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Review Article

Effects of Sequence Variations in Innate Immune Response Genes on Infectious Outcome in Trauma Patients

A Comprehensive Review

Bronkhorst, Maarten W.G.A.; Patka, Peter; Van Lieshout, Esther M.M.

Author Information
doi: 10.1097/SHK.0000000000000450

Abstract

INTRODUCTION

Trauma is a major public health problem worldwide, ranking as the fourth leading cause of death. In 2010, there were 5.1 million deaths from injuries, and the total number of deaths from injuries was greater than the number of deaths from HIV/AIDS, tuberculosis, and malaria combined (3.8 million) (1, 2). Infectious complications, sepsis, and multiple organ dysfunction syndrome (MODS) remain important causes for morbidity and mortality in patients who survive the initial trauma (3). Although the rate of MODS in trauma patients has diminished over the last decade, MODS-related mortality, intensive care unit stay, and mechanical ventilation duration have not changed significantly (4, 5). These complications increase the burden of cost to society.

The primary inflammatory insult determines the magnitude of systemic inflammation and subsequent immune exhaustion, which makes patients prone for septic complications. Both proinflammatory and anti-inflammatory responses appear to coexist in trauma patients, possibly leading to both additional tissue damage by the immune system as well as increased susceptibility for subsequent infections (6). The development of the systemic inflammatory response syndrome (SIRS) with liberation of proinflammatory cytokines is recognized as a part of the physiologic response to trauma. Tissue injury following trauma results in depressed cell-mediated immunity (especially T-cell) leading to an increased risk of infectious complications (7). Cytokine production varies between individuals because of genetic background and certain allelic variants of cytokine genes; in particular, single nucleotide polymorphisms (SNPs) in coding regions of cytokine genes are associated with higher or lower cytokine production. Polymorphism may be considered as an important genetic risk factor for susceptibility to posttraumatic sepsis and a potential target for immunotherapy. Increasing evidence suggests that genetic variants, particularly SNPs, are critical determinants for interindividual differences in both inflammatory responses and clinical outcome in sepsis patients (8). Although the effect of SNPs on sepsis and MODS has been studied in many populations and diseases, this review aims to summarize the current knowledge on SNPs in genes of the innate immune system in trauma patients only.

A literature search was performed in PubMed by using “genetic variation,” “trauma,” and “innate immunity” and synonyms as search string. The search was finalized by cross-checking references. Studies describing the effect of SNPs in innate immune response genes on infectious complications in trauma patients were included. An overview of the SNPs included is shown in Table S1, Supplemental Digital Content 1, at http://links.lww.com/SHK/A322.

Pattern recognition receptors and complexes

Toll-like receptors and associated genes

Toll-like receptor 1 (TLR1)

Three SNPs in TLR1 were studied in trauma patients (Tables 1 and S2, Supplemental Digital Content 1, at http://links.lww.com/SHK/A322) (9). The TLR1 −7202G allele (rs5743551) and the TLR1 742AG genotype (p.Asn248Ser) (rs4833095) were associated with increased risk of mortality in sepsis and gram-positive sepsis, respectively.

Table 1
Table 1:
Overview of association with outcome for SNPs in theTLR, CD14, IL, and TNF genes of trauma patients
Toll-like receptor 2 (TLR2)

Five SNPs in TLR2 have been studied in a trauma population (Tables 1 and S2, Supplemental Digital Content 1, at http://links.lww.com/SHK/A322). The TLR2 19216T>C (rs3804099) CC genotype conferred a significantly higher risk of developing sepsis and higher MOD scores than those with a TT or TC genotype (10). The TLR2 p.R753Q SNP was studied by two authors (11, 12). McDaniel et al. (12) found the AG genotype significantly more often in septic patients (62.5%) than in aseptic patients (25%) in African American patients (not so in whites). Bronkhorst et al. (11) found no association with sepsis or mortality in a mixed ethnic cohort of 219 trauma patients. For the TLR2 −16934T>A, the TA genotype increased the risk of a gram-positive infection and SIRS in a trauma population by Bronkhorst et al. (11).

Toll-like receptor 4 (TLR4)

Single nucleotide polymorphisms in TLR4 have been studied in trauma patients (11–15) and in burns patients (16–19) (Tables 1 and S2, Supplemental Digital Content 1, at http://links.lww.com/SHK/A322). In trauma patients, multiple SNPs in TLR4 have been studied making comparison difficult (11–15).

