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A -436C>A polymorphism in the human FAS gene promoter associated with severe childhood malaria.

ABSTRACT: Human genetics and immune responses are considered to critically influence the outcome of malaria infections including life-threatening syndromes caused by Plasmodium falciparum. An important role in immune regulation is assigned to the apoptosis-signaling cell surface receptor CD95 (Fas, APO-1), encoded by the gene FAS. Here, a candidate-gene association study including variant discovery at the FAS gene locus was carried out in a case-control group comprising 1,195 pediatric cases of severe falciparum malaria and 769 unaffected controls from a region highly endemic for malaria in Ghana, West Africa. We found the A allele of c.-436C>A (rs9658676) located in the promoter region of FAS to be significantly associated with protection from severe childhood malaria (odds ratio 0.71, 95% confidence interval 0.58-0.88, p(empirical)?=?0.02) and confirmed this finding in a replication group of 1,412 additional severe malaria cases and 2,659 community controls from the same geographic area. The combined analysis resulted in an odds ratio of 0.71 (95% confidence interval 0.62-0.80, p?=?1.8×10??, n?=?6035). The association applied to c.-436AA homozygotes (odds ratio 0.47, 95% confidence interval 0.36-0.60) and to a lesser extent to c.-436AC heterozygotes (odds ratio 0.73, 95% confidence interval 0.63-0.84), and also to all phenotypic subgroups studied, including severe malaria anemia, cerebral malaria, and other malaria complications. Quantitative FACS analyses assessing CD95 surface expression of peripheral blood mononuclear cells of naïve donors showed a significantly higher proportion of CD69+CD95+ cells among persons homozygous for the protective A allele compared to AC heterozygotes and CC homozygotes, indicating a functional role of the associated CD95 variant, possibly in supporting lymphocyte apoptosis.

SUBMITTER: Schuldt K

PROVIDER: S-EPMC3098189 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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A -436C>A polymorphism in the human FAS gene promoter associated with severe childhood malaria.

Schuldt Kathrin K Kretz Cosima C CC Timmann Christian C Sievertsen Jürgen J Ehmen Christa C Esser Claudia C Loag Wibke W Ansong Daniel D Dering Carmen C Evans Jennifer J Ziegler Andreas A May Jürgen J Krammer Peter H PH Agbenyega Tsiri T Horstmann Rolf D RD

PLoS genetics 20110519 5

Human genetics and immune responses are considered to critically influence the outcome of malaria infections including life-threatening syndromes caused by Plasmodium falciparum. An important role in immune regulation is assigned to the apoptosis-signaling cell surface receptor CD95 (Fas, APO-1), encoded by the gene FAS. Here, a candidate-gene association study including variant discovery at the FAS gene locus was carried out in a case-control group comprising 1,195 pediatric cases of severe fal ...[more]

PMID: 21625619

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Project description:The risk factors for cerebral malaria (CM) and the wide variation in clinical manifestations of malaria are poorly understood. Recent studies indicate that interferon gamma inducible chemokine, CXCL10, is a strong predictor of both human and experimental cerebral malaria. Increased plasma and cerebrospinal fluid levels of CXCL10 were tightly associated with fatal CM in Indian and Ghanaian patients. In the present study, we hypothesized that in a subset of malaria patients, CM susceptibility is associated with variation in CXCL10 expression. We determined whether polymorphisms in the CXCL10 gene promoter region played a role in the clinical status of malaria patients and addressed the genetic basis of CXCL10 expression during malaria infection. Following extensive bioinformatics analyses, two reported single nucleotide polymorphisms in the CXCL10 promoter (-135G>A [rs56061981] and -1447A>G [rs4508917]) were identified among 66 CM and 69 non-CM Indian patients using PCR-restriction fragment length polymorphism assay. Individuals with the -1447(A/G) genotype were susceptible to CM (adjusted odds ratio [AOR] = 2.60, 95% CI = 1.51-5.85, p = 0.021). In addition, individuals with the -1447(A/G) genotype had significantly higher plasma CXCL10 levels than individuals with the -1447(A/A) genotype. Stratifying patients according to gender, the observed association of CM with over expression of CXCL10 were more pronounced in males than in female patients (AOR = 5.47, 95% CI = 1.34-22.29, p = 0.018). Furthermore, -135G>A polymorphism conferred a decreased risk of CM among males (AOR = 0.19, 95% CI = 0.05-0.78, p = 0.021). Polymorphisms in the CXCL10 gene promoter sequence were associated with increased CXCL10 production, which is linked to severity of CM. These results suggest that the -1447A>G polymorphism in CXCL10 gene promoter could be partly responsible for the reported variation underlying severity of CM outcomes particularly in males.

Dataset Information

A -436C>A polymorphism in the human FAS gene promoter associated with severe childhood malaria.

Publications

A -436C>A polymorphism in the human FAS gene promoter associated with severe childhood malaria.

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