Journal Logo

Predisposition to Sepsis

Genetic polymorphisms in sepsis

Dahmer, Mary K. PhD; Randolph, Adrienne MD, MSc; Vitali, Sally MD; Quasney, Michael W. MD, PhD

Author Information
Pediatric Critical Care Medicine: May 2005 - Volume 6 - Issue 3 - p S61-S73
doi: 10.1097/01.PCC.0000161970.44470.C7
  • Free

Abstract

The medical field has long realized that not all individuals with a specific disease present with the same clinical manifestations, nor do they have identical prognoses or response to treatment. With the sequencing of the human genome and the recognition of the degree of genetic variation that exists in the human population, it has become clear that an individual's genetic makeup is likely to have an impact on clinical presentation, as well as, treatment and outcome. Indeed, recent evidence indicates that genetic makeup influences an individual's presentation of disease. In addition, not only is there genetic variability in the body's response to disease, but also genetic variability in drug uptake, binding, and metabolism, which will affect drug efficacy and treatment. Clearly, medicine is evolving toward individualized treatment based on a patient's genetic makeup.

The response to infection is variable between different individuals. Given the same therapies, most patients will recover and do well, while a small, but significant, portion will develop severe sepsis and may develop multiple organ system failure, refractory hypotension, and die. This variability has been attributed to a number of factors including the virulence or load of the etiological agent or the length of time between onset of symptoms and initiation of treatment. However, evidence is beginning to support the hypothesis that the genetic makeup of the host plays an important role in the susceptibility to and the development of sepsis, as well as its severity and outcome. In other words, a genetic predisposition to the development of sepsis and to poorer outcome from sepsis may exist. This hypothesis is supported by the data of Sorensen et al. (1), which demonstrate a strong genetic influence on death due to infection. In this article, we will review the evidence that genetic variability in specific genes plays a role in the development of sepsis and its outcome. An understanding of the host factors that contribute to the development and treatment of sepsis is important as sepsis has a major impact on the morbidity and mortality in neonatal, pediatric, and adult intensive care units.

Sequencing of the human genome has demonstrated that many genes are polymorphic, including a number of genes that have been implicated in the development of sepsis. A polymorphic gene is one in which a comparison of the DNA sequence of the gene in multiple individuals shows differences at a frequency of >1%. The sites within the genes that are different are called polymorphic sites and may differ by insertions, deletions, or substitutions of one or more base pairs or by the presence of a variable number of repeats of short, repetitive DNA sequences. There may be one or more polymorphic sites within a gene, and the sites may exist in coding regions of the gene or in noncoding regions that may be involved in the regulation of gene expression. Some of these variations have been shown to influence the level and/or activity of the resulting protein, thereby affecting cell function.

The genes most likely to play a role in the variability in susceptibility to, and outcome from, sepsis are polymorphic genes that encode for protein products involved in the pathogenesis of sepsis. Sepsis is an acute systemic response caused by a variety of noxious stimuli, but most frequently by bacterial toxins, and is manifested clinically by the syndrome of fever or hypothermia, tachycardia, tachypnea, and multiple organ system dysfunction (2). The body's response to bacterial infection requires first, recognition of the presence of pathogen-associated bacterial products via a number of receptors and accessory proteins, and second, the activation of the cellular components of signal transduction pathways that result in the body's response. Response to bacterial infection involves the systemic production of inflammatory cytokines counterbalanced by the production of antiinflammatory cytokines. Severe sepsis is perpetuated by the exaggerated systemic production of inflammatory cytokines not adequately counterbalanced by the production of antiinflammatory cytokines (3, 4). The central event in the pathophysiological cascade of sepsis is the release of proinflammatory cytokines in response to a stimulus, such as a bacterial infection. Normally, these cytokines activate a variety of cellular and humoral systems that are responsible, at least in part, for eliminating the inciting stimulus. However, an overly exuberant inflammatory response leading to excessive production of these mediators resulting in an imbalance between proinflammatory and antiinflammatory cytokines is thought to lead to the clinical symptoms of severe sepsis with multiple organ failure (5, 6).

A number of the components involved with the body's response to bacterial infection and sepsis are encoded by polymorphic genes, including proteins involved with the initial recognition of bacterial products such as Toll-like receptor 4 (TLR4), Fcγ receptors, mannose-binding lectin, and proteins involved with intracellular response to bacterial products such as tumor necrosis factor (TNF)-α, interleukins (ILs), and heat shock proteins (HSPs). Association studies have indicated that polymorphisms in some of these genes are associated with sepsis. The data examining the role of variability in these genes with predisposition to and outcome from sepsis are discussed below.

Recognition

The body's response to bacterial infection requires first, recognition of the presence of pathogen-associated bacterial products via receptors. A number of polymorphic genes responsible for this initial recognition step have been implicated in the variability seen in response to infection. Lipopolysaccharide (LPS), one of the major components of the cell wall of Gram-negative bacteria, is a powerful stimulator of the innate immune response. LPS elicits its response by binding to a cell surface receptor that is composed of at least three proteins: CD14, TLR4, and MD-2 (7–11). CD14 and TLR4 have been reported to have polymorphic sites associated with altered functioning of the LPS receptor complex (Table 1).

Table 1
Table 1:
Genetic polymorphisms involved in the recognition of bacterial pathogens in sepsis

TLR4

That the variability in response to LPS might be due to variability in the gene for TLR4 is suggested by studies in mice, which demonstrate that TLR4 is required for response to LPS (12) and that a single amino acid change can significantly reduce response to LPS (7, 13) and enhance susceptibility to infection. A number of single nucleotide polymorphisms (SNPs) have been identified in the promoter and coding regions of the TLR4 gene (14, 15). The SNP identified in the fourth exon of the TLR4 gene results in the replacement of a conserved aspartic acid at amino acid residue 299 with glycine. This SNP is in linkage disequilibrium with a second SNP at amino acid 399, which changes a threonine to an isoleucine. The Gly299Ile399 variant appears to be expressed at lower levels in human airway epithelia (14), and a number of studies have demonstrated an association of this variant with a reduced response to LPS as determined by examining airway reactivity or systemic cytokine response to inhaled LPS (14–16). In vitro studies using primary human epithelial cells heterozygous for the variant or studies using a transfected cell system in which the variant TLR4 is expressed also suggest this variant is associated with a decreased response to LPS (14). However, studies using whole blood or isolated blood leukocytes show no altered response to LPS in cells from individuals who are heterozygous for the variant (17–20). It is still unclear whether the in vivo response to LPS by blood leukocytes expressing one copy of the variant TLR4 varies from that seen with wild-type TLR4.

The decreased responsiveness of the variant TLR4 and its frequency in the general population suggested that the variant might be associated with Gram-negative bacterial infection and/or sepsis. Studies have shown an association of the variant with Gram-negative bacterial infections and septic shock (21, 22) and mortality in systemic inflammatory response syndrome (23). However, the variant showed no association with susceptibility to, or severity of, meningococcal disease (24), although rare TLR4 mutations have been implicated in meningococcal susceptibility (25). The lack of any association of the variant with meningococcal disease is complicated by findings demonstrating that Neisseria meningitidis is capable of eliciting an inflammatory response via TLR2 in the absence of LPS (26, 27). Clearly, additional carefully controlled studies with increased numbers of patients will be required to determine whether the TLR4 variant is associated with Gram-negative infection, sepsis, or severity of sepsis.

CD14

As mention above, CD14 is also a component of the LPS receptor complex, and LPS fails to elicit a response in CD14–null mice (28). A polymorphic site with a C to T change has been identified 159 nucleotides upstream of the transcription start site (260 base pairs upstream of the start of translation) (29–31). This polymorphic site is in the promoter region of the CD14 gene, and the T allele shows increased transcriptional activity when assayed in reporter assays (32). As would be predicted, individuals homozygous for the −159T allele have increased levels of CD14 (30, 31, 33). A number of studies have been performed to examine whether the −159 polymorphic site is associated with infection or sepsis, with conflicting results (34–36). The disparity in results may be due to a lack of any association of CD14 with sepsis or may be due to inherent differences between the studies, such as the number of patients analyzed, origin of the infection (surgery, trauma, pneumonia), or heterogeneity of the patient populations. Clearly, additional carefully controlled studies with increased numbers of patients will be required to determine whether the variant is associated with Gram-negative infection, sepsis, or severity of sepsis.

Fcγ Receptors

Leukocyte Fcγ receptors bind to the constant region of immunoglobulin G (IgG) and trigger a number of effects involved with host defense, including phagocytosis of IgG-coated bacteria and induction of an inflammatory response (37, 38). The human Fcγ receptors are grouped into three classes. The FcγRI class consists of the FcγRIa receptor, the FcγRII class consists of FcγRIIa, FcγRIIb, and FcγRIIc, and the FcγRIII class consists of FcγRIIIa and FcγRIIIb. The affinity of these receptors for the various subclasses of IgG differs, as does their cellular distribution.

