Risk of infection and sepsis in severely injured patients related to single nucleotide polymorphisms in the lectin pathway

Bronkhorst, M.W.G.A.; Lomax, M.A.Z.; Vossen, Rolf H. A. M.; Bakker, Jan; Lieshout, Esther M.M. Van

doi:10.1002/bjs.9319

Cited by 22 publications

(14 citation statements)

References 35 publications

(54 reference statements)

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“…The other variants that occur within this haplotype encode the common protein residues ( p.377*V and p.439*R ) and are synonymous ( g.24762*C ) or noncoding ( g.7164*A , g.7441*G and g.21081*T ). All three noncoding variants were formerly associated with opposite regulation of MASP‐2 and MAp19 levels (Boldt, Goeldner, Stahlke, Thiel et al., ; Bronkhorst et al., ) and were eQTLs for MASP2 gene expression. The synonymous variant (GTEx Project) SNP g.7164G>A in intron 4 was also identified as an eQTL modulating the expression of a MASP2 neighbour gene, TARDBP , in a lymphoblastoid cell line (Montgomery et al., ).…”

Section: Discussionmentioning

confidence: 99%

Effects of MASP2 haplotypes and MASP‐2 levels in hepatitis C‐infected patients

Silva

Catarino

Boldt

et al. 2018

Int J Immunogenetics

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Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) are components of the lectin pathway, which activate the complement system after binding to the HCV structural proteins E1 and E2. We haplotyped 11 MASP2 polymorphisms in 103 HCV patients and 205 controls and measured MASP-2 levels in 67 HCV patients and 77 controls to better understand the role of MASP-2 in hepatitis C susceptibility and disease severity according to viral genotype and fibrosis levels. The haplotype block MASP2*ARDP was associated with protection against HCV infection (OR = 0.49, p = .044) and lower MASP-2 levels in controls (p = .021), while haplotype block AGTDVRC was significantly increased in patients (OR = 7.58, p = .003). MASP-2 levels were lower in patients than in controls (p < .001) and in patients with viral genotype 1 or 4 (poor responders to treatment) than genotype 3 (p = .022) and correlated inversely with the levels of alkaline phosphatase, especially in individuals with fibrosis 3 or 4 (R = -.7, p = .005). MASP2 gene polymorphisms modulate basal gene expression, which may influence the quality of complement response against HCV. MASP-2 levels decrease during chronic disease, independently of MASP2 genotypes, most probably due to consumption and attenuation mechanisms of viral origin and by the reduced liver function, the site of MASP-2 production.

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Section: Discussionmentioning

confidence: 99%

Effects of MASP2 haplotypes and MASP‐2 levels in hepatitis C‐infected patients

Silva

Catarino

Boldt

et al. 2018

Int J Immunogenetics

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“…The blood biomarkers reported could be further developed and integrated with other diagnostic tools, such as genomic single nucleotide polymorphisms (SNPs) that predispose certain patients to infection, 51,52 and produce a more comprehensive prognosis of patient susceptibility. Physician decisions rely heavily on blood tests over the course of recovery, and a positive culture is still the most accepted and reliable method for diagnosing infection.…”

Section: Discussionmentioning

confidence: 99%

Prediction of Multiple Infections After Severe Burn Trauma

et al. 2015

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Objective To develop predictive models for early triage of burn patients based on hyper-susceptibility to repeated infections. Background Infection remains a major cause of mortality and morbidity after severe trauma, demanding new strategies to combat infections. Models for infection prediction are lacking. Methods Secondary analysis of 459 burn patients (≥16 years old) with ≥20% total body surface area burns recruited from six US burn centers. We compared blood transcriptomes with a 180-h cut-off on the injury-to-transcriptome interval of 47 patients (≤1 infection episode) to those of 66 hyper-susceptible patients (multiple [≥2] infection episodes [MIE]). We used LASSO regression to select biomarkers and multivariate logistic regression to built models, accuracy of which were assessed by area under receiver operating characteristic curve (AUROC) and cross-validation. Results Three predictive models were developed covariates of: (1) clinical characteristics; (2) expression profiles of 14 genomic probes; (3) combining (1) and (2). The genomic and clinical models were highly predictive of MIE status (AUROCGenomic = 0.946 [95% CI, 0.906–0.986]); AUROCClinical = 0.864 [CI, 0.794–0.933]; AUROCGenomic/AUROCClinical P = 0.044). Combined model has an increased AUROCCombined of 0.967 (CI, 0.940–0.993) compared to the individual models (AUROCCombined/AUROCClinical P = 0.0069). Hyper-susceptible patients show early alterations in immune-related signaling pathways, epigenetic modulation and chromatin remodeling. Conclusions Early triage of burn patients more susceptible to infections can be made using clinical characteristics and/or genomic signatures. Genomic signature suggests new insights into the pathophysiology of hyper-susceptibility to infection may lead to novel potential therapeutic or prophylactic targets.

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“…Most polymorphisms involved in multifactorial disorders are likely to confer only small risks (de Faria et al, 2014;Wang et al, 2014;Zakharyan et al, 2014). Clinically relevant effects are therefore only seen if variants in several or even many genes work together (Wong et al, 2012;Bronkhorst et al, 2013). So far it is not possible to decide if the polymorphic glucocorticoid receptor uORF described in the present study belongs to this group of susceptibility factors.…”

Section: Discussionmentioning

confidence: 49%