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A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults

BackgroundSevere 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.MethodsAn 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.ResultsNo associations between SNPs in the TNF/LTA/LTB locus and susceptibility to SM in highland Papuan children and adults were found.ConclusionsThese 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.

Age-related susceptibility to severe malaria associated with galectin-2 in highland Papuans

BACKGROUND Age and host genetics are important determinants of malaria severity. Lymphotoxin-alpha (LTalpha) has been associated with the development of cerebral malaria (CM) and other severe malaria (SM) syndromes. Mutations in genes regulating LTalpha production contribute to other acute vascular diseases and may contribute to malaria pathogenesis. METHODS We tested the association between rs7291467, a single-nucleotide polymorphism (SNP) in the LTalpha-related gene encoding galectin-2 (LGALS2), disease severity, and function in a case-control study of ethnic Highland Papuan adults and children with SM (n = 380) and asymptomatic malaria-exposed controls (n = 356) originating from a non-malaria-endemic region but residing in a lowland malaria-endemic area of Papua, Indonesia. RESULTS The LGALS2 SNP showed a significant association with susceptibility to SM (including CM), in children (odds ratio, 2.02 [95% confidence interval, 1.14-3.57]) but not in adults. In SM, the C allele at rs7291467 was associated with enhanced galectin-2 transcript levels. In a separate group of Tanzanian children originating from a malaria-endemic region, we found preservation of the major ancestral LGALS2 allele and no association with susceptibility to CM. CONCLUSIONS Results suggest differences in the inflammatory contribution to the development of SM between children and adults in the same population and potential differences between individuals originating from malaria-endemic and non-malaria-endemic areas.

Common Variation in the CYP17A1 and IFIT1 Genes on Chromosome 10 Does Not Contribute to the Risk of Endometriosis

Endometriosis is a complex disease involving multiple susceptibility genes and environmental factors. Our previous studies on endometriosis identified a region of significant linkage on chromosome 10q. Two biological candidate genes (CYP17A1 and IFIT1) located on chromosome 10q, have previously been implicated in endometriosis and/or uterine function. We hypothesized that variation in CYP17A1 and/or IFIT1 could contribute to the risk of endometriosis and may account for some of the linkage signal on chromosome 10q. We genotyped 17 single nucleotide polymorphisms (SNPs) in the CYP17A1 and IFIT1 genes including SNP rs743572 previously associated with endometriosis in 768 endometriosis cases and 768 unrelated controls. We found no evidence for association between endometriosis and individual SNPs or SNP haplotypes in CYP17A1 and IFIT1. Common variation in these genes does not appear to be a major contributor to endometriosis susceptibility in our Australian sample.