A targeted association study of immunity genes and networks suggests novel associations with placental malaria infection

Abstract

A large proportion of the death toll associated with malaria is a consequence of malaria infection during pregnancy, causing up to 200,000 infant deaths annually. We previously published the first extensive genetic association study of placental malaria infection, and here we extend this analysis considerably, investigating genetic variation in over 9,000 SNPs in more than 1,000 genes involved in immunity and inflammation for their involvement in susceptibility to placental malaria infection. We applied a new approach incorporating results from both single gene analysis as well as gene-gene interactions/non a protein-protein interaction network. We found suggestive associations of variants in the gene KLRK1 in the single gene/nanalysis, as well as evidence for associations of multiple members of the IL-7/IL-7R signalling cascade in the combined analysis. To our knowledge, this is the first large-scale genetic study on placental malaria infection to date, opening the door for follow-up studies trying to elucidate the genetic basis of this neglected form of malaria.This work was supported by grant SAF-2007-63171 awarded by Ministerio de Educación y Ciencia (Spain) to JB and the CIBERESP (CIBER of Epidemiology and Public Health, Ministry of Health). Funds were also obtained from Dirreció General de Recerca of Generalitat de Catalunya (Grup de Recerca Consolidat 2005SGR/00608) and from Banco de Bilbao, Vizcaya, Argentaria Foundation (grant number BBVA 02-0). The CISM receives core support from the Spanish Agency for International Cooperation and Development (AECID). All the genotyping was provided by the Spanish “Centro Nacional de Genotipado” (CEGEN; www.cegen.org); support for computations was provided by the National Institute for Bioinformatics (www.inab.org); both are platforms of Genoma España. MGN was supported by a Vici grant of the Netherlands Organization for Scientific Research. AM was supported by the Spanish Ministry of Health (Program for the Promotion of Biomedical Research and Health Sciences, Instituto de Salud Carlos III, CP-04/00220). MS was supported by a PhD fellowship from the Programa de becas FPU del Ministerio de Educación y Ciencia, Spain (AP2005-3982). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript