IAI Accepts, published online ahead of print on 2 November 2009

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Infect. Immun. doi:10.1128/IAI.00895-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A Novel Functional Variant in the Stem Cell Growth Factor (SCGF) Promoter (-539C/T) Protects Against Severe Malarial Anemia

Collins Ouma, Christopher C. Keller, Gregory C. Davenport, Tom Were, Steve Konah, Michael F. Otieno, James B. Hittner, John M. Vulule, Jeremy Martinson, John M. Ong'echa, Robert E. Ferrell, and Douglas J. Perkins^*

University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya; Department of Biomedical Sciences and Technology, Maseno University, Maseno, Kenya; Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Laboratory of Human Pathogens, Lake Erie College of Osteopathic Medicine, Erie, PA, USA; Global and Geographic Medicine Program, Division of Infectious Diseases, University of New Mexico School of Medicine, NM, USA; Department of Pathology, Kenyatta University, Nairobi, Kenya; Department of Pre-Clinical Sciences, Kenyatta University, Nairobi, Kenya; Department of Psychology, College of Charleston, Charleston, SC, USA; Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

^* To whom correspondence should be addressed. Email: dperkins{at}salud.unm.edu.

Plasmodium falciparum malaria is a leading global cause of infectious disease burden. In holoendemic P. falciparum transmission areas, such as western Kenya, severe malarial anemia (SMA) results in high rates of pediatric morbidity and mortality. Although the patho-physiological basis of SMA is multifactorial, we recently discovered that suppression of unexplored hematopoietic growth factors that promote erythroid and myeloid colony development, such as stem cell growth factor [SCGF, C-type lectin domain family member 11A (CLEC11A)], was associated with enhanced development of SMA and reduced erythropoietic responses. To extend these investigations, the relationship between a novel SCGF promoter variant (-539C/T, rs7246355), SMA (hemoglobin, Hb<6.0 g/dL), and reduced erythropoietic responses (reticulocyte production index, RPI<2.0) was investigated in Kenyan children (n=486) with falciparum malaria from western Kenya. Circulating SCGF was positively correlated with hemoglobin levels (r=0.251, P=0.022) and the RPI (r=0.268, P=0.025). Children with SMA also had lower SCGF levels than the non-SMA group (P=0.005). Multivariate logistic regression analyses controlling for covariates demonstrated that homozygous T individuals were protected against SMA (OR; 0.57, 95% CI, 0.34-0.94; P=0.027) relative to CC (wild type) carriers. Carriers of the TT genotype also had higher SCGF levels in circulation (P=0.018) and in peripheral blood mononuclear cell culture supernatants (P=0.041), as well as an elevated RPI (P=0.005) relative to individuals with the CC genotype. Results presented here demonstrate that homozygous T at -539 in the SCGF promoter is associated with elevated SCGF production, enhanced erythropoiesis, and protection against the development of SMA in children with falciparum malaria.