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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, 3-36months) 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.

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.

Titel:	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.
Autor/in / Beteiligte Person:	Achieng, AO ; Hengartner, NW ; Raballah, E ; Cheng, Q ; Anyona, SB ; Lauve, N ; Guyah, B ; Foo-Hurwitz, I ; Ong'echa, JM ; McMahon, BH ; Ouma, C ; Lambert, CG ; Perkins, DJ
Link:	Zum Volltext
Zeitschrift:	EBioMedicine, Jg. 45 (2019-07-01), S. 290
Veröffentlichung:	[Amsterdam] : Elsevier B.V., [2014]-, 2019
Medientyp:	academicJournal
ISSN:	2352-3964 (electronic)
DOI:	10.1016/j.ebiom.2019.06.043
Schlagwort:	Anemia genetics Anemia parasitology Child, Preschool Female Gene Expression Regulation Genotype Haplotypes genetics Humans Infant Kenya epidemiology Leukocytes, Mononuclear parasitology Malaria, Falciparum genetics Malaria, Falciparum parasitology Male Phagocytosis Signal Transduction genetics Anemia blood Malaria, Falciparum blood Receptors, Immunologic genetics
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [EBioMedicine] 2019 Jul; Vol. 45, pp. 290-302. <i>Date of Electronic Publication: </i>2019 Jul 02. MeSH Terms: Anemia / blood ; Malaria, Falciparum / blood ; Receptors, Immunologic / *genetics ; Anemia / genetics ; Anemia / parasitology ; Child, Preschool ; Female ; Gene Expression Regulation ; Genotype ; Haplotypes / genetics ; Humans ; Infant ; Kenya / epidemiology ; Leukocytes, Mononuclear / parasitology ; Malaria, Falciparum / genetics ; Malaria, Falciparum / parasitology ; Male ; Phagocytosis ; Signal Transduction / genetics References: Eur J Immunol. 1999 Oct;29(10):3160-7. (PMID: 10540327) ; J Biol Chem. 2000 Jun 9;275(23):17440-6. (PMID: 10764762) ; Am J Trop Med Hyg. 2001 Jan-Feb;64(1-2 Suppl):iv-vii. (PMID: 11425185) ; Biostatistics. 2003 Oct;4(4):513-22. (PMID: 14557108) ; Bioinformatics. 2005 Jan 15;21(2):263-5. (PMID: 15297300) ; Clin Diagn Lab Immunol. 2005 Jun;12(6):705-12. (PMID: 15939744) ; Am J Hum Genet. 2005 Aug;77(2):171-92. (PMID: 16001361) ; AIDS. 2006 Jan 9;20(2):275-80. (PMID: 16511422) ; Am J Trop Med Hyg. 2006 Mar;74(3):376-85. (PMID: 16525094) ; Haematologica. 2006 Oct;91(10):1396-9. (PMID: 17018392) ; J Leukoc Biol. 2008 Apr;83(4):799-803. (PMID: 18063695) ; Am J Trop Med Hyg. 2007 Dec;77(6 Suppl):23-8. (PMID: 18165471) ; PLoS One. 2008 May 21;3(5):e2196. (PMID: 18493319) ; Clin Infect Dis. 2008 Jul 15;47(2):158-60. (PMID: 18564928) ; J Infect Dis. 2008 Oct 15;198(8):1219-26. (PMID: 18781863) ; J Infect Dis. 2009 Aug 15;200(4):629-37. (PMID: 19591577) ; Br J Haematol. 2010 Jun;149(5):711-21. (PMID: 20408849) ; J Clin Microbiol. 2011 Feb;49(2):671-6. (PMID: 21106789) ; PLoS One. 2010 Nov 30;5(11):e15080. (PMID: 21151495) ; Heredity (Edinb). 2011 Oct;107(4):283-304. (PMID: 21427751) ; Exp Mol Pathol. 2011 Oct;91(2):626-30. (PMID: 21806986) ; Hum Genet. 2012 Feb;131(2):289-99. (PMID: 21818580) ; Infect Immun. 2011 Nov;79(11):4674-80. (PMID: 21859849) ; Infect Immun. 2011 Dec;79(12):4923-32. (PMID: 21969001) ; Int J Biol Sci. 2011;7(9):1427-42. (PMID: 22110393) ; Arthritis Rheum. 2011 Dec;63(12):3749-57. (PMID: 22127695) ; Tissue Antigens. 2012 Feb;79(2):104-13. (PMID: 22220719) ; PLoS One. 2012;7(2):e31903. (PMID: 22355402) ; Pediatr Hematol Oncol. 2014 Feb;31(1):68-75. (PMID: 24308819) ; Haematologica. 2014 May;99(5):881-7. (PMID: 24415628) ; Mol Med. 2015 Feb 05;20:559-68. (PMID: 25247291) ; Proc Biol Sci. 2015 Feb 22;282(1801):20142657. (PMID: 25567652) ; Nature. 2016 Jan 7;529(7584):105-109. (PMID: 26700814) ; Hum Genet. 2016 Feb;135(2):233-44. (PMID: 26721477) ; BMC Infect Dis. 2017 Apr 20;17(1):291. (PMID: 28427357) ; Nature. 2017 Aug 31;548(7669):597-601. (PMID: 28847005) ; Adv Healthc Mater. 2017 Dec;6(24):. (PMID: 29083540) ; Nature. 2017 Dec 7;552(7683):101-105. (PMID: 29186116) ; Malar J. 2018 Jan 18;17(1):37. (PMID: 29347942) ; Immunity. 1997 Aug;7(2):283-90. (PMID: 9285412) ; Eur J Immunol. 1998 Jul;28(7):2086-91. (PMID: 9692876) Grant Information: D43 TW005884 United States TW FIC NIH HHS; R01 AI130473 United States AI NIAID NIH HHS Contributed Indexing: Keywords: All-cause mortality; Leukocyte associated immunoglobulin like receptor 1; Plasmodium falciparum malaria; Severe malarial anaemia Substance Nomenclature: 0 (Receptors, Immunologic) ; 0 (leukocyte-associated immunoglobulin-like receptor 1) Entry Date(s): Date Created: 20190707 Date Completed: 20200106 Latest Revision: 20200225 Update Code: 20240513 PubMed Central ID: PMC6642287

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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.