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Polymorphisms in Genes Involved in Innate Immunity Predispose Toward Mycetoma Susceptibility

Wendy W. J. van de Sande^1,*, Ahmed Fahal, Henri Verbrugh^* and Alex van Belkum^*

^* Erasmus MC, University Medical Centre Rotterdam, Department of Medical Microbiology and Infectious Diseases, Rotterdam, The Netherlands; and Mycetoma Research Centre, University of Khartoum, Khartoum, Sudan

Madurella mycetomatis is the main causative agent of mycetoma, a tumorous fungal infection characterized by the infiltration of large numbers of neutrophils at the site of infection. In endemic areas the majority of inhabitants have Abs to M. mycetomatis, although only a small proportion of individuals actually develop mycetomal disease. It therefore appears that neutrophils are unable to clear the infection in some individuals. To test this hypothesis, 11 single nucleotide polymorphisms involved in neutrophil function were studied in a population of Sudanese mycetoma patients vs geographically and ethnically matched controls. Significant differences in allele distribution for IL-8 (CXCL8), its receptor CXCR2, thrombospondin-4 (TSP-4), NO synthase 2 (NOS2), and complement receptor 1 (CR1) were found. Further, the NOS2^Lambaréné polymorphism was clearly associated with lesion size. The genotypes obtained for CXCL8, its receptor CXCR2, and TSP-4 all predisposed to a higher CXCL8 expression in patients, which was supported by the detection of significantly elevated levels of CXCL8 in patient serum. The NOS2 genotype observed in healthy controls was correlated with an increase in NOS2 expression and higher concentrations of nitrate and nitrite in control serum. We present the first evidence of human genetic predisposition toward susceptibility to mycetoma, a neglected infection of the poor.

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¹ Address correspondence and reprint requests to Wendy van de Sande, Erasmus MC, PO Box 2040, Rotterdam, The Netherlands. E-mail address: w.vandesande{at}erasmusmc.nl

² Abbreviations used in this paper: MBL, mannose-binding lectin; CR1, complement receptor 1; HWE, Hardy-Weinberg equilibrium; McC, McCoy (blood group); NOS, NO synthase; Sl, Swain-Langley (blood group); SNP, single nucleotide polymorphism; TSP, thrombospondin.