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 childrenResearch in context
Angela O. Achieng,
Nicolas W. Hengartner,
Evans Raballah,
Qiuying Cheng,
Samuel B. Anyona,
Nick Lauve,
Bernard Guyah,
Ivy Foo-Hurwitz,
John M. Ong'echa,
Benjamin H. McMahon,
Collins Ouma,
Christophe G. Lambert,
Douglas J. Perkins
Affiliations
Angela O. Achieng
University of New Mexico-Kenya Global Health Programs, Kisumu and Siaya, Kenya; Department of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno University, Maseno, Kenya
Nicolas W. Hengartner
Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM, USA
Evans Raballah
University of New Mexico-Kenya Global Health Programs, Kisumu and Siaya, Kenya; Department of Medical Laboratory Sciences, School of Public Health Biomedical Sciences and Technology, Masinde Muliro University of Science and Technology, Kakamega, Kenya
Qiuying Cheng
University of New Mexico, Center for Global Health, Department of Internal Medicine, NM, USA
Samuel B. Anyona
University of New Mexico-Kenya Global Health Programs, Kisumu and Siaya, Kenya; Department of Medical Biochemistry, School of Medicine, Maseno University, Maseno, Kenya
Nick Lauve
University of New Mexico, Center for Global Health, Department of Internal Medicine, NM, USA
Bernard Guyah
Department of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno University, Maseno, Kenya
Ivy Foo-Hurwitz
University of New Mexico, Center for Global Health, Department of Internal Medicine, NM, USA
John M. Ong'echa
Kenya Medical Research Institute, Centre for Global Health Research, Kisumu, Kenya
Benjamin H. McMahon
Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM, USA
Collins Ouma
University of New Mexico-Kenya Global Health Programs, Kisumu and Siaya, Kenya; Department of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno University, Maseno, Kenya
Christophe G. Lambert
University of New Mexico, Center for Global Health, Department of Internal Medicine, NM, USA
Douglas J. Perkins
University of New Mexico-Kenya Global Health Programs, Kisumu and Siaya, Kenya; University of New Mexico, Center for Global Health, Department of Internal Medicine, NM, USA; Corresponding author at: Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, MSC10-5550, and Albuquerque, NM 87131-0001, USA.
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, <5 years) at enrolment and during a 36-month longitudinal follow-up. 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 < 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). Interpretation: These findings suggest LAIR1 is important for modulating susceptibility to SMA and all-cause childhood mortality. Keywords: Leukocyte associated immunoglobulin like receptor 1, Plasmodium falciparum malaria, Severe malarial anaemia, All-cause mortality
