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Two complement receptor one alleles have opposing associations with cerebral malaria and interact with ?+thalassaemia.

ABSTRACT: Malaria has been a major driving force in the evolution of the human genome. In sub-Saharan African populations, two neighbouring polymorphisms in the Complement Receptor One (CR1) gene, named Sl2 and McCb, occur at high frequencies, consistent with selection by malaria. Previous studies have been inconclusive. Using a large case-control study of severe malaria in Kenyan children and statistical models adjusted for confounders, we estimate the relationship between Sl2 and McCb and malaria phenotypes, and find they have opposing associations. The Sl2 polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the McCb polymorphism is associated with increased odds of cerebral malaria. We also identify an apparent interaction between Sl2 and ?+thalassaemia, with the protective association of Sl2 greatest in children with normal ?-globin. The complex relationship between these three mutations may explain previous conflicting findings, highlighting the importance of considering genetic interactions in disease-association studies.

SUBMITTER: Opi DH

PROVIDER: S-EPMC5953541 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Publications

Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia.

Opi D Herbert DH Swann Olivia O Macharia Alexander A Uyoga Sophie S Band Gavin G Ndila Carolyne M CM Harrison Ewen M EM Thera Mahamadou A MA Kone Abdoulaye K AK Diallo Dapa A DA Doumbo Ogobara K OK Lyke Kirsten E KE Plowe Christopher V CV Moulds Joann M JM Shebbe Mohammed M Mturi Neema N Peshu Norbert N Maitland Kathryn K Raza Ahmed A Kwiatkowski Dominic P DP Rockett Kirk A KA Williams Thomas N TN Rowe J Alexandra JA

eLife 20180425

Malaria has been a major driving force in the evolution of the human genome. In sub-Saharan African populations, two neighbouring polymorphisms in the Complement Receptor One (CR1) gene, named Sl2 and McCb, occur at high frequencies, consistent with selection by malaria. Previous studies have been inconclusive. Using a large case-control study of severe malaria in Kenyan children and statistical models adjusted for confounders, we estimate the relationship between ...[more]

PMID: 29690995

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Project description:Carriers of haemoglobin disorders have protection against falciparum malaria. Therefore, where this is common, carrier prevalence rises until this selective advantage is offset by deaths of affected children. Theory predicts a corresponding fall in carrier frequency following malaria eradication, but this has not been reported in practice. In the Maldives, malaria eradication (in 1972-1975) unmasked highly prevalent beta-thalassaemia and led to services for patient care and outreach carrier screening. Analysis of 68,986 laboratory screening records for subjects born between 1960 and 1990 showed carrier prevalences ranging from 10.1% to 28.2% by atoll (related to the prevalence of falciparum malaria before eradication) and a steady fall in average carrier prevalence from 21.3% among those born in 1970 to 16% in those born in 1989. Data for individuals born before 1970 suggest that earlier, when malaria was uncontrolled, carrier prevalence was 23-25%. The observed fall in carrier prevalence was broadly consistent with a model based on genetic theory, allowing for the heterogeneous distribution of carrier prevalence and the potential contribution of consanguineous marriage. The possible effects of population mixing and reproductive compensation were calculated, and any contribution to falling carrier prevalence was excluded. It is concluded that the observed fall in thalassaemia carrier prevalence in the Maldives is consistent with the predicted effect of malaria eradication and supportive of the population genetic theory. The observed fall in average carrier prevalence corresponds to a fall in minimum affected birth prevalence from approximately 12/1,000 in 1970 to approximately 6.9/1,000 in 2007. Allowing for this effect, the National Thalassaemia Register has documented a more than 60% fall in affected birth prevalence since outreach population screening was established in 1997. The main contributing factors are considered to be limitation of final family size by informed at-risk couples and utilisation of prenatal diagnosis.

Dataset Information

Two complement receptor one alleles have opposing associations with cerebral malaria and interact with ?+thalassaemia.

Publications

Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α<sup>+</sup>thalassaemia.

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