Specific genetic polymorphisms (Table 1) affecting function have been described in three of the Fcγ receptors (38). The FcγRIIIa has a polymorphism at amino acid 158, resulting in either a valine (V) or phenylalanine (F) at this position, which in turn affects its affinity for IgG1, IgG3, and IgG4 (39, 40). The FcγRIIIb has a polymorphism in its extracellular domain that is a 4-amino acid substitution (allotypes FcγRIIIb-Na1 or –Na2), resulting in differences in glycosylation (41) and changes in the efficiency with which phagocytosis of IgG1- and IgG3-opsonized particles occurs (42, 43). Individuals homozygous for the FcγRIIIb-Na1 allotype appear to have more efficient phagocytosis. The FcγRIIa gene has a polymorphic site at amino acid position 131 (44, 45). The FcγRIIa-R131 allotype has an arginine rather than a histidine at amino acid position 131. This amino acid is in the extracellular domain of the receptor, and the FcγRIIa-R131 allotype binds the Fc portion of IgG2 with lower affinity than the more common FcγRIIa-H131 allotype (45). As the FcγRIIa receptor is the only FcγR able to bind efficiently to the IgG2 subclass, it appears that the FcγRIIa genotype determines an individual's ability to bind IgG2. In vitro studies demonstrated reduced phagocytosis of IgG2-opsonized particles in cells from individuals homozygous for FcγRIIa-R131 compared with cells from individuals homozygous for FcγRIIa-H131 (46, 47). IgG2 is the main antibody subtype directed against encapsulated bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitides, and plays an important role in their phagocytosis (45, 48, 49).

Numerous studies have examined the association between the presence of the FcγRIIa-R131 and/or the FcγRIIIb-Na2 polymorphisms in individuals and an increased susceptibility to infections, particularly meningococcal disease. In most studies, higher frequencies of the FcγRIIa-R131/R131 or FcγRIIIb-Na2/Na2 genotypes have been found in patients with meningococcal disease (50–55). For example, a higher frequency of the FcγRIIa-R131/R131 genotype was observed in patients with severe meningococcal disease (52, 53) or fulminant meningococcal septic shock (51,54) compared with healthy controls. An association between the FcγRIIa polymorphism and infection with other encapsulated bacteria has also been reported (56, 57). Although the vast majority of reports have shown an association between infection and/or sepsis and the FcγRIIa and FcγRIIIb polymorphisms, there are two reports in which no association was seen (58, 59). It is not clear why the outcome from these studies differs from the ones previously described.

Mannose-Binding Lectin

Another molecule involved with opsonization is mannose-binding lectin (MBL) (60). It has two primary immunodefensive roles; first, it is involved with the opsonization of bacteria due to its ability to bind bacterial surface oligosaccharides N-acetyl glucosamine and mannose (61); second, the binding of MBL-associated serine proteases leads to activation of complement, independent of antibody (62). Deficiencies in MBL have been associated with increased susceptibility to infections (63). The heterotrimeric MBL protein contains a carbohydrate binding domain and a helical tail domain that is important in polymerization of the three peptides (64). Three genetic polymorphisms have been described in MBL in amino acids 52, 54, and 57 (referred to as variants D, C, and B, respectively). These polymorphic sites result in amino acid changes that diminish the ability of the helical tails to polymerize, resulting in an increased degradation of MBL (60, 65, 66) and reduced serum levels of MBL (65). A polymorphism at nucleotide −221 in the promoter has also been reported (67).

Studies have demonstrated associations between genetic polymorphisms in the MBL gene and hospitalizations due to infections in children (68), number of acute respiratory infections in children (69), increased risk for meningococcal infections (70), susceptibility to infections in patients with systemic lupus erythematosus (71), and increased risk for recurrent respiratory infections (72). Recently, an association has been demonstrated between the presence of invasive pneumococcal disease and any one of the three variants (B, C, D), but not the promoter polymorphism (73), although this observation was not demonstrated in a similar study (74). The frequency of each of the three variants (DD, BB, CC) or heterozygosity for the variants (BC, BD, CD) was significantly higher in patients than in a healthy control population (0.12 vs. 0.05; p < .002), suggesting an increased susceptibility to invasive pneumococcal disease in individuals with at least one copy of the variant polymorphism. There was no association with the presence of the −221 promoter polymorphism and invasive pneumococcal disease. No studies have been reported that directly eXamine the association between MBL polymorphisms and sepsis or severity of disease.

Response

Within minutes of a pathogenic stimulus, proinflammatory cytokines, notably TNF-α, IL-1, and IL-6, are elevated, followed by chemokines and subsequent recruitment of polymorphonuclear cells. This is followed by release of antiinflammatory cytokines such as IL-10 and a return to baseline of cytokine, chemokine, and leukocyte levels and the start of tissue repair (75, 76). This response includes multiple cytokines, chemokines, and coagulation factors. Genetic variability within the genes coding for these components of the response could potentially influence the overall susceptibility to and outcome from sepsis (Table 2).

Table 2
Table 2:
Genetic polymorphisms involved in the response to bacterial pathogens in sepsis

Tumor Necrosis Factor-α

TNF-α and the genetic polymorphisms within the regulatory regions of the gene coding for TNF-α are perhaps the most extensively studied of all cytokines induced in sepsis. As a proinflammatory cytokine, TNF-α plays a key role in the pathogenesis of the acute inflammatory response and is responsible for the initial activation of the inflammatory response. TNF-α also appears responsible for the development of the harmful effects of the systemic inflammatory response, such as capillary leak, hypotension, acute respiratory distress syndrome (ARDS), and multiple organ system failure (77–81). It is now generally accepted that an overexaggerated proinflammatory response resulting in an imbalance between the proinflammatory cytokines such as TNF-α and the antiinflammatory cytokines results in the clinical manifestation of sepsis and septic shock. The mechanism by which this exaggerated response develops is an area of intense research.

Several single nucleotide polymorphisms within the regulatory region of the gene coding for TNF-α have been identified that are associated with both spontaneous and stimulated TNF-α production either in vitro and/or in vivo (82–89). These include a G to A transition 308 base pairs upstream from the transcriptional start site for the TNF-α gene. The TNF-α-308 G/A polymorphism has been extensively studied. In vitro studies have demonstrated that the rarer TNF-α-308 A allele is associated with increased gene transcription as compared with the wild-type TNF-α-308 G allele (87). Furthermore, the TNF-α-308 A allele is associated with increased secretion of TNF-α from macrophages after LPS stimulation in vitro (85). These polymorphisms lie near putative DNA binding sites for several transcription factors. Indeed, electrophoretic mobility shift assays have demonstrated differential binding of nuclear proteins to DNA fragments containing either an A or a G at the TNF-α-308 position (90). Another polymorphism associated with altered levels of TNF-α is approximately 250 base pairs downstream from the transcriptional start site for the gene coding for lymphotoxin (LT)-α, also known as TNF-β. This site (also referred to as the TNFB allele, LT-α+250, or TNF-β+252 site; for this article, LT-α+250 site will be used) is approximately 3.2 kilobases upstream from the TNF-α gene and may be acting as an enhancer region, although the mechanisms by which this polymorphism results in higher TNF-α levels are unknown. An A at this position is associated with higher TNF-α production in vitro, as well as in adults with sepsis and children with bacteremia (82, 83, 89). Thus, there is convincing evidence that genetic variation within regulatory regions of the gene coding for TNF-α influences the amount of TNF-α produced.

A strong association has also been made between the TNF-α polymorphisms described above and clinical presentation and/or outcome in a variety of infectious diseases. These include Kawasaki's disease in children (91), cerebral malaria (92), human immunodeficiency virus dementia in adults (93), children with meningococcal infections (94) and bacteremia (89), septic shock in adults (82, 84, 95, 96), and community-acquired pneumonia in adults (97). For example, among adults with septic shock, the frequency of the less common A allele at the TNF-α-308 position was higher in those who died, and the risk of death was 3.7-fold greater in those patients with at least one copy of the TNF-α-308 A allele, even after controlling for age and severity of illness (95). A higher frequency of the TNF-α-308 A allele was found in those children with meningococcal disease who died compared with those children who survived (94). Even those children who were heterozygous at this position (TNF-α-308 GA) were at an increased risk for more fulminant meningococcal disease and death compared with those children who were homozygous for the wild-type genotype (TNF-α-308 GG). In a cohort of adults with community-acquired pneumonia, those with the LT-α+250 AA genotype were at greater risk for presenting with the clinical symptoms of sepsis (97). In postoperative and trauma intensive care patients, individuals who developed sepsis who were homozygous for an A at the LT-α+250 site had higher levels of TNF-α and a higher mortality (82, 98, 99). Likewise, in a small cohort of bacteremic children, our group demonstrated an association between an A at the LT-α+250 position, higher serum levels of TNF-α, and higher mortality (89). Children who were heterozygous at this position (LT-α+250 GA) had an intermediate mortality.

