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

EBioMedicine (Jul 2019)

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.

Journal volume & issue: Vol. 45
pp. 290 – 302

Abstract

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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

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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