Complement component 3 mutations alter the longitudinal risk of pediatric malaria and severe malarial anemia. Issue 8 (April 2022)

• Record Type: Journal Article
• Authors: Raballah, Evans; Anyona, Samuel B; Cheng, Qiuying; Munde, Elly O; Hurwitz, Ivy-Foo; Onyango, Clinton; Ndege, Caroline; Hengartner, Nicolas W; Pacheco, Maria Andreína; Escalante, Ananias A; Lambert, Christophe G; Ouma, Collins; Obama, Henri C Jr T; Schneider, Kristan A; Seidenberg, Philip D; McMahon, Benjamin H; Perkins, Douglas J
• Is Part Of: Experimental biology and medicine. Volume 247:Issue 8(2022)
• Page Start: 672
• Page End: 682
• Publication Date: 2022-04
• Subjects: C3 missense mutations -- complement system -- malaria -- severe malaria anemia -- incident risk ratio -- P. falciparum; Physiology -- Periodicals; Biology, Experimental -- Periodicals; Medicine, Experimental -- Periodicals; 610.72
• DOI: 10.1177/15353702211056272
• Languages: English
• ISSNs: 1535-3702

Abstract

Severe malarial anemia (SMA) is a leading cause of childhood morbidity and mortality in holoendemic Plasmodium falciparum transmission regions. To gain enhanced understanding of predisposing factors for SMA, we explored the relationship between complement component 3 (C3) missense mutations [rs2230199 (2307C>G, Arg>Gly 102 ) and rs11569534 (34420G>A, Gly>Asp 1224 )], malaria, and SMA in a cohort of children (n = 1617 children) over 36 months of follow-up. Variants were selected based on their ability to impart amino acid substitutions that can alter the structure and function of C3. The 2307C>G mutation results in a basic to a polar residue change (Arg to Gly) at position 102 (β-chain) in the macroglobulin-1 (MG1) domain, while 34420G>A elicits a polar to acidic residue change (Gly to Asp) at position 1224 (α-chain) in the thioester-containing domain. After adjusting for multiple comparisons, longitudinal analyses revealed that inheritance of the homozygous mutant (GG) at 2307 enhanced the risk of SMA (RR = 2.142, 95%CI: 1.229–3.735, P = 0.007). The haplotype containing both wild-type alleles (CG) decreased the incident risk ratio of both malaria (RR = 0.897, 95%CI: 0.828–0.972, P = 0.008) and SMA (RR = 0.617, 95%CI: 0.448–0.848, P = 0.003). Malaria incident risk ratio was also reduced in carriers of the GG (Gly 102 Gly 1224 ) haplotype (RR = 0.941, 95%CI: 0.888–0.997, P = 0.040). Collectively, inheritance of the missense mutations in MG1 and thioester-containing domain influence the longitudinal risk of malaria and SMA in children exposed to intense Plasmodium falciparum transmission.