CD36 polymorphism is associated with protection from cerebral malaria

The human protein CD36 is a major receptor for Plasmodium falciparum-infected erythrocytes and contributes to the pathology of P. falciparum malaria. We performed variation screening of the CD36 gene and examined the possible association between CD36 polymorphisms and the severity of malaria in 475 adult Thai patients with P. falciparum malaria. Accordingly, we identified nine CD36 polymorphisms with a high-frequency (>15%) minor allele. Of these, the frequencies of the -14T-->C allele in the upstream promoter region and the -53G-->T allele in the downstream promoter region were significantly decreased in patients with cerebral malaria compared to those with mild malaria (P=.016 for -14T-->C and P=.050 for -53G-->T). The analysis of linkage disequilibrium (LD) between the nine common polymorphisms revealed that there are two blocks with strong LD in the CD36 gene and that the -14T-->C and -53G-->T polymorphisms are within the upstream block of 35 kb from the upstream promoter to exon 8. Further association testing after the second variation screening in the upstream block indicated that the in3(TG)(12) (i.e., 12 TG repeats in intron 3) allele is most strongly associated with the reduction in the risk of cerebral malaria (odds ratio 0.59; 95% confidence interval 0.40-0.87; P=.0069). We found, by reverse-transcriptase PCR amplification, that in3(TG)(12) is involved in the nonproduction of the variant CD36 transcript that lacks exons 4 and 5. Since exon 5 of the gene is known to encode the ligand-binding domain for P. falciparum-infected erythrocytes, in3(TG)(12) itself or a primary variant on the haplotype with in3(TG)(12) may be responsible for protection from cerebral malaria in Thailand. Results of the present study suggest that LD mapping has potential for detecting a disease-associated variant on the basis of haplotype blocks.