Complement component 3 mutations alter the longitudinal risk of pediatric malaria and severe malarial anemia Journalartikel uri icon



  • 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>Gly102) and rs11569534 (34420G>A, Gly>Asp1224)], 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 (Gly102Gly1224) 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.


  • 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
  • Seidenberg, Philip D
  • McMahon, Benjamin H
  • Perkins, Douglas J


  • 2022


  • Open Access


  • 8


  • 247


  • 672

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