Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study.
Level 4 - case-series / case-control
Case-control association study
PubMed 30033078 · doi:10.1016/S2352-3026(18)30107-8
What was done
A case-control study in Kilifi County, Kenya, evaluated associations between 121 candidate gene polymorphisms across 70 genes and risk of severe Plasmodium falciparum malaria and specific phenotypes (cerebral malaria, severe malaria anaemia, and respiratory distress). Cases were 2,244 children presenting with severe malaria to a hospital high-dependency ward between June 11, 1995, and June 12, 2008. Controls were 3,949 infants born in the local community between August 1, 2006, and September 30, 2010. Permutation testing controlled for multiple testing, with p < 0.005 defining statistical significance for primary candidate gene analyses.
What was found
In-hospital mortality was 12% (263/2,244) among severe malaria cases overall and 16% (196/1,233) among cerebral malaria cases. Significant associations with severe malaria were identified across 15 loci (ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA1/HBA2, HBB, IL10, LPHN2/ADGRL2, LOC727982, RPS6KL1, CAND1, and GNAS), which together explained 5.2% of disease risk variance. Replicated protective factors included sickle-cell trait (OR 0.15, 95% CI 0.11-0.20; p = 2.61 x 10^-58), blood group O (OR 0.74, 95% CI 0.66-0.82; p = 6.26 x 10^-8), and -alpha 3.7-thalassaemia (OR 0.83, 95% CI 0.76-0.90; p = 2.06 x 10^-6). Significant associations were also found for ATP2B4 (OR 0.76, 95% CI 0.63-0.92; p = 0.001) and FREM3 (OR 0.64, 95% CI 0.53-0.79; p = 3.18 x 10^-14). The FREM3 association was driven by linkage disequilibrium with a structural variant encoding the rare Dantu blood group antigen in the glycophorin region, where heterozygosity yielded OR 0.57 (95% CI 0.49-0.68; p = 3.22 x 10^-11) and homozygosity yielded OR 0.26 (95% CI 0.11-0.62; p = 0.002).
Why it matters
This study confirms the central role of red blood cell variations in protection against severe Plasmodium falciparum malaria and identifies ATP2B4 and the Dantu blood group antigen as important protective determinants.
Limits
The study was conducted in a single hospital catchment area in Kenya. Cases and controls were recruited during different calendar timeframes (1995-2008 vs. 2006-2010), introducing potential temporal cohort bias. All 15 identified genetic loci combined accounted for only 5.2% of the variance in severe malaria risk.