Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α⁺thalassaemia

*Adjusted Odds Ratios (aOR) and 95% Confidence Intervals (CI) are presented for the Sl2 genotype in the recessive form (i.e. Sl2/Sl2 vs all other Sl genotypes) and McC^b genotype in the additive form (i.e. change in aOR with each additional McC^b allele). Sl and McC genotype were included together in a statistical model to examine their associations with malaria susceptibility. aORs displayed are adjusted for ethnicity, location of residence, sickle cell genotype, α⁺thalassaemia genotype and ABO blood group. An interaction term between Sl genotype and α⁺thalassaemia was included in the model. Model outputs following 2000 bootstrapped iterations are shown.

^†99 children (7 of whom died) were severe malaria cases whose CM status was not recorded, hence these children are included in the numbers for ‘All severe malaria’ and ‘Died’ but not in ‘with CM’ or ‘without CM’ categories.

^‡Models that showed significant evidence of interaction between Sl2 and α⁺thalassaemia.

^§CM, cerebral malaria (P. falciparum infection with a Blantyre coma score of < 3).

^#SMA, severe malarial anaemia (P. falciparum infection with Hb < 5 g/dl).

^¶34/56 cases who died with SMA also had CM.

**RD, respiratory distress (P. falciparum infection with abnormally deep breathing).

^††56/73 cases who died with RD also had CM.

*Data were collected from 22 Sl1/Sl1, 94 Sl1/Sl2 and 92 Sl2/Sl2 individuals during 49.4, 213.8 and 188.8 cyfu (child-years of follow-up), respectively, and 137 McC^a/McC^a, 63 McC^a/McC^b and 8 McC^b/McC^b individuals during 294.5, 143.2 and 14.3 cyfu, respectively. Both Sl2 and McC^b alleles were tested for their association with the disease outcomes of interest using Poisson regression in the ¹recessive, ²dominant, ³heterozygous and ⁴additive models. The best fitting models as examined using the Akaike information criterion (AIC) were used in the final analysis that included adjustment for McC genotype (for Sl analyses), Sl genotype (for McC analyses) α⁺thalassaemia and sickle cell genotype, ABO blood group, season (divided into 3 monthly blocks), ethnicity, age as a continuous variable and within-person clustering of events.

^†aIRRs: adjusted Incidence Rate Ratios.

^‡Models that showed significant evidence of interaction between either Sl2 or McC^b and α⁺thalassaemia.

^§LRTI: Lower Respiratory Tract Infection.

^#URTI: Upper Respiratory Tract Infection.

Incidence = number of episodes per child-year of follow up (cyfu). Data were collected from 22 Sl1/Sl1, 94 Sl1/Sl2 and 92 Sl2/Sl2 individuals during 49.4, 213.8 and 188.8 child-years of follow-up, respectively.

Comparisons performed using Pearson’s χ² test except *Kruskal Wallis test

CM, cerebral malaria; IQR, interquartile range. Significance testing uses uncomplicated malaria as the reference group. Age: Kruskal Wallis test. ^#: Fisher’s exact test. All other analyses: Pearson’s χ².