Not all studies have demonstrated an association between TNF-α and the above described polymorphisms. No difference in the frequency of the TNF-α-308 alleles was observed between healthy controls and an ethnically similar cohort of adults with severe sepsis or between survivors and nonsurvivors in the severe sepsis group (98). The various genotypes also had similar serum levels of TNF-α. No increased risk of septic shock or mortality was observed in a cohort of consecutively admitted postoperative surgical adults (100). In this latter study, however, those individuals with septic shock who had at least one copy of the A allele at the −308 position had higher serum TNF-α levels and a greater mortality than those patients with septic shock who did not have a copy of the A allele. A study examining the LT-α+250 site demonstrated no association between the genotypes at this site and survival in women with severe sepsis (101). Finally, a pilot study of high-risk term and premature infants with sepsis and culture-proven bacteremia did not demonstrate a risk of worse outcome (102). Although most evidence appears to support an association between certain genotypes in the regulatory region of the gene coding for TNF-α, levels of TNF-α production, and mortality in patients with sepsis, there are studies in which such an association is not observed.

Interleukin-1 and Interleukin-1 Receptor Antagonist (IL-1/IL-1RA)

IL-1α and IL-1β are also key proinflammatory cytokines secreted early in the response to a bacterial challenge and play an important role in the pathogenesis of sepsis and septic shock. These molecules stimulate the production of prostaglandins and nitric oxide, two mediators of the vasodilation observed in sepsis (103). In contrast, IL-1RA is an inhibitor that acts via competing with IL-1 for binding to its receptor (104, 105). Serum levels of IL-1 and IL-1RA are elevated in patients with meningococcal disease and appear to be higher in those with more severe disease (106).

The genes coding for IL-1α, IL-1β, and IL-1RA are clustered together on chromosome 2, and several polymorphisms have been described in this locus. Three types of polymorphisms have been described in the gene coding for IL-1α. One consists of a variable number of a 46-base pair repeats in intron 6, although its functional significance has not been determined (107). Another type is represented by a single nucleotide polymorphism (C to T transition) at position −889. This polymorphism appears to increase transcriptional activity of the IL-1α gene (108) and increase levels of IL-1α protein (109). Finally, several polymorphisms have been described in the 3′-untranslated region some of which have been shown to be associated with higher IL-1α levels in response to LPS in an in vitro system (110). Polymorphisms have also been described in the IL-1β gene located in promoter region (−511) and within the coding region (+3953), with this latter polymorphism associated with higher levels of LPS-stimulated IL-1β in vitro (111, 112). Polymorphisms have been identified in intron 2 of the IL-1RA gene consisting of a variable number of an 86-base pair sequence (113), as well as a single nucleotide polymorphism within exon 2 at nucleotide position +2018 (114). Most healthy individuals have either four copies (54%) (referred to as the A4 allele) or two copies (34%) (referred to as the A2 allele) of the 86-base pair repeat, and individuals with three, five, and six copies are much less common (115). The A2 allele is associated with higher serum levels of IL-1RA and lower levels of IL-1α. In addition, mononuclear cells isolated from individuals with the A2 allele produce more IL-1RAin vitro (116, 117).

Several of these polymorphisms have been examined for association with susceptibility to and outcome from sepsis, and the polymorphism most studied is the A2 allele in the IL-1RA gene. A higher frequency of the A2 allele was demonstrated in white adults with severe sepsis compared with the frequency in a healthy white population (115). There was no association with mortality within the population with sepsis. The authors suggested that individuals with the A2 allele are at increased risk for the development of severe sepsis but not at increased risk of worse outcome. A similar study demonstrated a higher frequency of the IL-1RA gene A2 allele in Chinese adults with sepsis when compared with a healthy Chinese population but not a higher frequency of the polymorphisms in the IL-1α or IL-1β genes (118). In contrast, Arnalich et al. (119) saw no increased susceptibility to the development of sepsis in adults, but adults with severe sepsis who had the IL-1RA gene A2 allele had an increased risk for mortality. A higher frequency of the A2 allele was not observed in a cohort of children with meningococcal disease compared with a healthy control population (120). Finally, in a large cohort of patients with meningococcal disease, the majority of whom were under 18 yrs of age, those with the IL-1RA+2018 polymorphism had a higher mortality (121); however, this polymorphism is in linkage disequilibrium with the IL-1RA gene A2 allele and, thus, may be a marker for the A2 allele, which appears to be associated with a poor outcome as described above. In summary, despite some conflicting findings, genetic variability in the IL-1 locus, particularly the IL-1RA A2 allele, appears to place patients with infections at greater risk for the development of sepsis and perhaps at greater risk for mortality once sepsis has developed.

Interleukin-6

IL-6 is a proinflammatory cytokine with stimulatory effects on both B- and T-lymphocytes and is involved in the induction of fever and the hepatic acute phase protein synthesis. Serum levels of IL-6 have been correlated with the severity and outcome of sepsis (122–124).

The promoter region for IL-6 has been shown to have several single nucleotide polymorphisms (125). The best studied of these polymorphisms is a relatively common regulatory polymorphism comprising a G to C substitution at position −174 in the promoter region. In in vitro reporter vector systems, the constructs containing a G at this position demonstrated an increased expression of IL-6 compared with constructs containing a C (126). In healthy adults, the G allele is associated with higher basal serum levels of IL-6 (126). However, in septic adult surgical patients, there was no association between the genotypes and serum levels of IL-6, nor was there a significant difference in genotype distribution between critically ill patients and healthy controls or between patients with or without sepsis (124). This would suggest that the IL-6 G-174C polymorphism is not associated with an increased susceptibility to sepsis. A significantly lower frequency of the GG genotype was demonstrated in nonsurviving septic patients compared with surviving septic patients, suggesting that the GG genotype was in some fashion protective, but the number of patients in this group was small. In monocytes isolated from neonates with the C allele at position −174, the IL-6 LPS-stimulated response is greater than the LPS-stimulated response of monocytes isolated from neonates with the G allele (127), the opposite of what is observed in adults. In this age group, the C allele also appears to be associated with a greater rise in IL-6 levels during an acute inflammatory response. This finding may by explained by changes in the immune response, which occur during development.

However, unlike the association with worse outcome from sepsis in individuals who produce high levels of TNF-α, it is the G allele associated with low levels of IL-6 that appear to be associated with septicemia in premature neonates. The presence of the GG genotype was more frequent in preterm infants <32 wks gestation with sepsis compared with premature infants without sepsis, suggesting a protective benefit from the development of sepsis of the C allele (128).

Interleukin-10

The overzealous inflammatory response and the potential harmful effects of many of the inflammatory mediators such as TNF-α are counterbalanced by antiinflammatory cytokines such as IL-10 (4, 129). IL-10 is produced primarily by monocytes and down-regulates the expression of cytokines such as TNF-α, IL-1α and -β, IL-6, and IL-8 by T-helper cells (130, 131). The antiinflammatory effects of IL-10 have been demonstrated in animal models of sepsis in which neutralization of IL-10 results in an exaggerated proinflammatory response and death, while administration of IL-10 confers protection (4, 132, 133). However, it has been proposed that overexpression of IL-10 may induce immunosuppression in bacterial sepsis and increase mortality by inhibiting bacterial clearance (134, 135).

IL-10 production appears to be regulated primarily at the transcriptional level. Located within the 5′-flanking region, which controls transcription of the IL-10 gene, are three single nucleotide polymorphisms upstream from the transcriptional start site, at positions −1082 (G to A), −819 (C to T), and −592 (C to A), that have been shown to affect IL-10 expression (136–138). The −1082 G/A substitution occurs within a putative Ets transcription factor binding site, the −819 C/T lies within a putative positive regulatory region, and the −592 C/A polymorphism lies within a putative STA 3 binding site and a negative regulatory region (138, 139). Linkage disequilibrium between the alleles at the −819 and −592 sites has been demonstrated such that −819 C is always with −592 C and −819 T is always with −592 A. Therefore, only four possible haplotypes of these three polymorphisms can occur: GCC, ACC, GTA, and ATA.

Several in vitro stimulation studies have been performed examining the influence of the IL-10 promoter polymorphisms on IL-10 production. Stimulated peripheral blood mononuclear cells have demonstrated that the GCC/GCC genotype is associated with higher IL-10 production (137). Likewise, in a study in which only the IL-10 −1082 site was examined, stimulated whole blood from individuals with the G allele resulted in higher amounts of IL-10 compared with whole blood from individuals with the A allele (140). In addition, the 5′-flanking regions from individuals homozygous for the three haplotypes identified in a white population, GCC, ACC, and ATA, were cloned into a luciferase vector and transiently transfected into cells. The GCC construct demonstrated significantly increased transcriptional activity compared with the ATA construct, with the ACC construct demonstrating an intermediate transcriptional activity (141). In an in vitro study in which only the IL-10 −592 site was examined, LPS-stimulated whole blood from healthy volunteers with the C allele produced higher amounts of IL-10 than individuals with the A allele at the −592 site (142). Thus, in vitro evidence suggests that genetic variation in the promoter region of the gene coding for IL-10 influences the amount of IL-10 produced.

