies, the TNF- promoter poly- morphisms appear to be related to severe expression of the malarial disease, but not to mild malaria. We undertook a prospective longitudinal study, over a 1-year period, in schoolchildren living in an area of Gabon where malaria is highly endemic, in order to examine the relationships between malaria prevalence and malaria-related morbidity. 14 We revealed in the same cohort several associations between disease susceptibility and immune responses directed to synthetic peptides of P. falciparum asexual blood stage antigens, 15 as well as the presence of genetic regulation via the locus HLA-A, and of specific immune responses directed to epitopes of Liver Stage Antigen-1 (LSA-1) of P. falciparum. 16 In the present study, we determined the prevalence rates of sev- eral red blood cell genetic polymorphisms (blood group, sickle cell trait, G6PD) which are known to be present at significant frequencies in sub-Saharan Africa. 4 We also