Variants in the Mannose-binding Lectin Gene MBL2 do not Associate With Sepsis Susceptibility or Survival in a Large European Cohort

Clinical Infectious Diseases, Aug 2015

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: 28-day 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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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. - 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)


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Tara C. Mills, Stephen Chapman, Paula Hutton, Anthony C. Gordon, Julian Bion, Jean-Daniel Chiche, Paul A. H. Holloway, Frank Stüber, Chris S. Garrard, Charles J. Hinds, Adrian V. S. Hill, Anna Rautanen. Variants in the Mannose-binding Lectin Gene MBL2 do not Associate With Sepsis Susceptibility or Survival in a Large European Cohort, Clinical Infectious Diseases, 2015, pp. 695-703, 61/5, DOI: 10.1093/cid/civ378