rs11036238 (HBB): Severe Malaria Risk Variant

Key takeaways

• A large study of Gambian children linked this locus to severe malaria risk at a statistical signal of P = 4 x 10^-14 after fine-resolution imputation.
• Standard genome-wide arrays almost missed the signal at this locus; the p-value was roughly 10 million times weaker before population-specific sequencing data were applied.
• The HbS (hemoglobin S) variant within the HBB gene is the single strongest known genetic determinant of severe malaria risk, explaining roughly 2% of total variation in disease outcome.
• Host genetic factors collectively account for roughly 25% of severe malaria risk in populations with repeated Plasmodium falciparum exposure.
• rs11036238 sits near HBB (hemoglobin beta) and OR51V1 (an olfactory receptor gene) on chromosome 11, in a region studied in the context of malaria resistance in West Africa.

What the research says A genome-wide association (GWA) study of severe malaria in The Gambia found a signal at the HBB locus - the chromosomal neighborhood where rs11036238 is annotated - that strengthened from P = 4 x 10^-7 to P = 4 x 10^-14 when fine-resolution multipoint imputation was applied using sequencing data from 62 Gambian individuals. The HbS variant in HBB, which encodes the beta-globin component of hemoglobin, accounts for approximately 2% of total variation in severe malaria risk, while host genetic factors as a whole explain roughly 25% of that risk across repeatedly exposed populations. This work showed that weak linkage disequilibrium (LD) in African genomes - meaning nearby genetic variants are less correlated with one another than in European genomes - had attenuated association signals at known malaria resistance loci, and that population-specific sequencing is a practical method for recovering those signals.

Reported associations

• Severe malaria (P. falciparum): The HBB locus, containing the chromosomal region where rs11036238 is annotated, was associated with severe malaria in Gambian children. After fine-resolution imputation using population-specific sequence data, the association signal reached P = 4 x 10^-14 in a sample of 958 cases and 1,382 controls from The Gambia, with the peak of the signal located precisely at the HbS causal variant.

Evidence quality The initial GWA scan covered 958 cases and 1,382 controls (Gambian children drawn 89% from four ethnic groups: Mandinka, Jola, Wolof, and Fula) genotyped on 402,814 quality-controlled SNPs from the Affymetrix 500K array; a replication cohort added approximately 3,400 children, bringing the combined study to more than 5,700 Gambian children. The association at the HBB locus reached P = 4 x 10^-14 after fine-resolution imputation, meeting a stringent genome-wide significance threshold. Population stratification was quantified (genomic inflation factor lambda = 1.23 before correction, reduced to 1.07 after adjustment for self-reported ethnicity and negligible after full principal components correction), and was addressed in final analyses. The study was conducted in a single geographic region of West Africa and may not generalize to other African populations or to non-African groups. The authors note that standard GWA arrays substantially underdetect true associations at this locus in African populations due to weaker LD, which is a recognized limitation for studies relying on array-based genotyping alone without population-specific imputation.

Lifestyle considerations No lifestyle considerations on file for this variant.