Genetic variation in bactericidal/permeability-increasing protein influences the risk of developing rapid airflow decline after hematopoietic cell transplantation

Chien, Jason W.; Zhao, Lue Ping; Hansen, John A.; Fan, Weiwen; Parimon, Tanyalak; Clark, John D.

doi:10.1182/blood-2005-06-2338

Cited by 37 publications

(31 citation statements)

References 81 publications

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“…Disease risk categories were ranked according to the outcomes we have observed at our Center and have been previously described. 17 Stem cell sources were classified as growth factor-mobilized blood cells, bone marrow, or other, which included cord blood or a combination of bone marrow and mobilized blood cells. Matching between the donor and recipient was determined according to donor-recipient HLA-A, HLA-B, and HLA-DR compatibility.…”

Section: Nested Case-control Studymentioning

confidence: 99%

Lipopolysaccharide binding protein promoter variants influence the risk for Gram-negative bacteremia and mortality after allogeneic hematopoietic cell transplantation

Chien

Boeckh

Hansen

et al. 2008

Blood

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Lipopolysaccharide binding protein (LBP)function is dependent on circulating LBP levels. Disturbance of LBP transcription regulation may influence the risk for clinical events. In a nested case-control study using a single nucleotide polymorphism haplotype tagging (tagSNP) approach, we assessed whether genetic variation in the LBP gene influences the risk for Gramnegative (GN) bacteremia after allogeneic hematopoietic cell transplantation (HCT), then validated the association in a prospective cohort by correlating genetic variation with basal serum LBP levels and mortality. Presence of the tagSNP 6878 C allele among patients was associated with a 2-fold higher risk for GN bacteremia (odds ratio ‫؍‬ 2.15; 95% confidence interval [CI], 1.31-3.52, P ‫؍‬ .002). TagSNP 6878 was in strong linkage disequilibrium with 3 SNPs in the LBP promoter, one of which was SNP 1683 (r 2 ‫؍‬ 0.8), located in a CAAT box that regulates LBP promoter efficiency. SNP 1683 was associated with higher median basal serum LBP levels (TT 8.07 g/mL; TC 10.40 g/mL; CC 17.39 g/mL; P ‫؍‬ .002), and a 5-fold increase in GN bacteremia related mortality after HCT (hazard ratio ‫؍‬ 4.83; 95% CI, 1.38-16.75, P ‫؍‬ .013). These data suggest that transcriptional regulation of the LBP gene contributes to the risk for developing GN IntroductionThe lethal effects of Gram-negative (GN) bacteria are attributable to lipopolysaccharide (LPS), a highly conserved glycolipid component of the cell wall of all GN bacteria. 1,2 One of the key components of the innate immune response to LPS is lipopolysaccharide binding protein (LBP), a secretory class I acute-phase protein synthesized by hepatocytes. LBP is involved in LPS recognition and signaling. 3 Circulating LBP can have both proinflammatory and anti-inflammatory effects on the host response to LPS. At low to normal concentrations, LBP catalyzes the transfer of disaggregated LPS to the binding site of membrane-bound and soluble forms of CD14, facilitating signaling via TLR4, 4-6 and binds directly to GN bacteria, resulting in enhanced phagocytosis and clearance from blood. 7 At high concentrations, LBP can inhibit LPS-induced host cell activation, reduce LPS binding to monocytes, and attenuate the release of proinflammatory cytokines, such as tumor necrosis factor-␣. 8,9 The dual nature of LBP activity makes this an interesting candidate for genetic analysis. LBP's concentration-dependent immunologic function must require precise genetic regulation of gene transcription, suggesting that genetic variation in the elements controlling LBP production may affect an individual's immune response to LPS and GN bacteria. This possibility is supported by a previous detailed study of the LBP promoter region; truncation mutation experiments indicate that a region of the LBP promoter is responsible for regulating the efficiency of gene transcription. 10 Based on this work, we hypothesized that genetic variation in the LBP gene may disturb LBP transcription and regulation may influence the risk for clinical events. To tes...

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Section: Nested Case-control Studymentioning

confidence: 99%

Lipopolysaccharide binding protein promoter variants influence the risk for Gram-negative bacteremia and mortality after allogeneic hematopoietic cell transplantation

Chien

Boeckh

Hansen

et al. 2008

Blood

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“…In humans with bronchiolitis obliterans after allogeneic HSCT, peribronchiolar infiltrate was composed of CD8+T-lymphocytes in one patient [145] and of B-lymphocytes in another patient [146]. Genetic variations in bactericidal/permeability-increasing protein influence the risk of BOS after allogeneic HSCT [147]. Recently, a new murine model for bronchiolitis obliterans after allogeneic HSCT has reproduced bronchiolar abnormalities mimicking human disease [148], and may provide insights into the pathogenesis of bronchiolitis obliterans in humans.…”

