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.
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Severe malarial anaemia (SMA) is a leading cause of childhood mortality in holoendemic Plasmodium falciparum regions.To gain an improved understanding of SMA pathogenesis, whole genome and transcriptome profiling was performed in Kenyan children (n=144, 3-36months) with discrete non-SMA and SMA phenotypes. Leukocyte associated immunoglobulin like receptor 1 (LAIR1) emerged as a predictor of susceptibility to SMA (P<1×10-2, OR: 0.44-1.37), and was suppressed in severe disease (-1.69-fold, P=0.004). To extend these findings, the relationship between LAIR1 polymorphisms [rs6509867 (16231C>A); rs2287827 (18835G>A)] and clinical outcomes were investigated in individuals (n=1512, <5years) at enrolment and during a 36-month longitudinal follow-up.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<0.05). Inheritance of 18,835 GA reduced all-cause mortality by 44.8% (HR=0.552, 95%CI: 0.329-0.925, P=0.024), while AG haplotype carriage increased susceptibility by 68% (HR=1.680, 95%CI: 1.020-2.770, P=0.040).These findings suggest LAIR1 is important for modulating susceptibility to SMA and all-cause childhood mortality.Copyright © 2019. Published by Elsevier B.V.