As previously mentioned, it has been proposed that excess IL-10 results in immunosuppression in bacterial sepsis (134) and increases mortality in pneumococcal pneumonia (135). Elevated serum levels of IL-10 have been demonstrated in adults with community-acquired pneumonia and are correlated with disease severity (143). Investigators have examined whether the genetic polymorphisms in the regulatory region of the gene coding for IL-10 are associated with disease severity and sepsis, with conflicting results. The “high secretor” G allele at position −1082 was associated with more severe disease when compared with the “low secretor” A allele in a cohort of adults with community-acquired pneumonia (144). In a cohort of patients with culture-proven pneumococcal disease, 54% of those patients who developed septic shock had the high secretor G allele, whereas only 16% of those patients who did not develop septic shock had this allele (140). At the IL-10 −592 site, there was no increased risk of sepsis in a cohort of critically ill adults in those patients with the low secretor A allele at the −592 site, but the mortality was higher in those patients with the A allele compared with those with the C allele, regardless of whether they met the criteria for sepsis (142). In contrast, Reid et al. (145) did not observe an association between the IL-10 haplotypes and either serum IL-10 levels or mortality in a cohort of adult intensive care unit (ICU) patients with a wide variety of medical, surgical, and traumatic problems. The variable results in these studies may be due to the types of patients enrolled in the studies; all of the patients enrolled in the study by Schaaf et al. (140) had an ongoing infectious process, whereas those enrolled in the study by Reid et al. (145) had a variety of illnesses not restricted to infectious etiologies. Thus, association studies between the regulatory polymorphisms in the promoter region of the gene coding for IL-10 are somewhat conflicting; on one hand, there appears to be an increased risk of more severe disease (development of septic shock) in those individuals who have the high secretor GG genotype at the −1082, yet there is a higher mortality in individuals with the low secretor genotype at the −592 site.

Heat Shock Proteins

Heat shock proteins are a family of stress-inducible proteins expressed in response to heat, as well as a number of other noxious stimuli, including endotoxin and other mediators of severe sepsis (146). These proteins are essential for cell survival during stress (147) and are involved in a number of important cellular functions, including the folding, assembly, and translocation of proteins across membranes (148, 149). The genes coding for three HSPs lie in the major histocompatibility complex near the genes coding for TNF-α and LT-α (150). Polymorphisms have been described in the gene coding for the stress-inducible HSP70–2, one of which has been associated with variable expression of HSP70–2 messenger RNA (mRNA); most individuals have a G at position +1267, which is associated with lower mRNA levels after ex vivo stimulation (151). However, no association between this allele and susceptibility to or outcome from severe sepsis was demonstrated in adult patients admitted to a surgical ICU (152). On the other hand, we have demonstrated that in adults with community-acquired pneumonia, those individuals with the AA genotype at the HSP70–2 +1267 were at greater risk for septic shock than those individuals who were either heterozygous or homozygous for the more common GG genotype at this position but consistent with the previously mentioned study this polymorphism did not increase the risk for mortality from severe sepsis (153).

Angiotensin I Converting Enzyme

Angiotensin I converting enzyme (ACE) is found on endothelial and epithelial cells and is primarily responsible for converting angiotensin I to angiotensin II. ACE is also involved in the metabolism of chemotactic peptides, suggesting that it may play a role in the inflammatory response. Individuals have been shown to have variable plasma and tissue levels of ACE, and evidence suggests that these variable levels are due, in part, to genetic factors (154). Specifically, an insertion (I)/deletion (D) of a 287 base repair repeat sequence in the noncoding intron 16 of the gene coding for ACE (155) is associated with variable plasma levels; individuals with the DD genotype have higher plasma and tissue levels of ACE compared with individuals who are homozygous for the insertion sequence or are heterozygous (156, 157). The mechanism by which the deletion of this sequence is associated with increased ACE levels is still controversial (158, 159) but may involve transcriptional regulation (160). The deletion may remove a binding site for a transcription inhibitory factor, allowing for increased transcription.

Several studies have examined the association of the ACE I/D polymorphism with sepsis. In the first study, the D/D genotype was associated with more severe meningococcal disease in children as measured by a higher predicted risk of mortality, greater prevalence of inotropic support and mechanical ventilation, and longer intensive care unit stay (161). In addition, the frequency of the D/D genotype was more frequent in those children who died compared with survivors, although this did not reach statistical significance (161). More recently, no significant difference was observed either in the susceptibility to bloodstream infection or sepsis-related mortality in a cohort of mechanically ventilated infants <1500 g (162). Plasma levels of ACE were not measured in either study. A third study should be mentioned in this discussion. In a cohort of adult ICU patients, the DD genotype was found to be more frequent in those patients with ARDS compared with those ICU patients without ARDS, and once ARDS developed, mortality was higher in those patients with the D genotype, suggesting a role for ACE in the pathogenesis of ARDS (163). Whereas these investigators also did not measure ACE plasma or bronchioalveolar fluid levels of ACE, ACE levels in bronchoalveolar lavage fluid and plasma have been shown to be elevated in ARDS (164). Furthermore, the use of an angiotensin receptor blocker in an animal model of lung injury attenuates the infiltration of neutrophils and apoptosis in lung tissue (165).

Plasminogen Activator Inhibitor 1

The pathogenesis of multiple organ system failure in sepsis is believed to involve in part endothelial dysfunction and intravascular fibrin deposition (166). Diminished activity of anticoagulants, or elevated levels of inhibitors of fibrinolysis, can lead to fibrin deposition and may contribute to multiple organ system failure. Plasminogen activator inhibitor 1 (PAI-1) is an inhibitor of fibrinolysis due to its ability to inhibit the potent fibrinolytic, plasminogen activator. High plasma concentrations of PAI-1 have been observed in sepsis (167) and severe meningococcal disease (168), and high concentrations are correlated with a worse outcome.

A single nucleotide insertion/deletion polymorphism exists within the promoter region of the gene coding for PAI-1 that appears to influence the amount of PAI-1 production. Individuals homozygous for four guanines (4G/4G) produce more PAI-1 than either individuals heterozygous (4G/5G) or homozygous for five guanines (5G/5G) (169). In a large cohort of children with meningococcal disease, children with the 4G/4G genotype had higher plasma levels of PAI-1 and an increased risk of death from sepsis compared with children with either the 4G/5G or 5G/5G genotypes (170). Individuals with meningococcal disease whose first degree relatives were carriers of the 4G/4G genotype also appear to be at a greater risk for the development of septic shock rather than meningitis (171). Finally, in a cohort of adult trauma patients, those with the 4G/4G genotype demonstrated higher plasma concentrations of PAI-1 compared with individuals with the other genotypes (172). Thus, there appears to be a strong association between the 4G/4G genotype in the PAI-1 gene, high plasma concentrations of PAI-1, and worse outcome in sepsis.

Surfactant Protein B

Surfactant is comprised of four major proteins, A, B, C, and D, whose primary role is to reduce the surface tension at the air-liquid interface; in addition, proteins A and D have demonstrated a role in the host immune system (173–178). SP-B appears to be required for stabilization of the phospholipids at the air-liquid interface (179), but no known immunologic function has been described. Several pulmonary disorders have been described in animals and humans with deficiencies in SP-B, including ARDS (180, 181, 182).

The gene coding for SP-B is located on chromosome 2 (183) and consists of 11 exons (184), including a 3′-untranslated sequence (183). Several genetic polymorphisms in the gene have been described and include variations in the coding, as well as noncoding regions. A C to T substitution at position 1580 in exon 4 results in a threonine to isoleucine change at amino acid position 131 (185). The functional consequences of this alteration have not been elucidated, but a recognition sequence for N-linked glycosylation is altered (186, 187). This alteration may potentially impact on the processing and/or function of SP-B (188), resulting in decreased functional SP-B. Our laboratory recently demonstrated that the frequency of the CC and CT genotypes at the SP-B +1580 site are associated with the need for mechanical ventilation, ARDS, and septic shock in adults with community-acquired pneumonia (189). This suggests that individuals with community-acquired pneumonia who have the C allele are at an increased risk for sepsis.

Limitations

There are several limitations to the associations studies discussed above that should be noted (190). These limitations are briefly discussed here and in more detail in the accompanying article by Vitali and Randolf. In many of the studies examining whether polymorphisms increase the risk of sepsis, the frequency of the polymorphism in the group of patients with sepsis is compared with the frequency of the polymorphism in a healthy control population. However, the control population may not have been exposed to the same pathogens to which the patients with sepsis were exposed. One cannot conclude from such a comparison that the group that developed sepsis was at an increased risk to sepsis without the control group being similarly exposed. Rather, a more appropriate control group for comparison would be a group of patients with a similar infection who did not develop sepsis. A second limitation is that in most cases, investigators describe the association between a specific genetic polymorphism and susceptibility to or outcome from a disease process. However, the specific nucleotide variation being investigated may, in fact, not be involved but rather is closely linked to the actual genetic variation causing the association. For example, the genes coding for TNF-α and LT-α lie on chromosome 6 within the major histocompatibility complex near the HLA loci and are in strong linkage disequilibrium with several HLA alleles that may be involved in controlling TNF-α secretion. Thus, the polymorphisms within the promoter region may not directly cause the increased TNF-α secretion but are a marker for some other closely linked genetic factor. A third limitation is that in many studies, subjects within the study and control groups are from different ethnic groups. It is now well known that the frequency of many of these polymorphisms varies between ethnic groups, and so comparisons should only be made within ethnic groups. Finally, in some, it is likely that single nucleotide polymorphisms by themselves are not the cause of the increased susceptibility to or outcome from sepsis but rather are markers for an extended haplotype of genetic variations.

