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Title: 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

Journal Article · · EBioMedicine
 [1];  [2];  [3];  [4];  [5];  [4];  [6];  [4];  [7];  [2];  [8];  [4];  [9]
  1. Univ. of New Mexico--Kenya Global Health Programs, Kisumu and Siaya (Kenya); Maseno Univ. (Kenya). School of Public Health and Community Development. Dept. of Biomedical Sciences and Technology; DOE/OSTI
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Division. Theoretical Biology and Biophysics Group
  3. Univ. of New Mexico--Kenya Global Health Programs, Kisumu and Siaya (Kenya); Masinde Muliro Univ. of Science and Technology, Kakamega (Kenya). School of Public Health Biomedical Sciences and Technology. Dept. of Medical Laboratory Sciences
  4. Univ. of New Mexico, Albuquerque, NM (United States). Center for Global Health. Dept. of Internal Medicine
  5. Univ. of New Mexico--Kenya Global Health Programs, Kisumu and Siaya (Kenya); Maseno Univ. (Kenya). School of Medicine. Dept. of Medical Biochemistry
  6. Maseno Univ. (Kenya). School of Public Health and Community Development. Dept. of Biomedical Sciences and Technology
  7. Kenya Medical Research Inst., Kisumu (Kenya). Centre for Global Health Research
  8. Univ. of New Mexico--Kenya Global Health Programs, Kisumu and Siaya (Kenya); Maseno Univ. (Kenya). School of Public Health and Community Development. Dept. of Biomedical Sciences and Technology
  9. Univ. of New Mexico--Kenya Global Health Programs, Kisumu and Siaya (Kenya); Univ. of New Mexico, Albuquerque, NM (United States). Center for Global Health. Dept. of Internal Medicine
+ Show Author Affiliations

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 b 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 (16231CNA); rs2287827 (18835GNA)] and clinical outcomes were investigated in individuals (n = 1512, b5 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 b 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.

Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1623664
Journal Information:
EBioMedicine, Journal Name: EBioMedicine Journal Issue: C Vol. 45; ISSN 2352-3964
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English

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Inhibitory Receptors CD85j, LAIR-1, and CD152 Down-Regulate Immunoglobulin and Cytokine Production by Human B Lymphocytes journal June 2005
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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
General & Internal Medicine
Research & Experimental Medicine
Leukocyte associated immunoglobulin like receptor 1
Plasmodium falciparum malaria
Severe malarial anaemia
All-cause mortality