The TLR4 896A>G SNP (rs4986790) was studied in four cohorts of burns patients. Three studies that used the same growing cohort used sepsis as endpoint (16, 17, 19) and two studies used mortality as endpoint (18, 19). The TLR4 896A>G SNP was significantly associated with an increased risk for severe sepsis (16, 17). Shalhub et al. (19) could not confirm this. Moreover, no association with mortality was found (18, 19). Carriage of the TLR4 896G allele was associated with a decreased risk of complicated sepsis in trauma (15). The cosegregating TLR4 p.D299G and TLR4 p.T399I were studied in trauma patients by two authors (11, 12), both of whom were not able to demonstrate an association between genotype and infection or outcome of sepsis. Chen et al. (13) studied the clinical relevance of five SNPs in TLR4 (−2381A>G, −2242T>C, −1892G>A, −1837A>G, and −1418T>C) in patients with major trauma. Only TLR4 −2242T>C polymorphism was associated with higher sepsis rates and multiple organ dysfunction scores were found. Duan et al. (14) prospectively studied the TLR4 11367G>C polymorphism in patients with major trauma. Patients with the C variant allele had significantly lower sepsis morbidity than those homozygous for the G allele. In addition, MOD scores in the patients with trauma who carry the C allele were also significantly lower than those in the patients carrying the G allele.

Toll-like receptor 9 (TLR9)

Several SNPs in TLR9 have been studied in trauma patients by two authors (Tables 1 and S2, Supplemental Digital Content 1, at http://links.lww.com/SHK/A322) (11, 20).

Chen et al. (20) studied the effect of five polymorphisms in TLR9 in 557 consecutive Han Chinese patients with severe multiple blunt trauma injuries. Median injury severity score (ISS) was 25; 37.9% of patients developed sepsis. The rs187084 (−1486A>G), rs352140 (2848C>T), and rs352162 (6577T>C) SNPs were significantly associated with TLR9-mediated TNF-α production. Patients with a minor allele of the rs187084, rs352139, or rs352162 polymorphism had a higher sepsis morbidity rate. Of these three SNPs, only the rs352162 polymorphism was significantly associated with MOD score, showing a recessive effect.

Bronkhorst et al. (11) studied TLR9 (−1486T>C and −1237T>C) in a cohort of 219 severely injured patients and found −1486T>C to cause a trend toward reduced prevalence of gram-positive bacteria and fungi for this SNP (P = 0.060), but no significant association with SIRS, sepsis, or septic shock.

Cluster of differentiation 14 (CD14)

The effects of CD14 −159C>T promoter SNP were studied in burns patients (16–19, 21–23) and in severely injured trauma patients (11, 24–26) in Chinese (22–24, 26) and mixed ethnic populations (Tables 1 and S2, Supplemental Digital Content 1, at http://links.lww.com/SHK/A322) (11, 16–19, 21, 25). Comparison of results is complicated by the fact that different outcome parameters were used, including wound cultures, SIRS, sepsis, severe sepsis, MODS, and mortality. Sepsis and MODS occurred more frequently in both burns and trauma patients with variant genotype in some reports (17, 22–24, 26), but was not influenced by genotype in other reports (11, 16, 19, 25). Remarkably, in some studies sepsis was associated with the C allele, whereas in other studies sepsis was associated with the T allele (17, 22). One can only speculate about the origin of this contrast which may be explained by differences in ethnicity of the study population. Mortality risk was increased by CD14 −159C variant genotype in burns patients (18, 21), but this effect was not found in another study (19). Differences in total body surface area (TBSA) of burns as well as ethnic demographic baseline characteristics may contribute to these opposing findings.

The effects of CD14 −1145G>A in trauma patients were studied in Chinese trauma patients (24, 26). In both studies, with a total of 211 trauma patients, the −1145G allele conferred an increased risk of sepsis and MODS.

Myeloid differentiation-2/lymphocyte antigen 96 (LY96)

Zeng et al. (27) studied 726 unrelated Han Chinese patients with major trauma for MD2. A total of 37 SNPs were identified in MD2. Thirty-five of them constructed three haplotype blocks. Sepsis developed in around 40% of patients. Only the rs11465996 was shown to be significantly associated with the risk of development of sepsis and MODS in major trauma patients. Patients carrying the variant G allele revealed significantly higher sepsis morbidity rate and MOD scores.

