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>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|E|https://orcid.org/0000-0002-3304-6836', 'Anyona|Samuel B|SB|', 'Cheng|Qiuying|Q|', 'Munde|Elly O|EO|', 'Hurwitz|Ivy-Foo|IF|https://orcid.org/0000-0003-1566-1111', 'Onyango|Clinton|C|', 'Ndege|Caroline|C|', 'Hengartner|Nicolas W|NW|', 'Pacheco|Maria Andreína|MA|', 'Escalante|Ananias A|AA|', 'Lambert|Christophe G|CG|', 'Ouma|Collins|C|', 'Obama|Henri C Jr T|HCJT|', 'Scheider|Kristan A|KA|', 'Seidenberg|Philip D|PD|', 'McMahon|Benjamin H|BH|', 'Perkins|Douglas J|DJ|https://orcid.org/0000-0001-9390-6255']
malaria incident risk ratio C3 missense mutations P. falciparum complement system severe malaria anemia