Variants in the Mannose-binding Lectin Gene MBL2 do not Associate With Sepsis Susceptibility or Survival in a Large European Cohort
CID
Variants in the Mannose-binding Lectin Gene MBL2 do not Associate With Sepsis Susceptibility or Survival in a Large European Cohort
Tara C. Mills 2
Stephen Chapman 2
Paula Hutton 1
Anthony C. Gordon 0
Julian Bion 6
Jean-Daniel Chiche 5
Paul A. H. Holloway 0
Frank Stüber 4
Chris S. Garrard 1
Charles J. Hinds 3
Adrian V. S. Hill 2
Anna Rautanen 2
for the ESICM/ECCRN GenOSept Investigators
0 Section of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London
1 John Radcliffe Hospital , Oxford
2 Wellcome Trust Centre for Human Genetics, University of Oxford
3 Barts and The London School of Medicine Queen Mary University of London , United Kingdom
4 Department of Anaesthesiology and Pain Medicine, Bern University Hospital and University of Bern , Switzerland
5 Hospital Cochin , Paris , France
6 School of Clinical and Experimental Medicine, University of Birmingham , United Kingdom
Background. Sepsis is an increasingly common condition, which continues to be associated with unacceptably high mortality. A large number of association studies have investigated susceptibility to, or mortality from, sepsis for variants in the functionally important immune-related gene MBL2. These studies have largely been underpowered and contradictory. Methods. We genotyped and analyzed 4 important MBL2 single nucleotide polymorphisms (SNPs; rs5030737, rs1800450, rs1800451, and rs7096206) in 1839 European community-acquired pneumonia (CAP) and peritonitis sepsis cases, and 477 controls from the United Kingdom. We analyzed the following predefined subgroups and outcomes: 28day and 6 month mortality from sepsis due to CAP or peritonitis combined, 28-day mortality from CAP sepsis, peritonitis sepsis, pneumococcal sepsis or sepsis in younger patients, and susceptibility to CAP sepsis or pneumococcal sepsis in the United Kingdom. Results. There were no significant associations (all P-values were greater than .05 after correction for multiple testing) between MBL2 genotypes and any of our predefined analyses. Conclusions. In this large, well-defined cohort of immune competent adult patients, no associations between MBL2 genotype and sepsis susceptibility or outcome were identified.
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The incidence of sepsis is increasing and mortality rates
remain high [1]. Sepsis was recently reported to be
responsible for 1 in 20 deaths in England [2]. The
frequency of hospitalizations with severe sepsis has
increased relentlessly, more than doubling each year
between 2000 and 2007, with sepsis complicated by
organ failure accounting for one in 40 hospitalizations
in 2007 [3]. It has long been apparent that host genetic
factors can significantly influence mortality from
infectious disease [4], but despite extensive research very few
robust associations between genetic polymorphisms and
sepsis phenotypes have been reported to date [5]. Possible
explanations for these inconsistent findings include
inadequate sample sizes (and hence a lack of study power),
unidentified population substructure, failure to correct
for multiple testing, variations in phenotype definition,
heterogeneous patient populations and unrecognized
host-pathogen interactions. Nevertheless, we recently
published a genome-wide association study (GWAS) in
which we identified a common single nucleotide
polymorphism (SNP) in the FER gene that protects against death
from sepsis caused by severe pneumonia [6].
MBL2 is one of the most extensively studied but still
controversial candidate genes reported to be associated with sepsis and
infectious disease phenotypes [7, 8]. More than 30 studies have
reported the presence or absence of associations between
polymorphisms in the MBL2 gene, circulating MBL levels, and
susceptibility and outcomes in sepsis phenotypes, with sample
sizes ranging from 6 to 848 patients [8–10].
The MBL2 gene encodes mannose-binding lectin, which
binds carbohydrates on the surface of a wide variety of bacteria,
viruses, yeasts, fungi, and protozoa and subsequently triggers
host innate immune responses through activation of the
complement system, in addition to promoting opsono-phagocytosis
by a complement-independent pathway [11]. The function of
MBL is known to be influenced by common SNPs found both
in the promoter region and in exon 1 of this gene, which affect
the level of gene expression and the structure of the MBL protein
respectively [12–18].
Three functional SNPs (denoted B-rs1800450, C-rs1800451,
and D-rs5030737) in exon 1 of MBL2 affect the stability, ligand
binding capacity, complement activating ability and half-life
of the encoded protein [12–15]. Because their effect on serum
MBL levels is very similar, wild-type alleles for these SNPs are
denoted A, whereas the B, C, and D variants are pooled and
given the designation O (Supplementary Figure 1). If an
individual is heterozygous (A/O) for any one of these 3 variants,
MBL levels are 10%–20% that of wild-type individuals, whereas
in variant homozygotes or compound heterozygotes (O/O), (...truncated)