Gu et al. (28) studied MD2 −1625C>G in 105 severely injured patients of whom 40% developed sepsis. The MOD scores in trauma patients carrying G allele at position −1625 were significantly higher than those carrying C allele. Moreover, trauma patients carrying G allele appeared to have higher risk of sepsis compared with those carrying C allele. Sepsis morbidity was significantly different between subject with C and G alleles.

Lipopolysaccharide-binding protein (LBP)

Zeng et al. (29) used haplotype tagging to study SNPs in LBP in two independent cohorts of major trauma patients recruited from southwest and eastern China. Of the nine known SNPs in LBP, only the rs2232618 (p.F436L) was significantly associated with higher susceptibility to sepsis and MODS. Patients carrying the variant C allele revealed significantly higher sepsis morbidity rate and MOD scores when compared with patients carrying the T allele.

Lectin pathway proteins

Mannose-binding Lectin (MBL2)

Heterozygosity for the variants in exon 1 (A/0) conferred an increased risk of wound colonization and infection in severely injured patients (30). This had previously been demonstrated only in a murine model of burns (31). Also, the YX promoter genotype increased the risk of fungal colonization and infection in trauma patients (30).

MBL-associated serine-protease 2 (MASP2)

MASP2 p.Y371D DD homozygosity increased the risk of SIRS and septic shock in trauma patients significantly (30). Moreover, a trend was noted for an increased risk of gram-positive infections in patients with DD genotype. For the MASP2 p.D120G genotype polymorphism, no statistically significant differences were found for all endpoints, although, strikingly, fungi, positive blood cultures, and septic shock were only found in DD patients (22.2%, 15.5%, and 17.9%, respectively). Another striking, yet nonsignificant, finding was that only 8.3% of DG patients developed sepsis versus 37.7% in DD patients (P = 0.060).

Ficolin 2 (FCN2)

The homozygous FCN2 p.A258S AS genotype increased the risk of developing septic shock in trauma patients (30). Also, wound colonization and infection risks were significantly increased. A trend was noted for gram-negative infections.

No significant associations between the FCN2 p.T236 M genotype and infectious events were found. Positive blood cultures developed in 25.0% of patients with a variant MM genotype versus only 11.3% of patients with the common TT genotype, but this difference was not statistically significant in a multivariate model (30).

Other receptors

Receptor for advanced glycation endproducts (RAGE)

A total of 728 unrelated patients with major trauma were studied by Zeng et al. (32) and genotyped for RAGE. Sepsis occurred in around 40% of patients with median time between trauma to sepsis being 6 days. From different genetic variants selected in this study, only the RAGE -429T>C polymorphism (rs1800625) was shown to be significantly associated with the risk of development of sepsis and MODS in major trauma patients. The patients carrying the variant C allele revealed a significantly lower sepsis morbidity rate and MOD scores, when compared with those carrying the T allele. Moreover, in vitro LPS-induced TNF-α production was significantly lower in patients with the variant C allele than in those with wildtype T allele.

NOD-like receptor family, pyrin domain containing 3 (NLRP3)

Zhang studied six SNPs in the NLRP3 gene of 718 Chinese patients with major blunt trauma with a mean ISS of 22.5 (33). A total of 40% of patients developed sepsis with a mean time to sepsis of 7 days. The NLRP3 −1017G>A polymorphism (rs2027432), although it was found in only three patients with AA variant homozygotes in this study cohort, was significantly associated with higher risk of MODS. In addition, the NLRP3 5134A>G (rs12048215) polymorphism was significantly associated with a lower sepsis morbidity rate, showing 26.4% in GG versus 44% in AA. Data from multiple logistic regression analyses further indicated that the patients with the rs12048215 polymorphism had a lower risk of developing sepsis after adjusting for possible confounders. The rs2027432 polymorphism was significantly associated with higher IL-1β levels.

Glucocorticoid receptor (GR)

Duan et al. (34) studied a cohort of 95 severe trauma patients with a mean ISS of 27. It appeared that the BclI mutation in the GR gene was not associated with posttraumatic sepsis or organ dysfunction.