CONCLUSIONS

In summary, genetic variability appears to play an important role in sepsis. By altering the ability of the host to recognize a pathogenic stimulus or by altering the intensity of the inflammatory response, genetic polymorphisms influence the clinical presentation and outcome of sepsis. In some types of infectious diseases common in intensive care units, genetic polymorphisms may increase the risk of developing the clinical manifestations of sepsis including shock. Genetic polymorphisms may also influence the severity of sepsis and may be useful in predicting those individuals who will develop more severe disease. The disparate results seen in many studies of polymorphisms in sepsis emphasize the need for future studies to be larger, to include the analysis of multiple polymorphisms, and to be better designed with respect to control populations to identify the degree of influence that genetic variability has on sepsis.

REFERENCES

1. Sorensen TI, Nielsen GG, Andersen PK, et al: Genetic and environmental influences on premature death in adult sepsis. N Engl J Med 1988; 318:727–732
2. Bone RC, Balk RA, Cerra FB, et al: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101:1644–1655
3. Parrillo JE, Parker MM, Natanson C, et al: Septic shock in humans: Advances in the understanding or pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990; 113:227–242
4. Walley KR, Lukacs NW, Standiford TJ, et al: Balance of inflammatory cytokines related to severity and mortality of murine sepsis. Infect Immun 1996; 64:4733–4738
5. Blackwell TS, Christman JW: Sepsis and cytokines: Current status. Br J Anaesth 1996; 77:110–117
6. Parrillo JE: Pathogenic mechanisms of septic shock. N Engl J Med 1993; 328:1471–1477
7. Poltorak A, He X, Smirnova I, et al: Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in the Tlr4 gene. Science 1998; 282:2085–2088
8. Chow JC, Young DW, Golenbock DT, et al: Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem 1999; 274:10689–10692
9. Aderem A, Ulevitch RJ: Toll-like receptors in the induction of the innate immune response. Nature 2000; 406:782–787
10. Beutler B, Poltorak A: Sepsis and evolution of the innate immune response. Crit Care Med 2001; 29:S2–S7
11. Ulevitch RJ: Regulation of receptor-dependent activation of the innate immune response. J Infect Dis 2003; 187:S351–S355
12. Hoshino K, Takeuchi O, Kawai, T et al: Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: Evidence for TLR4 as the LPS gene product. J Immunol 1999; 162:3749–3752
13. Qureshi ST, Lariviere L, Leveque G, et al: Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (TLR4). J Exp Med 1999; 189:615–625
14. Arbour NC, Lorenz E, Schutte BC, et al: TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 2000; 25:187–191
15. Michel O, LeVan TD, Stern D, et al: Systemic responsiveness to lipopolysaccharide and polymorphisms in the Toll-like receptor 4 gene in human beings. J Allergy Clin Immunol 2003; 112:923–929
16. Werner M, Topp R, Wimmer K, et al: TLR4 gene variants modify endotoxin effects on asthma. J Allergy Clin Immunol 2003; 112:323–330
17. Schippers EF, van't Veer C, van Voorden S, et al: TNF-alpha promoter, Nod2 and Toll-like receptor-4 polymorphisms and the in vivo and ex vivo response to endotoxin. Cytokine 2004; 26:16–24
18. Heesen M, Bloemeke B, Kunz D: The cytokine synthesis by heterozygous carriers of the Toll-like receptor 4 asp299bly polymorphism does not differ from that of wild type homozygotes. Eur Cytokine Netw 2003; 14:234–237
19. von Aulock S, Schroder NWJ, Gueinzius K, et al: Heterozygous Toll-like receptor 4 polymorphism does not influence lipopolysaccharide-induced cytokine release in human whole blood. J Infect Dis 2003; 188:938–943
20. Imahara SD, Jelacic S, Junker CE, et al: The TLR4 +896 polymorphism is not associated with lipopolysaccharide hypo-responsiveness in leukocytes. Genes Immun 2005; 6:37–43
21. Agnese DM, Calvano JE, Hahm SJ, et al: Human Toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of Gram-negative infections. J Infect Dis 2002; 186:1522–1525
22. Lorenz E, Mira JP, Frees KL, et al: Relevance of mutations in the TLR4 receptor in patients with Gram-negative septic shock. Arch Intern Med 2002; 162:1028–1032
23. Child NJA, Yang IA, Pulletz MCK, et al: Polymorphisms in Toll-like receptor 4 and the systemic inflammatory response syndrome. Biochem Soc Trans 2003; 31:652–653
24. Read RC, Pullin J, Gregory S, et al: A functional polymorphism of Toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease. J Infect Dis 2001; 184:640–642
25. Smirnova I, Mann N, Dols A, et al: Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Nat Acad Sci U S A 2003; 100:6075–6080
26. Pridmore AC, Wyllie DH, Abdillahi F, et al: A lipopolysaccharide-deficient mutant of Neisseria meningitides elicits attenuated cytokine release by human macrophages and signals via Toll-like receptor (TLR) 2 but not via TKR4/MD2. J Infect Dis 2001; 183:89–96
27. Ingalls RR, Lien E, Golenbock T: Membrane-associated proteins of a lipopolysaccharide-deficient mutant of Neisseria meningitides activate the inflammatory response through Toll-like receptor 2. Infect Immun 2001; 69:2230–2236
28. Moore KJ, Andersson LP, Ingalls RR, et al: Divergent responses to LPS and bacteria in CD14-deficient murine macrophages. J Immunol 2000; 165:4272–4280
29. Unkelback K, Gardemann A, Kostrzewa M, et al: A new promoter polymorphism in the gene of lipopolysaccharide receptor CD14 is associated with expired myocardial infarction in patients with low atheroslcerotic risk profile. Arterioscler Thromb Vasc Biol 1999; 19:932–938
30. Baldini M, Lohman IC, Halonene M, et al: A polymorphism in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 1999; 20:976–983
31. Hubacek JA, Pitha J, Skodova Z, et al: C(-260) to T polymorphism in the promoter of the CD14 monocyte receptor gene as a risk factor for myocardial infarction. Circulation 1999; 99:3218–3220
32. LeVan TD, Bloom JW, Bailey TJ, et al: A common single nucleotide polymorphism in the CD14 promoter decreases the affinity of Sp protein binding and enhances transcriptional activity. J Immunol 2001; 167:5834–5844
33. Koenig W, Khuseyinova N, Hoffman MM, et al: CD14 C(-260) –>T polymorphism, plasma levels of the soluble endotoxin receptor CD14, their association with chronic infections and risk of stable coronary artery disease. J Am Coll Cardiol 2002; 40:43–42
34. Gibot S, Cariou A, Drouet L, et al: Association between a genomic polymorphism within the CD14 locus and septic shock susceptibility and mortality rate. Crit Care Med 2002; 30:969–973
35. Heesen M, Bloemeke B, Schade U, et al: The -260C to T promoter polymorphism of the lipopolysaccharide receptor CD14 and severe sepsis in trauma patients. Intens Care Med 2002; 28:1161–1163
36. Hubacek JA, Stuber F, Frohlich D, et al: The common functional C(-159)T polymorphism within the promoter region of the lipopolysaccharide receptor CD14 is not associated with sepsis development or mortality. Genes Immun 2001; 1:405–407
37. van der Pol WL, van de Winkel JGJ: IgG receptor polymorphisms: Risk factors for disease. Immunogenetics 1998; 48:222–232
38. van Sorge NM, van der Pol WL, van de Winkel JGJ: FcγR polymorphisms: Implications for function, disease susceptibility and immunotherapy. Tissue Antigens 2003; 61:189–202
39. Wu J, Edberg JC, Redecha PB, et al: A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest 1997; 100:1059–1070
40. Koene HR, Kleijer M, Algra J, et al: Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gamma RIIIa-48L/R/H phenotype. Blood 1997; 90:1109–1114
41. Huizinga TW. Kleijer M, Tetteroo PA, et al: Biallelic neutrophil Na-antigen system is associated with a polymorphism on the phosphor-inositol-linked Fc gamma receptor III (CD16). Blood 1990; 75:213–217
42. Salmon JE, JC Edberg, RP Kimberly: Fc gamma receptor III on human neutrophils: Allelic variants have functionally distinct capacities. J Clin Invest 1990; 85:1287–1295
43. Salmon JE, Millard SS, Brogle NL, et al: Fc gamma receptor IIIb enhances Fc gamma receptor IIa function in an oxidant-dependent and allele-sensitive manner. J Clin Invest 1995; 95:2877–2885
44. Warmerdam PA, van de Winkel JG, Gosselin EJ, et al: Molecular basis for a polymorphism of human Fc gamma receptor II (CD32). J Exp Med 1990; 172:19–25
