SERPINE1 rs1799768 polymorphism contributes to sepsis risk and mortality

Abstract

Introduction:

The present meta-analysis aimed to investigate whether there is an association between SERPINE1 rs1799768 polymorphism and sepsis risk and mortality.

Materials and methods:

Published reports were searched in PubMed, PubMed Central, Gene, PubChem and Google Scholar. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were assessed in a random-effects model.

Results:

The results of the overall meta-analysis indicated that an increased sepsis risk was evidently associated with SERPINE1 rs1799768 polymorphism (OR = 1.30; 95% CI 1.08–1.56; p = 0.006). When studies were stratified by ethnicity, no significant association was observed between SERPINE1 rs1799768 polymorphism and sepsis risk in the Asian group. As for the Caucasian population, overall OR was 1.24 (95% CI 1.02–1.51; p = 0.03). The results of the overall meta-analysis indicated that an increased sepsis mortality risk was evidently associated with SERPINE1 rs1799768 polymorphism (OR = 1.73; 95% CI 1.31–2.28; p < 0.0001). When studies were stratified by ethnicity, significant association was observed between SERPINE1 rs1799768 polymorphism and sepsis risk mortality in the Asian group and the Caucasian population.

Conclusions:

In conclusion, the meta-analysis suggests that there are significant associations between SERPINE1 rs1799768 polymorphism and risk of sepsis and sepsis mortality.

Keywords

Sepsis meta-analysis polymorphism

Introduction

Sepsis is a life-threatening condition that arises when the body’s response to an infection injures its own tissues and organs.¹ Despite advances in antibiotic therapy and modern life support, the fatality rate of patients with sepsis has remained as high as 30%–60% worldwide.² Early identification of patients at high risk of dying from sepsis may help initiate rapid and appropriate therapeutic interventions and may have a great impact on sepsis-related morbidity and mortality.

Serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1 (SERPINE1) is a single-chain, glycosylated protein composed of three β-sheets (A, B, C) and nine α-helical domains (A–I) with a strained reactive center loop (RCL) positioned in the carboxy terminus. SERPINE1 is a major inhibitor of urokinase (uPA) and tissue-type (tPA) plasminogen activators. By limiting the conversion of plasminogen to plasmin, SERPINE1 attenuates fibrinolysis, promotes extracellular matrix (ECM) accumulation and contributes to both physiologic and pathophysiologic stromal remodeling.³ Sepsis increases bacterial content in all fluids and organs and increases SERPINE1 messenger RNA and enzymatic activity in the lung and liver.⁴ A single measurement of SERPINE1 activity could identify patients with ongoing severe coagulopathy early in the course of sepsis.⁵

During the past decade, various studies have been carried out to examine whether there is an association between SERPINE1 rs1799768 polymorphism and sepsis risk and mortality, but the results from these studies were controversial.^6
–21 In the present study, we performed a meta-analysis that covers 16 studies to clarify whether there is an association between SERPINE1 rs1799768 polymorphism and sepsis.

Methods

Publication search

Published reports were searched in the National Center for Biotechnology Information (NCBI) Global Cross-database, including PubMed, PubMed Central, Gene, PubChem and Google Scholar, with the following key words: “SERPINE1,” “PAI-1,” “plasminogen activator inhibitor-1” and “sepsis.” Publication language was not restricted in this search. Reference lists of articles retained for review were examined manually to further identify potentially relevant reports.

Inclusion and exclusion criteria

Abstracts of all retrieved studies were reviewed. Studies that met the following criteria were included: (1) addressing the association between SERPINE1 rs1799768 polymorphism and sepsis risk and mortality; (2) having a case-control or cohort design; and (3) providing sufficient data for calculating odds ratios (ORs) and 95% confidence intervals (CI). Studies were excluded if any of the following facts existed: (1) books and other literature that were not case-control or cohort studies; (2) studies whose primary goal is not the investigation of the association between SERPINE1 rs1799768 polymorphism and sepsis risk and mortality; or (3) articles without control group information or without the retrievable original data. When analyzing sepsis risk, the control group comprised health participants. When analyzing sepsis mortality, the control group comprised the patients who died from sepsis. When the studies that were covered in different articles overlapped, only the ones showing the most extensive results were included in this study.