Signal transducing adaptor proteins

Interleukin-1 receptor-associated kinase 1 (IRAK1)

Sperry et al. (35) studied a cohort of 321 patients with a median ISS of 16 for the T>C substitution (rs1059703) at position 1595 in exon 12 of IRAK1 which results in a nonsynonymous mutation (p.L532S). They found this SNP to be a very strong independent predictor of posttrauma multiple organ failure and mortality.

Interleukin-1 receptor-associated kinase 3 (IRAK3)

Meyer et al. (36) genotyped 474 patients with acute lung injury (ALI) from a prospective critically ill trauma patients’ cohort study for 25 candidate genes using the IBC chip. The prevalence of ALI in their cohort was 30%. IRAK3 was found to be associated with ALI in patients from African descent.

Inflammatory cytokines

Interleukins

Interleukin-IA (IL1A)

In a cohort of 308 Han Chinese trauma patients with ISS > 16, the IL1A −889C>T TT genotype had the highest risk of sepsis and produced the lowest serum levels of Il-1α (Tables 1 and S2, Supplemental Digital Content 1, at http://links.lww.com/SHK/A322) (37).

Interleukin-IB (IL1B)

Carrying an IL1B-Taq-1 3953C>T CT genotype in combination with the IL10 −592A>C AC genotype predisposed to acute respiratory failure in Caucasian trauma patients (n = 216; ISS > 16) (P = 0.003) (Tables 1 and S2, Supplemental Digital Content 1, at http://links.lww.com/SHK/A322) (38).

The IL1BI -170G>C SNP was studied in two overlapping cohorts of severely injured Han Chinese patients from the same hospital (37, 39). Chinese trauma patients carrying the major −1470G allele were more likely to develop sepsis than those with the minor −1470C allele in both studies.

The IL1B −511T>C SNP (rs16944) was studied in the previously overlapping cohorts of 238 and 308 Han Chinese patients with severe trauma (37, 39). The CC genotype conferred a statistically significant increase in the risk of sepsis. In a Caucasian cohort of 119 multiple trauma patients IL1B −511T>C variation was not found to confer any effect on sepsis (38).

The IL1B SNP most studied is the −31C>T (16–19, 21, 37, 39). In mixed-ethnic burns patients from the United States (TBSA > 15%), this SNP seems to be no relevant risk factor for the development of sepsis nor for mortality (16–19, 21). In Han Chinese multiple trauma patients, however, the IL1B −31C>T major CC genotype seemed to protect against sepsis (30.3% and 37.9%) following major trauma (37, 39).

Interleukin-IRN (IL1RN)

In one study, the effect of IL1RN variant 2 variable number tandem repeat (VNTR) polymorphism was studied in patients with traumatic brain injury (TBI) (Tables 1 and S2, Supplemental Digital Content 1, at http://links.lww.com/SHK/A322) (40). IL1RN VNTR allele 2 carriers were more likely to have hemorrhagic events after TBI. In another study in severe trauma patients, a IL1RN SNP 130T>C (rs315952), distinct from the well-described VNTR SNP, was associated with decreased risk of ARDS (41).

Interleukin-4 (IL4)

Two studies from the same hospital with overlapping patient cohorts reported the influence of IL4 −589T>C genotype in a cohort of 308 Chinese severe trauma patients with a mean ISS of 25.5 (Tables 1 and S2, Supplemental Digital Content 1, at http://links.lww.com/SHK/A322) (37, 42). A total of 48.4% of patients developed sepsis. The frequency of the TC heterozygous genotype in the sepsis group (37.6%) was significantly higher than in nonsepsis group (25.2%). There was a significant influence of the minor C allele. No relationship was observed between IL4 −589T>C and MODS in these major trauma patients.

Interleukin-6 (IL6)

The IL6 −174G>C SNP (rs1800795) was studied in three cohorts of burns patients (16–19, 43), six cohorts of trauma patients (12, 38, 44–47), and a cohort of TBI patients (Tables 1 and S2, Supplemental Digital Content 1, at http://links.lww.com/SHK/A322) (48). Only two out of these articles described an increased risk of sepsis with presence of the minor −174C allele (17, 45). In a cohort of TBI patients, the GG genotype was found significantly more frequently in the survivor group than in nonsurviving patients (48).