45. Warmerdam PA, van de Winkel JG, Vlug A, et al: A single amino acid in the second Ig-like domain of the human Fc gamma receptor II is critical for human IgG2 binding. J Immunol 1991; 147:1338–1343
46. Salmon JE, Edberg JC, Brogle NL, et al: Allelic polymorphisms of human Fc gamma receptor IIA and Fc gamma receptor IIIB: Independent mechanisms for differences in human phagocyte function. J Clin Invest 1992; 89:1274–1281
47. Sanders LA, Feldman RG, Voorhorst-Ogink MM, et al: Human immunoglobulin G (IgG) Fc receptor IIA (CD32) polymorphism and IgG2-mediated bacterial phagocytosis by neutrophils. Infect Immun 1995; 63:73–81
48. Herman DJ, Hamilton RG, Barington T, et al: Quantitation of human IgG subclass antibodies to Haemophilus influenzae type b capsular polysaccharide. J Immunol Methods 1992; 148:101–114
49. Siber GR, Schur PH, Aisenberg AC, et al: Correlation between serum IgG2 concentrations and the antibody response to bacterial polysaccharide antigens. N Engl J Med 1980; 303:178–182
50. Fijen CA, Bredius RG, Kuijper EJ: Polymorphism of IgG Fc receptors in meningococcal disease. Ann Intern Med 1993; 119:636
51. Bredius RG, Derkx BH, Fijen CA, et al: Fc gamma receptor IIa (CD32) polymorphism in fulminant meningococcal septic shock in children. J Infect Dis 1994; 170:848–853
52. Platonov E, Shipulin GA, Vershinina IV, et al: Association of human Fc gamma RIIa (CD32) polymorphism with susceptibility to and severity of meningococcal disease. Clin Infect Dis 1998; 27:746–750
53. Platanov AE, Kuijper EJ, Vershinina IV, et al: Meningococcal disease and polymorphism of FcgammaRIIa (CD32) in late complement-deficient individuals. Clin Exp Immunol 1998; 111:97–101
54. Domingo P, Muniz-Diaz E, Baraldes MA, et al: Associations between Fc gamma receptor IIA polymorphisms and the risk and prognosis of meningococcal disease. Am J Med 2002; 112:19–25
55. van der Pol WL, Huizinga TW, Vidarsson G, et al: Relevance of Fc gamma receptor and interleukin-10 polymorphisms for meningococcal disease. J Infect Dis 2001; 184:1548–1555
56. Yee AMF, Phan HM, Zuniga R, et al: Association between FcγRIIa-R131 allotype and bacteremic Pneumococcal pneumonia. Clin Infect Dis 2000; 30:25–28
57. Lieke A, Sanders M, van de Winkel JGJ, et al: Fcγ receptor IIa (CD32) heterogeneity in patients with recurrent bacterial respiratory tract infections. J Infect Dis 1994; 170:854–861
58. Tezcan I, Berkel AI, Ersoy F, et al: Fc gamma receptor allotypes in children with bacterial meningitis: A preliminary study. Turk J Pediatr 1998; 40:533–538
59. Smith I, Vedeler C, Halstensen A: FcγRIIa and FcγRIIIb polymorphisms were not associated with meningococcal disease in Western Norway. Epidemiol Infect 2003; 130:193–199
60. Turner MW: Mannose-binding lectin (MBL) in health and disease. Immunobiology 1998; 199:327–339
61. Kuhlman M, Joiner K, Ezekowitz RA: The human mannose-binding protein functions as an opsonin. J Exp Med 1989; 169:1733–1745
62. Matsushita M, Endo Y, Fujita T: MASP1 (MBL-associated serine protease 1). Immunobiology 1998; 199:340–347
63. Summerfield JA, Ryder S, Sumiya M, et al: Mannose binding protein gene mutations associated with unusual and severe infections in adults. Lancet 1995; 345:886–889
64. Sastry K, Herman GA, Day L, et al: The human mannose-binding protein gene: exon structure reveals its evolutionary relationship to a human pulmonary surfactant gene and localization to chromosome 10. J Exp Med 1989; 170:1175–1189
65. Sumiya M, Super M, Tabona P, et al: Molecular basis of opsonic defect in immunodeficient children. Lancet 1991; 337:1569–1570
66. Lipscombe RJ, Sumiya M, Hill AV, et al: High frequencies in African and non-African populations of independent mutations in the mannose binding protein gene. Hum Mol Genet 1992; 1:709–715
67. Madsen HO, Garred P, Thiel S, et al: Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein. J Immunol 1995; 155:3013–3020
68. Summerfield JA, Sumiya M, Levin M, et al: Association of mutations in mannose binding protein gene with childhood infection in consecutive hospital series. BMJ 1997; 314:1229–1232
69. Koch A, Melbye M, Sorensen P, et al: Acute respiratory tract infections and mannose-binding lectin insufficiency during early childhood. JAMA 2001; 285:1316–1321
70. Hibberd ML, Sumiya M, Summerfield JA, et al: Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Lancet 1999; 353:1049–1053
71. Garred P, Madsen HO, Halberg P, et al: Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus. Arthritis Rheum 1999; 42:2145–2152
72. Gomi K, Tokue Y, Kobayashi T, et al: Mannose-binding lectin gene polymorphism is a modulating factor in repeated respiratory infections. Chest 2004; 126:95–99
73. Roy S, Knox K, Segal S, et al: MBL genotype and risk of invasive pneumococcal disease: A case control study. Lancet 2002; 359:1569–1573
74. Kronborg G, Weis N, Madsen HO, et al: Variant mannose-binding lectin alleles are not associated with susceptibility to or outcome of invasive pneumococcal infection in randomly included patients. JID 2002; 185:1517–1520
75. Nathan C: Points of control in inflammation. Nature 2002; 420:846–852
76. Cohen J: The immunopathogenesis of sepsis. Nature 2002; 420:885–891
77. Furman WL, Strother D, McClain K, et al: Phase I clinical trail of recombinant tumor necrosis factor in children with refractory solid tumors: A pediatric oncology group study. J Clin Oncol 1993; 11:2205–2210
78. Tracey KJ, Beutler B, Lowry SF, et al: Shock and tissue injury induced by recombinant human cachectin. Science 1986; 234:470–473
79. Wheeler AP, Jesmok G, Brigham KL: Tumor necrosis factor's effects on lung mechanics, gas exchange, and airway reactivity in sheep. J Appl Physiol 1990; 68:2542–2549
80. Selleri C, Sato T, Anderson S, et al: Interferon-γ and tumor necrosis factor-α suppress both early and late stages of hematopoiesis and induce programmed cell death. J Cell Physiol 1995; 165:538–546
81. van Hinsbergh VWM, Bauer KA, Kooistra T, et al: Progress of fibrinolysis during tumor necrosis factor infusions in humans: Concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrinogen degradation products. Blood 1990; 76:2284–2289
82. Stuber F, Petersen M, Bokelmann F, et al: A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-α concentrations and outcome of patients with severe sepsis. Crit Care Med 1996; 24:381–384
83. Pociot F, Briant L, Jongeneel CV, et al: Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-α and TNF-β by human mononuclear cells: A possible link to insulin-dependent diabetes mellitus. Eur J Immunol 1993; 23:224–231
84. Appoloni O, Dupont E, Vandercruys M, et al: The association of tumor necrosis factor-2 allele with plasma tumor necrosis factor-alpha levels and mortality from septic shock. Am J Med 2001; 110:486–488
85. Louis E, Franchimont D, Piron A, et al: Tumor necrosis factor (TNF) gene polymorphism influences TNF-α production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol 1998; 113:401–406
86. Higuchi T, Seki N, Kamizono S, et al: Polymorphisms of the 5′flanking region of the human tumor necrosis factor (TNF)-α gene in Japanese. Tissue Antigens 1998; 51:605–612
87. Wilson AG, Symons JA, McDowell TL, et al: Effects of a polymorphism in the human tumor necrosis factor a promoter on transcriptional activation. Proc Nat Acad Sci U S A 1997; 94:3195–3199
88. Wilson AG, Di Giovnine FS, Blakemoor AIF, et al: Single base polymorphism in the human tumour necrosis alpha (TNFα) gene detectable by NcoI restriction of PCR product. Hum Mol Genet 1992; 1:353
89. McArthur JA, Zhang Q, Quasney MW: Association between the A/A genotype at the lymphotoxin-alpha+250 site and increased mortality in children with positive blood cultures. Pediatr Crit Care Med 2002; 3:341–344
90. Kroeger KM, Carville KS, Abraham LJ: The −308 tumor necrosis factor-α promoter polymorphism effects transcription. Mol Immunol 1997; 34:391–399
91. Quasney MW, Bronstein DE, Cantor RM, et al: Increased frequency of alleles associated with elevated tumor necrosis factor-α levels in children with Kawasaki disease. Pediatr Res 2001; 49:686–690
92. McGuire W, Hill AVS, Allsopp CEM, et al: Variations in the TNF-α promoter region associated with susceptibility to cerebral malaria. Nature 1994; 371:508–510
93. Quasney MW, Zhang Q, Sargent S, et al: Increased frequency of the tumor necrosis factor-α-308 A allele in adults with human immunodeficiency virus dementia. Ann Neuro, 2001; 50:157–162
