Genetic polymorphisms in the endotoxin receptor may influence platelet count as part of the acute phase response in critically ill children.
OBJECTIVE
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.
Paediatric Intensive Care Unit and Cardiac Critical Care Unit, Great Ormond Street Hospital, London, UK. r.agbeko@ich.ucl.ac.uk
Rachel S
RS
Agbeko
John W
JW
Holloway
Meredith L
ML
Allen
Shu
S
Ye
Katy J
KJ
Fidler
John
J
Pappachan
Allan
A
Goldman
David
D
Pontefract
John
J
Deanfield
Nigel J
NJ
Klein
Mark J
MJ
Peters
D000208:Acute Disease; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016638:Critical Illness; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010976:Platelet Count; D011110:Polymorphism, Genetic / Q000502:physiology*; D011446:Prospective Studies; D011971:Receptors, Immunologic / Q000235:genetics*; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D051197:Toll-Like Receptor 4 / Q000235:genetics
D011971:Receptors, Immunologic; D051197:Toll-Like Receptor 4; C048071:endotoxin receptor