Chinese trauma patients carrying the IL6 −572G>C CC genotype had significantly more sepsis morbidity than with a CG or GG genotype (37, 46). A small Bosnian cohort, however, failed to demonstrate any influence of this SNP (47).

Interleukin-8 (IL8)

The effect of IL8 −251A>T on the development of ARDS was studied in one cohort of 97 blunt trauma patients of whom 23 developed ARDS (Tables 1 and S2) (49). The allele and genotype distribution of the polymorphism in this cohort did not exhibit a significant association with the development of ARDS or mortality. Patients with the AA genotype showed a significantly longer duration of mechanical ventilation than patients with the IL8 −251TT genotype.

Interleukin-10 (IL10)

The effects of IL10 −592A>C in trauma patients have been described in seven studies (Tables 1 and S2, Supplemental Digital Content 1, at http://links.lww.com/SHK/A322) (12, 37, 38, 50–52). Three studies (12, 50, 51) found conflicting results of genetic variation in this gene on outcome. Schröder et al. found an increased risk for MODS in −592AC genotypes. Huebinger et al. found that carriage of the minor −592A allele was associated with a decreased risk of mortality. McDaniel et al. found that patients carrying the IL10 ACC/ATA low-producing genotypes were at a lower risk of developing sepsis.

IL10 −819C>T SNP was studied in five cohorts of trauma patients (12, 37, 43, 50, 52). Three studies describe an effect on outcome (12, 37, 50). Huebinger et al. found that the minor −819T allele was significantly associated with a decreased risk of mortality. McDaniel et al. found that patients carrying the IL10 ACC/ATA low-producing genotypes were at a lower risk of developing sepsis. In a cohort of Chinese trauma patients (where C appeared to be the minor allele), it was shown that this C allele conferred a decreased risk of sepsis (37).

IL10 −1082G>A SNP was studied by 10 authors (12, 36–38, 43, 51–55). Six authors observed effects on outcome (12, 36, 38, 52–54). McDaniel et al. (12) found that patients who carried the IL10 ACC/ATA low-producing genotypes were at a lower risk of developing sepsis. Zeng et al. (52), however, found that patients with the major A allele had significantly higher risk of sepsis. Jin et al. (54) as well as Schroeder et al. (38) described a reduced risk of ARDS and acute respiratory failure in GG genotypes. In contrast, Gong et al. found the −1082GG genotype to be associated with an increased risk of ARDS in patients younger than 52 years old.

Interleukin-17F (IL17F)

Accardo Palumbo et al. (43) studied the effect of 7488T>C (His161Arg)(rs763780) in IL17 in a cohort of burns patients (Tables 1 and S2, Supplemental Digital Content 1, at http://links.lww.com/SHK/A322). At the third day, burn patients had a very significant increase in IL-17 plasma levels. There were, however, no statistically significant differences in IL17 genotype distributions among patients that did or did not develop sepsis.

Interleukin-18 (IL18)

McDaniel et al. (12) were unable to demonstrate a significant effect of SNPs in IL18 in trauma patients (Tables 1 and S2). Stassen et al. (56) studied IL18 −137G>C and IL18 −607C>A in 69 trauma patients. Although the individual SNPs were not associated with outcome, patients carrying both the −607CA genotype and a −137GC genotype (CA/GC) had a significantly reduced risk of sepsis. These data suggest that IL18 genetic variability may play a role in the predisposition for the development of postinjury sepsis.

Other inflammatory cytokines

High-mobility group box 1 (HMGB1)

Three HMGB1 polymorphisms −1514T>C, 2179C>G, and 6850G>A were studied in a cohort of 556 Han Chinese patients with major trauma. A total of 39.7% of patients developed sepsis. The HMGB1 2179C>G variant GG genotype predisposed to the occurrence of sepsis (P = 0.003) and MODS (P = 0.011) in trauma patients (57). With respect to the other two SNPs, there were no significant differences in sepsis morbidity rates and MOD scores.

Interferon-γ (IFNG)

In a mixed-ethnic cohort of 68 trauma patients (ISS > 15) of whom 42% to 50% developed sepsis (12) the IFNG 841T>A AA genotype protected against sepsis in African American patients, whereas this was not clear for Caucasian patients. The authors suggest that the carriage of the AA genotype could cause faster elimination of the pathogens (12). In an other cohort of 308 Han Chinese trauma patients (ISS > 16), the IFNG 541T>A polymorphism was unrelated to sepsis or MODS (37).

