Integrated OMICS platforms identify LAIR1 genetic variants as novel predictors of cross-sectional and longitudinal susceptibility to severe malaria and all-cause mortality in Kenyan children

Abstract Background Severe malarial anaemia (SMA) is a leading cause of childhood mortality in holoendemic Plasmodium falciparum regions. Methods To gain an improved understanding of SMA pathogenesis, whole genome and transcriptome profiling was performed in Kenyan children (n = 144, 3–36 months) with discrete non-SMA and SMA phenotypes. Leukocyte associated immunoglobulin like receptor 1 (LAIR1) emerged as a predictor of susceptibility to SMA (P  A); rs2287827 (18835G>A)] and clinical outcomes were investigated in individuals (n = 1512, Findings Inheritance of the 16,231 recessive genotype (AA) increased susceptibility to SMA at enrolment (OR = 1.903, 95%CI: 1.252–2.891, P = 0.003), and longitudinally (RR = 1.527, 95%CI: 1.119–2.083, P = 0.008). Carriage of the 18,835 GA genotype protected against SMA cross-sectionally (OR = 0.672, 95%CI: 0.480–0.9439, P = 0.020). Haplotype carriage (C16231A/G18835A) also altered cross-sectional susceptibility to SMA: CG (OR = 0.717, 95%CI: 0.527–0.9675, P = 0.034), CA (OR = 0.745, 95%CI: 0.536–1.036, P = 0.080), and AG (OR = 1.641, 95%CI: 1.160–2.321, P = 0.005). Longitudinally, CA carriage was protective against SMA (RR = 0.715, 95%CI: 0.554–0.923, P = 0.010), while AG carriage had an additive effect on enhanced SMA risk (RR = 1.283, 95%CI: 1.057–1.557, P = 0.011). Variants that protected against SMA had elevated LAIR1 transcripts, while those with enhanced risk had lower expression (P  Interpretation These findings suggest LAIR1 is important for modulating susceptibility to SMA and all-cause childhood mortality.