Each year, more than 500 million people become ill with malaria. About one million – mostly infants, young children, and pregnant women – die as a result of the disease. Due to differences in their immune systems, however, individuals respond to malaria in different ways. While some die, others survive, and still others are infected without becoming ill. Understanding how and why some people naturally resist malaria may help lead to the development of an effective vaccine against the disease.
 
Dr. Kwiatkowski is leading the Malaria Genomic Epidemiology Network, or MalariaGEN, an international partnership of malaria research groups. MalariaGEN partners in 20 countries, including in 14 countries where malaria is endemic, are combining genomic technology with large-scale epidemiological analyses to identify mechanisms of protective immunity against malaria in humans. Their ultimate goal is to guide the development of tools and markers to facilitate the design and testing of vaccines against malaria.

In addition, the project seeks to provide the training and resources needed to enhance the research capacity of scientists from the malaria endemic countries.
 
In the past two years, MalariaGEN partners have assembled the platforms and pipelines necessary to generate data, including a central repository of about 30,000 DNA samples and a high-throughput pipeline for sample processing and data analysis. Investigators have completed a pilot genome-wide association study of 500,000 SNPs in 1,000 cases of severe malaria and 1,500 population controls. Some of the most significant associations identified by this study include:

• A macrophage-specific gene that was first identified in the spleen of malaria-infected mice.
• A seven transmembrane G-protein coupled receptor that could possibly be involved in parasite invasion of host cells.
• A calmodulin-binding transcription activator that is specifically associated with the cerebral malaria phenotype.

Investigators will not regard any of these results as conclusive until they have been replicated in different samples and are working toward that goal.
 
Project members believe an important outcome of the pilot study relates to questions about technical and analytical challenges facing genome-wide association analysis in Africa, notably the need to use very small amounts of DNA and the need to correct for population stratification. Nonetheless,  pilot data show that investigators can provide proof-of-principle for genome-wide association analysis as a discovery platform for malaria resistance determinants in African children.
 
Based on this, investigators believe there is a strong scientific case to proceed to a major program of genome-wide association analysis with statistical power to discover malaria resistance genes across a number of different populations. They have collected the clinical samples and put in place the laboratory infrastructure needed to analyze 650,000 SNPs in about 10,000 individuals from case-control and family-based association studies of severe malaria, and aim to achieve this in the next two years.