Abstract
Copy number variation can contribute to the variation observed in susceptibility to complex diseases. Here we present the first study to investigate copy number variation of the chemokine gene CCL3L1 with susceptibility to malaria. We present a family-based genetic analysis of a Tanzanian population (n=922), using parasite load, mean number of clinical infections of malaria and haemoglobin levels as phenotypes. Copy number of CCL3L1 was measured using the paralogue ratio test (PRT) and the dataset exhibited copy numbers ranging between 1 and 10 copies per diploid genome (pdg). Association between copy number and phenotypes was assessed. Furthermore, we were able to identify copy number haplotypes in some families, using microsatellites within the copy variable region, for transmission disequilibrium testing. We identified a high level of copy number haplotype diversity and find some evidence for an association of low CCL3L1 copy number with protection from anaemia.
Highlights
Malaria caused by Plasmodium falciparum is a major cause of mortality and morbidity, especially in sub-Saharan Africa
In total there were 922 Tanzanian samples successfully genotyped for CCL3L1 copy number
The paralogue ratio test (PRT) system for copy number measurement of CCL3L1 has previously been shown to have a high degree of accuracy in integer copy number prediction (Carpenter et al, 2011; Walker et al, 2009)
Summary
Malaria caused by Plasmodium falciparum is a major cause of mortality and morbidity, especially in sub-Saharan Africa. Individuals who live in endemic areas may be subjected to constant exposure to infective mosquito bites and depending on the level of immunity, develop parasitaemia (parasites in the blood) and/or clinical disease. Resolution of P. falciparum infection requires the production of cytokines, and the activation of macrophages leading to the destruction of parasites (Luty et al, 2001). Activation of macrophages and the recruitment to sites of infection is through chemoattractant cytokines, including macrophage inflammatory protein This chemokine is secreted from most mature leucocytes and acts as a proinflammatory cytokine, being inhibited by IL-4, IL-10 and IL-13 (Berkman et al, 1995; Standiford et al, 1993)
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