Tumor necrosis factor (TNF)

Three SNPs in TNF have been studied in trauma and burns patients by nine authors (Tables 1 and S2, Supplemental Digital Content 1, at http://links.lww.com/SHK/A322) (12, 16–19, 21, 37, 58–62).

The TNF −308G>A SNP (rs1800629) was described in burns patients by two authors in five studies (16–19, 21) and in trauma patients in eight studies (12, 15, 19, 37, 58–62). Increased risk of sepsis and of mortality has been observed by seven authors (16, 17, 19, 37, 58, 61, 62), but was not seen by four authors (12, 15, 18, 21, 60). Moreover, Gill et al. (59) demonstrated in a cohort of trauma patients that the A allele was significantly associated with the risk of microchimerism after allogenic transfusion of cells.

The TNF −238G>A SNP (rs361525) was studied in trauma patients by one author (62). There was no influence of −238G>A variation on sepsis outcome in a cohort of 152 severely injured patients.

Also, the TNF −376G>A SNP (rs1800750) was studied in trauma patients by one author (62). There was no influence of −238G>A variation on sepsis outcome in a cohort of 152 severely injured patients.

Lymphotoxin-α (LTA)

Effects of variation in lymfotoxin-α LTA 252A>G (rs909253) (previously known as TNF-β NcO1) was studied in trauma patients in five manuscripts (45, 58, 60, 61, 63). Three authors observed an effect on clinical outcome (60, 61, 63) and two did not (45, 58).

Majetschak et al. (63) found that severe posttraumatic sepsis was significantly increased in patients homozygous for the allele TNFB2 (presently termed the A allele). Three years later, Majetschak et al. (60) again found that patients developing severe sepsis after trauma were significantly more likely to be homozygous for TNFB2 and this time also homozygous for TNFB1 (presently termed the G allele). Menges et al. (61) also found that carriage of the G allele (TNFB1) conferred an increased risk of developing sepsis. Hildebrand et al. (45) and Duan et al. (58) found no effect on sepsis morbidity.

Other genes

In addidtion to the genes listed above, the following genes not belonging to the innate immune system have also been studied in cohorts of trauma patients (see Table S1, Supplemental Digital Content 1, at http://links.lww.com/SHK/A322): MYLK(64), PRDX6(65), HSPA1B(66), HSPA1L(66), HSP90B1(67), SERPINE1(18, 68), VEGFA(36), ANGPT2(69), mtDNA(70), and microRNA(71).

CONCLUSION

Severe injury or multiple trauma (the so-called “first hit”) evokes a SIRS in trauma patients. In uncomplicated cases, this response is temporary and predictable to a certain extent. If the initial hit, however, is big enough it may produce a SIRS. The following emergency damage-control surgery and later definitive surgical procedures (the “second hit”) may further exhaust the immune system potentially leading to immune paralysis causing the compensatory anti-inflammatory response syndrome. Several mechanisms contribute to the development of SIRS such as hormonal, metabolic, hemodynamic, immunological, cell-mediated, and ischemia/reperfusion processes (72).

The outcome following major trauma is thus determined by many factors of which sequence variation in the human genome may well be one such factor. A number of genes have been studied so far, but these studies are generally unique and numbers are often small. Outcome parameters of studies, as shown in this review, are sometimes different making pooling of results or comparison complicated. Nevertheless, some SNPs clearly appear to exert an effect on the outcome.

Identifying patients at risk of developing infectious complications may improve their outcome by targeted treatments such as antibiotic prophylaxis, substitution therapy, or plasma transfusions.

But unfortunately too little information is currently available to draw firm conclusions. Further research in this field is necessary. Because systemic response to trauma is a complex and polygenic phenotype, more genes will have to be studied in larger cohorts to determine their exact influence on outcome in severely injured patients. State-of-the-art techniques like exome sequencing and whole genome SNP arrays should be used in future studies to identify relevant sequence variations in other immune response genes and signalling pathways as well.

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Keywords:

Inflammatory response, injury; multiple organ dysfunction score, sepsis, single nucleotide polymorphism

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