Genetic determinants of resistance to malaria (CP1)
This consortial project addresses the question of why, in regions where every individual is repeatedly exposed to malaria parasites, some people die from the infection while others survive. Each partner study has collected detailed clinical data and DNA from people with severe malaria, i.e. those who develop life-threatening clinical complications such as cerebral malaria and severe malarial anaemia.
Partner studies
- Burkina Faso: Centre National de Recherche et de Formation sur le Paludisme: Study>>
- Cameroon: University of Buea: Study>>
- Gambia: MRC Laboratories: Study>>
- Ghana: Noguchi Memorial Institute for Medical Research with Navrongo Health Research Centre: Study>>
- Ghana: Kwame Nkrumah University of Science and Technology: Study>>
- Kenya: KEMRI-Wellcome Research Programme: Study>>
- Malawi: Blantyre Malaria Project with Malawi-Liverpool-Wellcome Programme: Study>>
- Mali: University of Bamako: Study>>
- Nigeria: University of Ibadan: Study>>
- Papua New Guinea: Papua New Guinea Institute for Medical Research: Study>>
- Tanzania: Joint Malaria Programme, Kilimanjaro Christian Medical Centre: Study>>
- Vietnam: Oxford University Clinical Research Unit: Study>>
Data
Below are links to MalariaGEN datasets that are currently available. We are working hard to release more datasets, so please check again in a few months.
Background information
An individual’s risk of developing severe malaria is influenced by many different genetic and environmental factors, but we know relatively little about their precise nature and how they interact. This project seeks to discover the human genetic factors involved, which could provide vital clues about molecular mechanisms of protective immunity and thereby accelerate the development of an effective vaccine.
The MalariaGEN Ethics Team has worked to balance the intrinsic importance of paying attention to the ethical aspects of this consortial project and the fact that successful and appropriate genomic research in the context of collaboration between low and high income countries depends upon the identification and addressing of a range of important ethical issues such as those relating to data-sharing and the obtaining of consent. You can read more about how these issues have been considered in the Ethics & Governance section.
Across the different partner studies, we have now recruited more than 13,000 cases of severe malaria, plus a similar number of ethnically matched population controls, as well as the parents of about 2000 cases. This provides a unique resource for case-control and family-based studies of genetic resistance and susceptibility to severe malaria. An immediate question is whether we can confirm genetic variants that have previously been reported to be associated with severe malaria. There has been much debate in the malaria research community about whether such observations are merely due to chance, since most are from isolated studies with relatively small sample size. In 2012, MalariaGEN plans to publish the first detailed case-control analysis of more than 40 genetic variants that are reported in the literature, integrating clinical and genetic data from more than 20,000 individuals from 12 different locations.
The main reason for developing this unique resource has been to conduct a systematic genome-wide association (GWA) analysis of resistance to severe malaria. This involves genotyping millions of single nucleotide polymorphisms (SNPs) in thousands of cases and controls, and looking for those that are statistically associated with the risk of disease. GWA analysis is a relatively new field of medical research that has been hugely productive over the past 4 years, particularly in populations of European or Asian ancestry. To date, only a handful of GWA studies have been conducted in Africa, the first being published by MalariaGEN in 2009.
The methodological issues confronting multi-centre GWA studies in Africa are considerably more challenging than those experienced in European or Asian populations. One of the biggest challenges is to build the necessary clinical research infrastructure, and this is an area where MalariaGEN partner studies have already made much progress. There are also major analytical challenges, arising from the much higher levels of genetic diversity that are found in Africa compared to other parts of the world. This means that a greater number of genetic variants need to be typed in an African study to achieve the same level of statistical power as a comparable study in a European population. There are also much higher levels of ethnic diversity and population structure in Africa than on other continents, making it challenging to combine GWA data from different locations in large-scale meta-analyses. Many of these obstacles are now being overcome by advances in genome sequencing, high-density SNP assays and statistical methods for genotype imputation. The MalariaGEN community has been at the forefront of methods development for GWA analysis in Africa, and in 2012 plans to complete an initial GWA analysis of over 12,000 individuals from four different African populations.