A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults.
Randall LM., Kenangalem E., Lampah DA., Tjitra E., Mwaikambo ED., Handojo T., Piera KA., Zhao ZZ., de Labastida Rivera F., Zhou Y., McSweeney KM., Le L., Amante FH., Haque A., Stanley AC., Woodberry T., Salwati E., Granger DL., Hobbs MR., Price RN., Weinberg JB., Montgomery GW., Anstey NM., Engwerda CR.
BACKGROUND: Severe malaria (SM) syndromes caused by Plasmodium falciparum infection result in major morbidity and mortality each year. However, only a fraction of P. falciparum infections develop into SM, implicating host genetic factors as important determinants of disease outcome. Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LTα) may be important for the development of cerebral malaria (CM) and other SM syndromes. METHODS: An extensive analysis was conducted of single nucleotide polymorphisms (SNPs) in the TNF, LTA and LTB genes in highland Papuan children and adults, a population historically unexposed to malaria that has migrated to a malaria endemic region. Generated P-values for SNPs spanning the LTA/TNF/LTB locus were corrected for multiple testing of all the SNPs and haplotype blocks within the region tested through 10,000 permutations. A global P-value of < 0.05 was considered statistically significant. RESULTS: No associations between SNPs in the TNF/LTA/LTB locus and susceptibility to SM in highland Papuan children and adults were found. CONCLUSIONS: These results support the notion that unique selective pressure on the TNF/LTA/LTB locus in different populations has influenced the contribution of the gene products from this region to SM susceptibility.