94. Nadel S, Newport MJ, Booy R, et al: Variation in the tumor necrosis factor-alpha gene promoter region may be associated with death from meningococcal disease. J Infect Dis 1996; 174:878–880
95. Mira JP, Cariou A, Grall F, et al: Association of TNF2, a TNF-α promoter polymorphism, with septic shock susceptibility and mortality. JAMA 1999; 282:561–568
96. Majetschak M, Obertacke U, Schade FU, et al: Tumor necrosis factor gene polymorphisms, leukocyte function, and sepsis susceptibility in blunt trauma. Clin Diagn Lab Immunol 2002; 9:1205–1211
97. Waterer G, Quasney MW, Cantor RM, et al: Septic shock and respiratory failure in community-acquired pneumonia have different TNF polymorphism associations. Am J Respir Crit Care Med 2001; 163:1599–1604
98. Stuber F, Udalova IA, Book M, et al: -308 tumor necrosis factor (TNF) polymorphism is not associated with survival in severe sepsis and is unrelated to lipopolysaccharide inducibility of the human TNF promoter. J Inflamm 1996; 46:42–50
99. Majetschak M, Flohe S, Obertacke U, et al: Relation of a TNF gene polymorphism to severe sepsis in trauma patients. Ann Surg 1999; 230:207–2214
100. Tang GJ, Huang SL, Yien HW, et al: Tumor necrosis factor gene polymorphism and septic shock in surgical infection. Crit Car Med 2000; 28:2733–2736
101. Schroder J, Kahlke V, Book M, et al: Gender differences in sepsis: Genetically determined? Shock 2000; 14:307–313
102. Weitkamp JH, Stuber F, Bartmann P: Pilot study assessing TNF gene polymorphism as a prognostic marker for disease progression in neonates with sepsis. Infection 2000; 28:92–96
103. Dinarello CA, SM Wolff: The role of interleukin-1 in disease. N Engl J Med 1993; 328:106–113
104. Dinarello CA: Proinflammatory and anti-inflammatory cytokines as mediators in the pathogenesis of septic shock. Chest 1997; 112:321S–329S
105. Arend WP, Malyak M, Gutheridge CJ, et al: Interleukin-1 receptor antagonist: Role in biology. Annu Rev Immunol 1998; 16:27–55
106. van Deuren M, van der Ven-Jongekrijg J, Vannier E, et al: The pattern of interleukin-1beta (IL-1beta) and its modulating agents IL-1 receptor antagonist and IL-1 soluble receptor type II in acute meningococcal infections. Blood 1997; 90:1101–1108
107. Bailly S, di Giovine FS, Blakemore AL, et al: Genetic polymorphism of human interleukin-1 alpha. Eur J Immunol 1993; 23:1240–1245
108. Dominici R, Cattaneo M, Malferrari G, et al: Cloning and functional analysis of the allelic polymorphism in the transcription regulatory region of interleukin-1 alpha. Immunogenetics 2002; 54:82–86
109. Shirodaria S, Smith J, McKay IJ, et al: Polymorphisms in the IL-1A gene are correlated with levels of interleukin-1alpha protein in gingival crevicular fluid of teeth with severe periodontal disease. J Dent Res 2000; 79:1864–1869
110. Bensen JT, Langefeld CD, Li L, et al: Association of an IL-1A 3′UTR polymorphism with end-stage renal disease and IL-1 alpha expression. Kidney Int 2003; 63:1211–1219
111. Pociot F, Molvig J, Wogensen L, et al: A TaqI polymorphism in the human interleukin-1 beta (IL-1beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest 1992; 22:396–402
112. di Giovine FS, Takhsh E, Blakemore AI, et al: Single base polymorphism at −511 in the human interleukin-1 beta gene (IL1 beta) Hum Mol Genet 1992; 1:450
113. Tarlow JK, Blakemore AI, Lennard A, et al: Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet 1993; 91:403–404
114. Cox A, Camp NJ, Nicklin MJ, et al: AN analysis of linkage disequilibrium in the interleukin-1 gene cluster, using a NOMVE grouping method for multiallelic markers. Am J Hum Genet 1998; 62:1180–1188
115. Fang XM, Schroder S, Hoeft A, et al: Comparison of two polymorphisms of the interleukin-1 gene family: interleukin-1 receptor antagonist polymorphism contributes to susceptibility to severe sepsis. Crit Care Med 1999; 27:1330–1334
116. Hurme M, Anttila S: IL-1 receptor antagonist (IL-1Ra) plasma levels are co-ordinately regulated by both IL-1Ra and IL-1beta genes. Eur J Immunol 1998; 28:2598–2602
117. Danis VA, Millington M, Hyland VJ, et al: Cytokine production by normal human monocytes: Inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism. Clin Exp Immunol 1995; 99:303–310
118. Ma P, Chen D, Pan J, et al: Genomic polymorphism within interleukin-1 family cytokines influences the outcome of septic patients. Crit Care Med 2002; 30:1046–1050
119. Arnalich F, Lopez-Madeuruelo D, Codoceo R, et al: Interleukin-1 receptor antagonist gene polymorphism and mortality in patients with severe sepsis. Clin Exp Immunol 2002; 127:331–336
120. Carrol ED, Mobbs KJ, Thomson APJ, et al: Variable number tandem repeat polymorphism of the interleukin-1 receptor antagonist gene in meningococcal disease. Clin Inf Dis 2002; 35:495–497
121. Read RC, Cannings C, Naylor SC, et al: Variation within genes encoding interleukin-1 and the interleukin-1 receptor antagonist influence the severity of meningococcal disease. Ann Intern Med 2003; 138:534–541
122. Hack CE, de Groot ER, Felt-Bersma RJ, et al: Increased plasma levels of interleukin-6 in sepsis. Blood 1989; 74:1704–1710
123. Schluter B, Konig B, Bergmann U, et al: Interleukin 6-a potential mediator of lethal sepsis after major thermal trauma: Evidence for increased IL-6 production by peripheral blood mononuclear cells. J Trauma 1991; 31:1663–1670
124. Schluter B, Raufhake C, Erren M, et al: Effect of the interleukin-6 promoter polymorphism (−174 G/C) on the incidence and outcome of sepsis. Crit Care Med 2002; 30:32–37
125. Terry CF, Loukaci V, Green FR: Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem 2000; 275:18138–18144
126. Fishman D, Faulds G, Jeffery R, et al: The effect of novel polymorphisms in the interleukin-6 (IL-6) gene in IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998; 102:1369–1376
127. Kilpinen S, Hulkkonen J, Wang XY, et al: The promoter polymorphism of the interleukin-6 gene regulates interleukin-6 production in neonates but not in adults. Eur Cytokine Netw. 2001; 12:62–68
128. Harding D, Dhamrait S, Millar A, et al: Is Interleukin-1–174 genotype associated with the development of septicemia in preterm infants? Pediatrics 2003; 112:800–803
129. van der Poll T, Marchant A, van Deventer SJ: The role of interleukin-10 in the pathogenesis of bacterial infection. Clin Microbiol Infect 1997; 3:605–607
130. de Waal Malefyt R, Abrams J, Bennett B, et al: Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: An autoregulatory role of IL-10 produced by monocytes. J Exp Med 1991; 174:1209–1220
131. Moore KW, de Waal Malefyt R, Coffman RL, et al: Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001; 19:683–765
132. Howard M, Muchamuel T, Andrade S, et al: Interleukin 10 protects mice from lethal endotoxemia. J Exp Med 1993; 177:1205–1208
133. Gerard C, Bruyns C, Marchant A, et al: Interleukin 10 reduces the release of tumor necrosis factor and prevents lethality in experimental endotoxemia. J Exp Med 1993; 177:547–550
134. Steinhauser ML, Hogaboam CM, Kunkel SL, et al: IL-10 is a major mediator of sepsis-induced impairment in lung antibacterial host defense. J Immunol 1999; 162:392–399
135. van der Poll T, Marchant A, Keogh CV, et al: Interleukin-10 impairs host defense in murine pneumococcal pneumonia. J Infect Dis 1996; 174:994–1000
136. Eskdale J, Kube D, Tesch H, et al: Mapping of the human IL10 gene and further characterization of the 5′ flanking sequence. Immunogenetics 1997; 26:120–128
137. Turner DM, Williams DM, Sankaran D, et al: An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 1997; 24:1–8
138. Lazarus M, Hajeer AH, Turner D, et al: Genetic variation in the interleukin10 gene promoter and systemic lupus erythematosus. J Rheumatol 1997; 24:2314–2317
139. Kube D, Platzer C, von Knethen A, et al: Isolation of the human interleukin 10 promoter: Characterization of the promoter activity in Burkitts lymphoma cell lines. Cytokine 1995; 7:1–7
140. Schaaf BM, Boehmke F, Esnaashari J, et al: Pneumococcal septic shock is associated with the interleukin-10–1082 gene promoter polymorphism. Am J Respir Crit Care Med 2003; 168:476–480
141. Crawley E, Kay R, Sillibourne J, et al: Polymorphic haplotypes of the interleukin-10 5′ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arth Rheum 1999; 42:1101–1108
142. Lowe PR, Galley HF, Abdel-Fattah A, et al: Influence of interleukin-10 polymorphisms on interleukin-10 expression and survival in critically ill patients. Crit Care Med 2003; 31:34–38
