Identification of single nucleotide polymorphisms in hematopoietic cell transplant patients affecting early recognition of, and response to, endotoxin

Eva C Guinan; Christine D Palmer; Christy J Mancuso; Lisa Brennan; Liat Stoler-Barak; Leslie A Kalish; Eugenie E Suter; Leighanne C Gallington; David P Huhtelin; Maria Mansilla; Ralf R Schumann; Jeffrey C Murray; Jerrold Weiss; Ofer Levy

doi:10.1177/1753425913505122

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Identification of single nucleotide polymorphisms in hematopoietic cell transplant patients affecting early recognition of, and response to, endotoxin

Journal article

Peer reviewed

Identification of single nucleotide polymorphisms in hematopoietic cell transplant patients affecting early recognition of, and response to, endotoxin

Eva C Guinan, Christine D Palmer, Christy J Mancuso, Lisa Brennan, Liat Stoler-Barak, Leslie A Kalish, Eugenie E Suter, Leighanne C Gallington, David P Huhtelin, Maria Mansilla, …

Innate immunity (London, England), Vol.20(7), pp.697-711

10/2014

DOI: 10.1177/1753425913505122

PMCID: PMC4128912

PMID: 24107515

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Abstract

Hematopoietic cell transplant (HCT) is a life-saving therapy for many malignant and non-malignant bone marrow diseases. Associated morbidities are often due to transplant-related toxicities and infections, exacerbated by regimen-induced immune suppression and systemic incursion of bacterial products. Patients undergoing myeloablative conditioning for HCT become endotoxemic and display blood/plasma changes consistent with lipopolysaccharide (LPS)-induced systemic innate immune activation. Herein, we addressed whether patients scheduled for HCT display differences in recognition/response to LPS ex vivo traceable to specific single nucleotide polymorphisms (SNPs). Two SNPs of LPS binding protein (LBP) were associated with changes in plasma LBP levels, with one LBP SNP also associating with differences in efficiency of extraction and transfer of endotoxin to myeloid differentiation factor-2 (MD-2), a step needed for activation of TLR4. None of the examined SNPs of CD14, bactericidal/permeability-increasing protein (BPI), TLR4 or MD-2 were associated with corresponding protein plasma levels or endotoxin delivery to MD-2, but CD14 and BPI SNPs significantly associated with differences in LPS-induced TNF-α release ex vivo and infection frequency, respectively. These findings suggest that specific LBP, CD14 and BPI SNPs might be contributory assessments in studies where clinical outcome may be affected by host response to endotoxin and bacterial infection.

Tumor Necrosis Factor-alpha - metabolism

Humans

Hematopoietic Stem Cell Transplantation

Genotype

Acute-Phase Proteins - genetics

Bone Marrow Diseases - genetics

Membrane Glycoproteins - genetics

Carrier Proteins - genetics

Bone Marrow Diseases - therapy

Lipopolysaccharide Receptors - genetics

Polymorphism, Single Nucleotide - genetics

Chemokines - metabolism

Endotoxins - toxicity

Cohort Studies

Details

Title: Subtitle: Identification of single nucleotide polymorphisms in hematopoietic cell transplant patients affecting early recognition of, and response to, endotoxin
Creators: Eva C Guinan - Boston Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA Dana-Farber Cancer Institute, Boston, MA, USA
Christine D Palmer - Boston Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Boston, MA, USA
Christy J Mancuso - Boston Children's Hospital, Boston, MA, USA
Lisa Brennan - Dana-Farber Cancer Institute, Boston, MA, USA
Liat Stoler-Barak - Boston Children's Hospital, Boston, MA, USA
Leslie A Kalish - Boston Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA
Eugenie E Suter - Boston Children's Hospital, Boston, MA, USA
Leighanne C Gallington - Boston Children's Hospital, Boston, MA, USA
David P Huhtelin - University of Iowa and Veterans' Administration Medical Center, Coralville, Iowa City, IA, USA
Maria Mansilla - Department of Pediatrics, University of Iowa, IA, Iowa City, USA
Ralf R Schumann - Institute for Microbiology, Charité-University Medical Center, Berlin, Germany
Jeffrey C Murray - Department of Pediatrics, University of Iowa, IA, Iowa City, USA
Jerrold Weiss - University of Iowa and Veterans' Administration Medical Center, Coralville, Iowa City, IA, USA
Ofer Levy - Boston Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA ofer.levy@childrens.harvard.edu
Resource Type: Journal article
Publication Details: Innate immunity (London, England), Vol.20(7), pp.697-711
DOI: 10.1177/1753425913505122
PMID: 24107515
PMCID: PMC4128912
NLM abbreviation: Innate Immun
ISSN: 1753-4259
eISSN: 1753-4267
Publisher: United States
Grant note: 1U19AI091173-01 / NIAID NIH HHS P30 ES005605 / NIEHS NIH HHS U19 AI091173 / NIAID NIH HHS U19 AI067751 / NIAID NIH HHS 8UL1TR000170-05 / NCATS NIH HHS R01 AI059372 / NIAID NIH HHS R21 HL089659 / NHLBI NIH HHS UL1 TR000170 / NCATS NIH HHS 5R21HL089659 / NHLBI NIH HHS 5U19 AI067751 / NIAID NIH HHS
Language: English
Date published: 10/2014
Academic Unit: Anatomy and Cell Biology; Infectious Diseases; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Pharmacy Practice and Science; Dental Research; Internal Medicine; Iowa Institute of Human Genetics
Record Identifier: 9984025306302771

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