Short communication Genetics of susceptibility to malaria related phenotypes Danielle Carpenter a, *, Ingegerd Rooth b , Anna Fa ¨ rnert c , Hind Abushama a , Rupert J. Quinnell a , Marie-Anne Shaw a a Institute of Integrative and Comparative Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK b Nyamisati Malaria Research, Rufiji, National Institute for Medical Research, Dar-es-Salaam, Tanzania c Unit of Infectious Diseases, Department of Medicine, Karolinska Institute, Karolinska University Hospital Solna, S-17176 Stockholm, Sweden 1. Introduction Plasmodium falciparum malaria is a major cause of mortality and morbidity, particularly in sub-Saharan Africa. Individuals living in endemic areas may be subjected to constant sub-clinical malaria infection, but only a minority develop severe disease. Variations in disease pattern are attributable to a number of different factors, both environmental and genetic, that can determine whether an exposed individual develops parasitaemia (parasites in the blood), and the risk of a parasitaemic individual developing clinical disease. Over the course of the last decade a number of studies have evaluated genetics of quantitative malaria phenotypes, such as parasite density and the frequency of malaria episodes. Complex segregation analyses have established a genetic component of susceptibility to P. falciparum blood infection level (Garcia et al., 1998a; Rihet et al., 1998; Abel et al., 1993) and to clinical infection of malaria in a mixed P. falciparum and Plasmodium vivax population (Mackinnon et al., 2000). There are a number of studies which have aimed to identify loci involved with control of blood infection level and asymptomatic malaria. Linkage studies provided evidence for linkage between blood infection levels and the 5q31–q33 region in populations from Burkina Faso (Flori et al., 2003a) and Cameroon (Garcia et al., 1998b). Two-point and multipoint analyses provided evidence of linkage between mild malaria and the MHC region (Jepson et al., 1997; Flori et al., 2003b), and TDT analysis identified associations with a number of different TNF polymorphisms with both mild malaria and parasite density (Flori et al., 2005). More recently a genome-wide linkage analysis of malaria infection and mild disease showed evidence for linkage to chromosome 10p15 (Timmann et al., 2007). In the current study, we have investigated polymorphisms within a number of candidate genes that may play a role in susceptibility to parasite density and clinical infection, in a well- studied Tanzanian population. We build on previous studies by using family-based association methods to investigate blood infection levels and clinical infection data collected over a period of 7 years. Candidate gene regions (MHC class II and III, IL1, IL10, IL4, IL13, and TCRBV) were chosen from their identification in prior case control studies and/or their potential role in the control of malaria infection. Infection, Genetics and Evolution 9 (2009) 97–103 ARTICLE INFO Article history: Received 10 April 2008 Received in revised form 18 July 2008 Accepted 16 October 2008 Available online 31 October 2008 Keywords: Plasmodium falciparum Parasite density Clinical episodes TDT Association TNF ABSTRACT Previous studies have established a genetic component for susceptibility to malaria. Here we use a pedigree based approach, and transmission disequilibrium testing (TDT), to identify immune response genes that influence susceptibility to Plasmodium falciparum malarial phenotypes (parasite density and frequency of clinical episodes) in a Tanzanian population. Evidence for association was observed between markers in the TNF gene cluster and both the malarial phenotypes. There was weaker evidence for associations between HLA-DRB1*04, HLA-DRB1*10, and loci in the TCRBV region with parasite density. There was no evidence for association with polymorphisms in the IL10 promoter, IL1 gene cluster, or from the IL4/IL13 region. ß 2008 Elsevier B.V. All rights reserved. * Corresponding author at: Institute of Genetics, School of Biology, Queens Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK. Tel.: +44 115 823 0309. E-mail address: danielle.carpenter@nottingham.ac.uk (D. Carpenter). Contents lists available at ScienceDirect Infection, Genetics and Evolution journal homepage: www.elsevier.com/locate/meegid 1567-1348/$ – see front matter ß 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.meegid.2008.10.008