Data extraction

Two investigators independently extracted the data from each eligible paper. Disagreements were resolved by discussion and a consensus was reached on all items between the two investigators. The following data were collected from each study: first author, year of publication, study design and ethnicity of the participants, and genetic numbers of cases and controls.

Statistical analysis

Statistical analysis was conducted using STATA 12.0 (Stata Corp LP, College Station, TX, USA). A p value < 0.05 was considered as statistically significant. In addition to the overall database, two ethnic subgroups were created that covered all studies with Caucasians and Asians. ORs were calculated with 95% CIs in the recessive model. The heterogeneity between studies was tested using the I² index (I² < 25%, no heterogeneity; I² = 25%–50%, moderate heterogeneity; I² > 50%, large or extreme heterogeneity). Forest plots were generated to summarize the results. Publication bias was evaluated with Begg’s funnel plots based on the analysis results and database size. Moreover, Egger’s test was also completed for each dataset for a better analysis on the publication bias.

Results

Study characteristics

A total of 320 papers were retrieved after the first search, and 304 of them were excluded from the analysis. As a result, 16 studies that met the inclusion criteria were included in the final meta-analysis. The data collection flowchart is shown in Figure 1. The characteristics of all studies are included in Table 1.

Figure 1.

Flowchart of study identification.

Table 1.

Characteristics of the included studies.

Author/year	Study design	Ethnicity	No. of participants	Sepsis			Control
Author/year	Study design	Ethnicity	No. of participants	4G/4G	4G/5G	5G/5G	4G/4G	4G/5G	5G/5G
Hermans/1999⁶	Case-control	Caucasian	380	40	85	29	59	114	53
Westendorp/1999⁷	Case-control	Caucasian	216	31	45	9	35	69	27
Menges/2001⁸	Case-control	Caucasian	61	16	11	2	13	14	5
Haralambous/2003⁹	Case-control	Caucasian	385	78	108	44	48	74	33
Geishofer/2005¹⁰	Case-control	Caucasian	453	45	67	25	91	149	76
Zhan/2005¹¹	Case-control	Asian	189	39	37	13	25	50	25
Sipahi/2006¹²	Case-control	Caucasian	155	23	14	5	28	57	28
García-Segarra/2007¹³	Case-control	Caucasian	245	37	85	43	22	42	16
Jessen/2007¹⁴	Cohort	Caucasian	317	90	183	44	NA	NA	NA
Wei/2008¹⁵	Case-control	Asian	329	47	68	33	50	91	40
Henckaerts/2009¹⁶	Case-control	Caucasian	950	140	177	78	162	280	113
Perés Wingeyer/2009¹⁷	Case-control	Caucasian	302	42	54	70	33	64	39
Lorente/2009¹⁸	Cohort	Caucasian	122	23	60	39	NA	NA	NA
Madách/2010¹⁹	Cohort	Caucasian	207	63	105	39	NA	NA	NA
Perés Wingeyer/2012²⁰	Case-control	Caucasian	380	41	58	67	49	99	66
Lorente/2015²¹	Cohort	Caucasian	260	82	126	52	NA	NA	NA

NA: not available.

Quantitative data synthesis

Figure 2.

Meta-analysis of the association between SERPINE1 rs1799768 polymorphism and sepsis risk.

Table 2.

Risk of sepsis.

Study	OR (95% CI)	p value	I² (%)
Overall	1.30 (1.08–1.56)	0.006	37.0
Caucasian	1.24 (1.02–1.51)	0.03	34.0
Asian	1.64 (0.87–3.09)	0.13	63

OR: odds ratio; CI: confidence interval.

