title: CXCL10 gene promoter polymorphism -1447A>G correlates with plasma CXCL10 levels and is associated with male susceptibility to cerebral malaria.
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.
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Nana
authors.initials: N
authors.lastname: Wilson
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Adel
authors.initials: A
authors.lastname: Driss
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Wesley
authors.initials: W
authors.lastname: Solomon
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Carmen
authors.initials: C
authors.lastname: Dickinson-Copeland
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Hassana
authors.initials: H
authors.lastname: Salifu
authors.affiliation: Regional Medical Research Center for Tribals (ICMR), Nagpur Road, Garha, Jabalpur, Madhya Pradesh, India.
authors.forename: Vidhan
authors.initials: V
authors.lastname: Jain
authors.affiliation: Regional Medical Research Center for Tribals (ICMR), Nagpur Road, Garha, Jabalpur, Madhya Pradesh, India ; National Institute of Malaria Research Field Unit (ICMR), Jabalpur, Madhya Pradesh, India.
authors.forename: Neeru
authors.initials: N
authors.lastname: Singh
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Stiles
mesh_terms: D000293:Adolescent; D000328:Adult; D054357:Chemokine CXCL10 / Q000097:blood* / Q000235:genetics*; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D016779:Malaria, Cerebral / Q000097:blood* / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D055815:Young Adult
chemical_list: D054357:Chemokine CXCL10