143. Glynn P, Coakley R, Kilgallen I, et al: Circulating interleukin 6 and interleukin 10 in community acquired pneumonia. Thorax 1999; 54:512–555
144. Gallagher PM, Lowe G, Fitzgerald T, et al: Association of IL-10 polymorphism with severity of illness in community acquired pneumonia. Thorax 2003; 58:154–156
145. Reid CL, Perry C, Pravica V, et al: Genetic variation in proinflammatory and anti-inflammatory cytokine production in multiple organ dysfunction syndrome. Crit Care Med 2002; 30:2216–2221
146. Deitch EA, Beck SC, Cruz NC, et al: Induction of heat shock gene expression in colonic epithelial cells after incubation with Escherichia coli or endotoxin. Crit Care Med 1995; 23:1371–1376
147. Hightower LE: Heat shock, stress proteins, chaperones and proteotoxicity. Cell 1991; 66:191–197
148. Hendrick JP, Hartl FU: Molecular chaperone functions of heat shock proteins. Annu Rev Biochem 1993; 62:349–384
149. Parsell DA, Lindquist S: The function of heat shock proteins in stress tolerance: Degradation and reactivation of damaged proteins. Annu Rev Genet 1993; 27:437–496
150. The MHC Sequencing Consortium: Complete sequence and gene map of a human major histocompatibility complex. Nature 1999; 401:921–923
151. Poicot F, Ronningen KS, Nerup J: Polymorphic analysis of the human MHC-linked heat shock protein 70 (HSP 70–2) and HSP 70-HOM genes in insulin dependent diabetes mellitus (IDDM). Scand J Immunol 1993; 38:491–495
152. Schroeder S, Reck M, Hoeft A, et al: Analysis of two human leukocyte antigen-linked polymorphic heat shock protein 70 genes in patients with severe sepsis. Crit Care Med 1999; 27:1265–1270
153. Waterer GW, ElBahlawan, Quasney MW, et al: Heat shock protein 70–2+1267 AA homozygotes have an increased risk of septic shock in adults with community-acquired pneumonia. Crit Care Med 2003; 31:1367–1372
154. Cambien F, Alhenc-Gelas F, Herbeth B, et al. Familial resemblance of plasma angiotensin-converting enzyme level: The Nancy study. Am J Hum Genet 1988; 43:774–780
155. Rigat B, Hubert C, Alhenc-Gelas F, et al: An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990; 86:1343–1346
156. Tiret L, Rigat B, Visvikis S, et al: Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet 1992; 51:197–205
157. Costerousse O, Allegrini J, Lopez M, et al: Angiotensin I converting enzyme in human circulating mononuclear cells: Genetic polymorphism of expression in T-lymphocytes. Biochem J 1993; 290:33–40
158. Spruth E, Zurbrugg HR, Warnecke C, et al: Expression of ACE mRNA in the human atrial myocardium is not dependent on left ventricular function, ACE inhibitor therapy, or the ACE I/D genotype. J Mol Med 1999; 77:804–810
159. Rosatto N, Pontremoli R, De Ferrari G, et al: Intron 16 insertion of the angiotensin converting enzyme gene and transcriptional regulation. Nephrol Dial Transplant 1999; 14:868–871
160. Suehiro T, Morita T, Inoue M, et al: Increased amount of the angiotensin-converting enzyme (ACE) mRNA originating from the ACE allele with deletion. Hum Genet 2004; 115:91–96
161. Harding D, Baines PB, Brull D, et al: Severity of meningococcal disease in children and the angiotensin-converting enzyme insertion/deletion polymorphism. Am J Respir Crit Care Med 2002; 165:1103–1106
162. John Baier R, Loggins J, Yanamandra K: Angiotensin converting enzyme insertion/deletion polymorphism does not alter sepsis outcome in ventilated very low birth weight infants. J Perinatal 2004; Epub
163. Marshall RP, Webb S, Bellingan GJ, et al: Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med 2002; 166:646–650
164. Idell S, Kueppers F, Lippman M, et al: Angiotensin converting enzyme in bronchoalveolar lavage in ARDS. Chest 1991:52–56
165. Lukkarinen H, Laine J, Lehtonen J, et al: Angiotensin II receptor blockade inhibits pneumocyte apoptosis in experimental meconium aspiration. Pediatr Res 2004; 55:326–333
166. Aird WC: Vascular bed-specific hemostasis: Role of endothelium in sepsis pathogenesis. Crit Care Med 2001; 29:S28–S35
167. Paramo JA, Perez JL, Serrano M, et al: Types 1 and 2 plasminogen activator inhibitor and tumor necrosis factor alpha in patients with sepsis. Thromb Haemost 1990; 64:3–6
168. Brandtzaeg P, Joo GB, Brusletto B, et al: Plasminogen activator inhibitor 1 and 2, alpha-2-antiplasmin, plasminogen, and endotoxin levels in systemic meningococcal disease. Thromb Res 1990; 57:271–278
169. Eriksson P, Kallin B, van't Hooft FM, et al: Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A 1995; 92:851–1855
170. Hermans PW, Hibberd ML, Booy R, et al: 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Lancet 1999; 354:556–560
171. Westendorp RG, Hottenga JJ, Slagboom PE: Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock. Lancet 1999; 354:561–563
172. Menges T, Hermans PW, Little SG, et al: Plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism and prognosis of severely injured patients. Lancet 2001; 357:1096–1097
173. Floros J, Karinch AM: Human SP-A: Then and now. Am J Physiol 1995; 268:L162–L165
174. Wright JR: Immunomodulatory functions of surfactant. Physiol Rev 1997; 77:931–962
175. LeVine AM, Kurak KE, Bruno MD, et al: Surfactant protein-A-deficient mice are susceptible to Pseudomonas aeruginosa infection. Am J Respir Cell Mol Biol 1998; 19:700–708
176. van Iwaarden JF, Claassen E, Jeurissen SH, et al: Alveolar macrophages, surfactant lipids, and surfactant protein B regulate the induction of immune responses via the airways. Am J Respir Cell Mol Biol 2001; 24:452–458
177. Chiba H, Pattanajitvilai S, Mitsuzawa J, et al, Pulmonary surfactant proteins A and D recognize lipid ligands on Mycoplasma pneumoniae and markedly augment the innate immune response to the organism. Chest 2003; 123:426S
178. Wu H, et al: Surfactant proteins A and D inhibit the growth of Gram-negative bacteria by increasing membrane permeability. J Clin Invest 2003; 111:1589–1602
179. Cochrane CG, Revak SD: Pulmonary surfactant protein B (SP-B): Structure-function relationships. Science 1991; 254:566–568
180. Gregory TJ, Longmore WJ, Moxley MA, et al: Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome. J Clin Invest 1991; 88:1976–1981
181. Greene KE, Wright JR, Steinberg KP, et al: Serial changes in surfactant-associated proteins in lung and serum before and after onset of ARDS. Am J Respir Crit Care Med 1999; 160:1843–1850
182. Lin Z, Pearson C, Chinchilli V, et al: Polymorphisms of human SP-A, SP-B, and SP-D genes: Association of SP-B Thr131Ile with ARDS. Clin Genet 2000; 58:181–191
183. Pilot-Maties TJ, Kister SE, Fox JL, et al: Structure and organization of the gene encoding human pulmonary surfactant proteolipid SP-B. DNA, 1989; 8:75–86
184. White RT, Hawgood S, Damm D, et al: Sequence of pulmonary surfactant protein SP18 and evidence for cooperation between SP18 and SP28–36 in surfactant lipid adsorption. Am Rev Resp Dis, 1987; 4:379A
185. Lin Z, deMello DE, Wallot M, et al: AN SP-B gene mutation responsible for SP-B deficiency in fatal congenital alveolar proteinosis: Evidence for a mutation hotspot in exon 4. Mol Genet Metab 1998; 64:25–35
186. Jacobs KA, Phelps DS, Steinbrink R, et al: Isolation of a cDNA clone encoding a high molecular weight precursor to a 6-kDa pulmonary surfactant-associated protein. J Biol Chem 1987; 292:9808–9811
187. Wang G, Christensen ND, Wigdahl B, et al: Differences in N-linked glycosylation between human surfactant protein-B variants of the C or T allele at the single-nucleotide polymorphism at position 1580: implications for disease. Biochem J 2003; 369:179–184
188. Roberts SJ, Petropavlovskaja, Chung KN, et al: Role of individual N-linked glycosylation sites in the function and intracellular transport of the human a folate receptor. Arch Biochem Biophys 1998; 351:227–235
189. Quasney MW, GW Waterer, MK Dahmer, et al: Association between surfactant protein B+1580 polymorphism and the risk of respiratory failure in adults with community-acquired pneumonia. Crit Care Med 2004; 32:1115–1119
190. Lazarus R, Vercelli D, Palmer LJ, et al: Single nucleotide polymorphisms in innate immunity genes: Abundant variation and potential role in complex human disease. Immunol Rev 2002; 190:9–25
Keywords:

sepsis; polymorphism; predisposition; outcome; genetics

©2005The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies