Leffler, E. M.; Band, G.; Jeffreys, A. E.; Rowlands, K.; Hubbart, C.; Bojang, K. A.; Conway, D. J.; Jallow, M.; Sisay-Joof, F.; D'Alessandro, U.; Ndila, C. M.; Macharia, A. W.; Marsh, K.; Williams, T. N.; Kachala, D.; Molyneux, M.; Nyirongo, V.; Taylor, T. E.; Rockett, K. A.; Kwiatkowski, D. P.

PIEZO1 forms a mechanosensitive ion channel involved in regulating calcium levels in red blood cells. E756del, a deletion allele within a short tandem repeat (STR) in PIEZO1, is common in many African populations and has been proposed to be associated with protection from malarial disease, but epidemiological evidence has been inconsistent. Here, we use Illumina sequencing of amplicons covering the PIEZO1 STR to genotype 5,558 severe malaria cases and 8,174 population controls from The Gambia, Kenya, and Malawi. We estimate a modest effect for E756del and meta-analysis with two published studies, for a total of 8,224 cases and 10,103 controls, reveals a consistent protective effect (OR=0.93, 95% CI 0.88-0.99). By comprehensively genotyping the STR, we identify additional, less common alleles, with two (Q745del and E756ins) showing consistent, but also modest, risk effects across studies. Although allele frequency differentiation between African and non-African populations could be consistent with a selective effect, we show that it is not exceptional compared with STR variants genome wide. Thus, our results support a protective effect of E756del against risk of malaria but with a much smaller effect size than initially reported.