Section: Bronchiolitis Obliterans After Lung Transplantationmentioning

confidence: 99%

Small airways diseases, excluding asthma and COPD: an overview

Burgel¹,

Bergeron²,

Blic³

et al. 2013

Eur Respir Rev

105

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This review is the summary of a workshop on small airways disease, which took place in Porquerolles, France in November 2011. The purpose of this workshop was to review the evidence on small airways (bronchiolar) involvement under various pathophysiological circumstances, excluding asthma and chronic obstructive pulmonary disease. Histopathological patterns associated with small airways disease were reviewed, including cellular and obliterative bronchiolitis. Many pathophysiological conditions have been associated with small airways disease including airway infections, connective tissue diseases and inflammatory bowel diseases, bone marrow and lung transplantation, common variable immunodeficiency disorders, diffuse panbronchiolitis, and diseases related to environmental exposures to pollutants, allergens and drugs. Pathogenesis, clinical presentation, a computed tomography scan and pulmonary function test findings are reviewed, and therapeutic options are described with the objective of providing an integrative approach to these disorders.

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“…78 Finally, polymorphisms in the bactericidal/permeability-increasing (BPI) gene were recently noted to be significantly associated with the risk of developing bronchiolitis obliterans after HSCT. 79 BPI belongs to a family of lipid transport proteins that have a critical role in the innate immune response to bacterial infection.…”

Section: Polymorphisms In Innate Immunity Genesmentioning

confidence: 99%

“…Evaluation of candidate gene pathways using a linkage disequilibrium approach targeting SNPs in a particular haplotype is a more rational and recently applied method of investigation in this area. 79 Similarly unclear are the importance of SNPs determined to be of significance in individual studies, relative to that of SNPs identified in other studies. In fact, many studies have demonstrated conflicting results.…”

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confidence: 99%

Beyond HLA: the significance of genomic variation for allogeneic hematopoietic stem cell transplantation

Mullally

Ritz

2006

Blood

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The last 2 years have seen much excitement in the field of genetics with the identification of a formerly unappreciated level of "structural variation" within the normal human genome. Genetic structural variants include deletions, duplications, and inversions in addition to the recently discovered, copy number variants. Single nucleotide polymorphisms are the most extensively evaluated variant within the genome to date. Combining our knowledge from these studies with our rapidly accumulating understanding of structural variants, it is apparent that the extent of genetic dissimilarity between any 2 individuals is considerable and much greater than that which was previously recognized. Clearly, this more diverse view of the genome has significant implications for allogeneic hematopoietic stem cell transplantation, not least in the generation of transplant antigens but also in terms of individual susceptibility to transplant-related toxicities. With advances in DNA sequencing technology we now have the capacity to perform genome-wide analysis in a high throughput fashion, permitting a detailed genetic analysis of patient and donor prior to transplantation. Understanding the significance of this additional genetic information and applying it in a clinically meaningful way will be one of the challenges faced by transplant clinicians in the future. Introduction Structural variation in the human genomeRecently, much focus has been directed at documenting the extent of normal human genomic variation, particularly in the form of single nucleotide polymorphisms (SNPs; Table 1). In October 2005, phase 1 of the International Hapmap Project was published. 2 This project catalogued more than one million SNPs, genomewide, into a publicly accessible database (www.hapmap.org). Approximately 11 500 of the SNPs recorded in phase 1 are nonsynonymous coding SNPs. Other examples of genomic variation include gene deletions, inverted gene sequences, multiple copy gene duplications, segmental duplications and large-scale copy number variants (CNVs). Each of these structural variants is shown schematically in Figure 1.In the year prior to the Hapmap publication, 2 landmark studies reported that large-scale CNVs are distributed widely throughout the human genome and that a high proportion of these encompass known genes. 3,4 These studies were groundbreaking because they challenged the previously held view that the complete DNA sequences of any 2 individuals are 99.9% identical, the 0.1% difference being largely attributed to SNPs. Subsequently, several studies on CNVs followed, 5-7 culminating in a large international study of the Hapmap population by Redon et al 101 that identified more than 1400 CNVs spanning approximately 12% of the human genome. Even with this comprehensive evaluation, it is likely that this present index of CNVs is far from complete and new variants are continually being discovered. 8 In 2006, 3 studies specifically characterized deletion variants in the human genome. 9-11 Combined, these investigations described ap...

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Genetic variation in bactericidal/permeability-increasing protein influences the risk of developing rapid airflow decline after hematopoietic cell transplantation

Cited by 37 publications

References 81 publications

Lipopolysaccharide binding protein promoter variants influence the risk for Gram-negative bacteremia and mortality after allogeneic hematopoietic cell transplantation

Lipopolysaccharide binding protein promoter variants influence the risk for Gram-negative bacteremia and mortality after allogeneic hematopoietic cell transplantation

Small airways diseases, excluding asthma and COPD: an overview

Beyond HLA: the significance of genomic variation for allogeneic hematopoietic stem cell transplantation

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