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Genetic polymorphisms in the endotoxin receptor may influence platelet count as part of the acute phase response in critically ill children

Genetic polymorphisms in the endotoxin receptor may influence platelet count as part of the acute phase response in critically ill children
Genetic polymorphisms in the endotoxin receptor may influence platelet count as part of the acute phase response in critically ill children
Purpose
To determine if common polymorphisms in the endotoxin recognition complex influence the acute phase response as determined by the development of the systemic inflammatory response syndrome (SIRS) and platelet count on admission.
Methods
This was a prospective observational cohort study. Paediatric intensive care patients (n = 913) were genotyped for common functional polymorphisms in the endotoxin recognition complex, including Toll-like receptor 4 (TLR4). We also selected potentially confounding polymorphisms in other genes of the innate immune system. SIRS was defined by age-specific consensus criteria. Platelet counts were recorded on admission.
Results
The development of SIRS was primarily determined by the nature of the insult, but carriers of TLR4 variant alleles had lower platelet counts than children with wild-type genotype [mean ± standard error of the mean (SEM) 143 ± 7 vs. 175 ± 4; p = 0.0001)—independent of other innate immune system polymorphisms. These findings were validated using a patient cohort of 1,170 adults with coronary artery disease. Carriers of TLR4 polymorphisms with a history of myocardial infarction (n = 573) had lower platelet counts than those with the wild-type genotype (217 ± 7 vs. 237 ± 2.8; p = 0.021).
Conclusions
Our results show that TLR4 variant alleles are associated with lower platelet counts across a range of ages and precipitating insults but that they do not influence the incidence of SIRS. This result may reflect redundancy and ‘robustness’ in the pathways leading to SIRS or the lack of specificity of this endpoint. Platelet count may vary with TLR4 genotype because it may be sufficiently sensitive and more linearly related to inflammation than other markers or, alternatively, there may be a direct TLR4-mediated platelet effect.
Electronic supplementary material The online version of this article (doi:10.1007/s00134-010-1857-x) contains supplementary material, which is available to authorized users
critical illness, sepsis SIRS, thrombocytopenia, toll-like receptor 4, child
0342-4642
1023-1032
Agbeko, Rachel S.
9b57d2d3-53c4-4760-bbda-5a0a71b9b190
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Allen, Meredith L.
d4e06cb3-4b05-4eed-a252-814a53b36771
Ye, Shu
132b6474-1927-4f93-80db-2c620a31c1ab
Fidler, Katy J.
98a2bdf5-500d-44f0-a442-85143e2d6c53
Pappachan, John
f6e7747a-dbf7-432d-99c1-1136d0581a71
Goldman, Allan
c1c65fa0-c4d0-4de6-a637-459ab0ecdc55
Pontefract, David
d5da4ee5-b312-4e8c-9b1d-4142e320b2b8
Deanfield, John
3ffa04cf-a239-4dd7-8d77-dfc9cfe716fd
Klein, Nigel J.
f01b50e5-cb25-4558-99aa-b697d534fb55
Peters, Mark J.
a1db2568-cc2a-4672-8765-6340ee2d4972
Agbeko, Rachel S.
9b57d2d3-53c4-4760-bbda-5a0a71b9b190
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Allen, Meredith L.
d4e06cb3-4b05-4eed-a252-814a53b36771
Ye, Shu
132b6474-1927-4f93-80db-2c620a31c1ab
Fidler, Katy J.
98a2bdf5-500d-44f0-a442-85143e2d6c53
Pappachan, John
f6e7747a-dbf7-432d-99c1-1136d0581a71
Goldman, Allan
c1c65fa0-c4d0-4de6-a637-459ab0ecdc55
Pontefract, David
d5da4ee5-b312-4e8c-9b1d-4142e320b2b8
Deanfield, John
3ffa04cf-a239-4dd7-8d77-dfc9cfe716fd
Klein, Nigel J.
f01b50e5-cb25-4558-99aa-b697d534fb55
Peters, Mark J.
a1db2568-cc2a-4672-8765-6340ee2d4972

Agbeko, Rachel S., Holloway, John W., Allen, Meredith L., Ye, Shu, Fidler, Katy J., Pappachan, John, Goldman, Allan, Pontefract, David, Deanfield, John, Klein, Nigel J. and Peters, Mark J. (2010) Genetic polymorphisms in the endotoxin receptor may influence platelet count as part of the acute phase response in critically ill children. Intensive Care Medicine, 36 (6), 1023-1032. (doi:10.1007/s00134-010-1857-x).

Record type: Article

Abstract

Purpose
To determine if common polymorphisms in the endotoxin recognition complex influence the acute phase response as determined by the development of the systemic inflammatory response syndrome (SIRS) and platelet count on admission.
Methods
This was a prospective observational cohort study. Paediatric intensive care patients (n = 913) were genotyped for common functional polymorphisms in the endotoxin recognition complex, including Toll-like receptor 4 (TLR4). We also selected potentially confounding polymorphisms in other genes of the innate immune system. SIRS was defined by age-specific consensus criteria. Platelet counts were recorded on admission.
Results
The development of SIRS was primarily determined by the nature of the insult, but carriers of TLR4 variant alleles had lower platelet counts than children with wild-type genotype [mean ± standard error of the mean (SEM) 143 ± 7 vs. 175 ± 4; p = 0.0001)—independent of other innate immune system polymorphisms. These findings were validated using a patient cohort of 1,170 adults with coronary artery disease. Carriers of TLR4 polymorphisms with a history of myocardial infarction (n = 573) had lower platelet counts than those with the wild-type genotype (217 ± 7 vs. 237 ± 2.8; p = 0.021).
Conclusions
Our results show that TLR4 variant alleles are associated with lower platelet counts across a range of ages and precipitating insults but that they do not influence the incidence of SIRS. This result may reflect redundancy and ‘robustness’ in the pathways leading to SIRS or the lack of specificity of this endpoint. Platelet count may vary with TLR4 genotype because it may be sufficiently sensitive and more linearly related to inflammation than other markers or, alternatively, there may be a direct TLR4-mediated platelet effect.
Electronic supplementary material The online version of this article (doi:10.1007/s00134-010-1857-x) contains supplementary material, which is available to authorized users

Full text not available from this repository.

More information

Published date: 18 March 2010
Keywords: critical illness, sepsis SIRS, thrombocytopenia, toll-like receptor 4, child

Identifiers

Local EPrints ID: 143583
URI: https://eprints.soton.ac.uk/id/eprint/143583
ISSN: 0342-4642
PURE UUID: 8201c574-553b-41e8-afc4-0759cadf889f
ORCID for John W. Holloway: ORCID iD orcid.org/0000-0001-9998-0464

Catalogue record

Date deposited: 12 Apr 2010 12:12
Last modified: 06 Jun 2018 12:59

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