doi: 10.1111/j.1469-1809.2007.00424.x Significant Association Between TIM1 Promoter Polymorphisms and Protection Against Cerebral Malaria in Thailand P. Nuchnoi 1 , J. Ohashi 2, ∗ , R. Kimura 2 , H. Hananantachai 1 , I. Naka 2 , S. Krudsood 1 , S. Looareesuwan 1 , K. Tokunaga 2 and J. Patarapotikul 1, ∗ 1 Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand 2 Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan Summary Although cerebral malaria is a major life-threatening complication of Plasmodium falciparum infection, its pathophysiology is not well understood. Prolonged activation of the T helper type 1 (Th1) response characterized by the production of pro-inflammatory cytokines such as IFN-γ and TNF-α has been suggested to be responsible for immunopathological process leading to cerebral malaria unless they are downregulated by the anti-inflamatory cytokines produced by the Th2 response. The T cell immunoglobulin and mucin domain (TIM ) family of proteins are cell surface proteins involved in regulating Th1 and Th2 immune responses. In this study, the possible association between the polymorphisms of TIM1, TIM3, and TIMD4 genes and the severity of malaria was examined in 478 adult Thai patients infected with P. falciparum malaria. The TIM1 promoter haplotype comprising three derived alleles, -1637A (rs7702919), -1549C (rs41297577) and -1454A (rs41297579), which were in complete linkage disequilibrium, was significantly associated with protection against cerebral malaria (OR = 0.41; 95% CI = 0.24–0.71; P = 0.0009). Allele-specific transcription quantification analysis revealed that the level of mRNA transcribed from TIM1 was higher for the protective promoter haplotype than for the other promoter haplotype (P = 0.004). Engagement with TIM1 in combination with T cell receptor stimulation induces anti-inflammatory Th2 cytokine production, which can protect the development of cerebral malaria caused by overproduction of pro-inflammatory Th1 cytokines. The present results suggest that the higher TIM1 expression associated with the protective TIM1 promoter haplotype confers protection against cerebral malaria. Keywords: cerebral malaria, TIM1, promoter, polymorphism, Thailand Introduction Malaria is a debilitating infectious disease that is commonly found in tropical and sub-tropical countries. In any given year, 300–500 million cases of malaria are reported, and at least 1 million people die. There are four human malaria parasites, of ∗ Address for correspondence: Dr. Jun Ohashi, Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113- 0033, Japan. Tel: +81-3-5841-3693; Fax: +81-3-5802-8619; E-mail: juno-tky@umin.ac.jp and Dr. Jintana Patarapotikul, De- partment of Microbiology & Immunology, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand. Tel: +66-2354-9100 to 19; Fax: +66-2354-9139; E-mail: tmjpt@mahidol.ac.th which Plasmodium falciparum is responsible for cerebral malaria which is a major cause of death due to malaria. Although the pathogenesis of cerebral malaria is not well understood, host genetic factors are thought to influence the clinical outcome (Hill 1999). During the acute stage of malaria infection, the T helper type 1 (Th1) immune response, characterized by the pro- duction of pro-inflammatory cytokines such as IFN-γ and TNF-α, plays an important role in the elimination of par- asites. In addition, these Th1 cytokines are thought to be involved in the development of cerebral malaria (Hunt & Grau 2003). Production of Th1 cytokines can be inhibited by Th2 cytokines, so it is possible that relative overproduction of Th1 cytokines and/or underproduction of Th2 cytokines could lead to the development of cerebral malaria (Hunt & Grau 2003). Therefore, polymorphisms of genes involved in C  2008 The Authors Journal compilation C  2008 University College London Annals of Human Genetics (2008) 72,327–336 327