Figure 3.

Funnel plot of the association between SERPINE1 rs1799768 polymorphism and sepsis risk.

The results of the overall meta-analysis indicated that an increased sepsis mortality risk was evidently associated with SERPINE1 rs1799768 polymorphism (OR = 1.73; 95% CI 1.31–2.28; p < 0.0001; Figure 4). When studies were stratified by ethnicity, a significant association was observed between SERPINE1 rs1799768 polymorphism and sepsis risk mortality in the Asian group (OR = 2.89; 95% CI 1.37–6.12; p = 0.006) and the Caucasian population (OR = 1.61; 95% CI 1.37–2.15; p = 0.001). Results are shown in Table 3. No significant publication bias was found (Figure 5).

Figure 4.

Meta-analysis of the association between SERPINE1 rs1799768 polymorphism and sepsis mortality.

Table 3.

Risk of mortality.

Study	OR (95% CI)	p value	I² (%)
Overall	1.73 (1.31–2.28)	<0.0001	46.0
Caucasian	1.61 (1.37–2.15)	0.001	43.0
Asian	2.89 (1.37–6.12)	0.006	8.0

OR: odds ratio; CI: confidence interval.

Figure 5.

Funnel plot of the association between SERPINE1 rs1799768 polymorphism and sepsis mortality.

Discussion

Elevated SERPINE1 levels are, in fact, a significant causative factor in the pathophysiology of septic coagulopathy, particularly in the context of increased tissue transforming growth factor beta 1 (TGF-β1) levels.²² SERPINE1 rs1799768 polymorphism is a major genetic determinant of plasma SERPINE1 levels.²³ Recently, many studies have investigated the association between SERPINE1 rs1799768 polymorphism and the risk of sepsis, but the results were not consistent. Thus this meta-analysis aimed for better insight regarding the association between this single-nucleotide polymorphism (SNP) and sepsis risk. After a comprehensive search and careful selection, 16 studies were critically reviewed and included in our analysis. The result of this meta-analysis shows that there is a significant association between SERPINE1 rs1799768 polymorphism and increased risk of sepsis and sepsis mortality.

When studies were stratified by ethnicity, no significant association was observed between SERPINE1 rs1799768 polymorphism and sepsis risk in the Asian group. Only two studies included Asians. Thus small sample size and limited number of studies for this ethnic subgroup in this meta-analysis could be the major factors that contribute to the discrepancies between overall and subgroup analysis. A note of caution should be sounded when interpreting our findings, especially in subgroup analyses in light of the limited sample sizes involved. This is well exemplified in the comparison of the small and large studies, where significance was attained only in the small studies. It has been suggested that to achieve satisfactory power, at least 1000 subgroups are required and often more, depending on the prevalence of the examined polymorphism.²⁴ We therefore must regard our findings as preliminary, which should be viewed as hypothesis-generating and a call for validation in future large and well-design studies.

There were several possible limitations of this meta-analysis. First, this meta-analysis is based on the summaries of case-control and cohort studies, which rarely establish causal relationship, and it is encouraging to incorporate the concept of Mendelian randomization into observational association studies.²⁵ Second, only one polymorphism in the SERPINE1 gene was evaluated in this study, which might not be sufficient to address the complex genetic architecture of sepsis. Third, only published articles written in the English language were retrieved for inclusion and some unpublished small and/or negative articles might be missing, leading to the potential existence of publication bias. Fourth, it is essential to examine gene-environment and gene-gene interactions at the level both of individual studies and meta-analysis. To achieve this goal, one usually needs to perform a meta-analysis of individual participant data, which is not always practical for the majority of published meta-analyses.

In conclusion, the result of our meta-analysis suggests that there are significant associations between SERPINE1 rs1799768 polymorphism and the risk of sepsis and sepsis mortality.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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