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

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 (beta-chain) in the macroglobulin-1 (MG1) domain, while 34420G>A elicits a polar to acidic residue change (Gly to Asp) at position 1224 (alpha-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.

Automated summary

The study explored the relationship between C3 missense mutations and severe malarial anemia (SMA) in children exposed to intense Plasmodium falciparum transmission. The findings showed that specific mutations in the MGI and thioester-containing domain of C3 influenced the longitudinal risk of malaria and SMA in children. The study suggested that certain genetic variations may play a role in predisposing children to severe malarial anemia and malaria in high transmission areas.