Abstract
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.
Highlights
Malaria remains a major cause of global morbidity and mortality
Patient characteristics In the present study, blood samples drawn from 135 Indian malaria patients (69 non-Cerebral malaria (CM) and 66 CM) were genotyped for CXCL10 promoter polymorphisms at position 2135 and 21447
Cerebral malaria accounts for approximately 80% of fatal malaria cases [2]
Summary
Malaria remains a major cause of global morbidity and mortality. An estimated 219 million cases of malaria were reported in 2010 resulting in 660,000 deaths [1]. Mortality is unacceptably high, about 20% of malaria cases develop into CM [3,4,5] suggesting that CM is a sub-population-specific targeted syndrome [5]. Several factors have been implicated in the development of CM including host and parasite genetic factors considered as major contributors [5]. The risk factors for CM and the wide variation in clinical manifestations of malaria are poorly understood [6]. Variations in disease severity and syndromic phenotype constitute a major challenge to our understanding of the disease, its treatment, and control [6]
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