Characteristics of eligible studies
Figure
1 shows the flow diagram detailing the process of trial identification and selection. Finally, 349 articles were eligible for inclusion in this analysis. The characteristics of the eligible studies are shown in Additional file
2: Table S1. Overall, data on 405 genetic variants of 172 distinct genes were available (Additional file
3: Table S2). The sample sizes in the included studies ranged from 42 to 18,358 (cases: 16–5468, median: 275). Approximately 95% of the eligible studies (331/349) were published after 2002 (with a steep positive trend over time; Additional file
4: Figure S1). With regard to ethnicity, 68% of the studies were in white populations. The majority of the studies (60%) were hospital-based case-control studies, and the remaining were population-based case-control studies. Data were also available from one GWAS [
15].
The types of variants were mainly SNPs (
n = 379, 94%), followed by insertion/deletions (
n = 17) and VNTRs (
n = 9). These genetic variants were located upstream of the gene (including the promoter region) (
n = 83), in the 5′UTR (
n = 15), in exons (
n = 113), in introns (
n = 149), in the 3′UTR (
n = 34), and downstream of the gene (
n = 11). Among the exonic SNPs, the functional effects were generally missense (
n = 96) and synonymous coding changes (
n = 12), with the remaining being frameshift, stop-gain, or splicing variants (
n = 5). The distribution of these variants across chromosomes is depicted in Additional file
5: Figure S2. Of note, most of the variants were located on chromosome 6 (
n = 48), none were on chromosome 21 and Y, and only 2 variants were in mitochondrial DNA.
The majority of candidate genes were PPRs (n = 22, 12.8%), cytokines (n = 39, 22.7%), and other immune-related genes. Based on the number of different independent studies of each variant (ranging from 1 to 41), the 5 most commonly studied variants were the following: TNFA rs1800629 (n = 41), LTA rs909253 (n = 32), TLR4rs4986790 (n = 28), IL6 rs1800795 (n = 25), and IL10 rs1800896 (n = 24). Based on the country/region of origin, most studies were performed in China (n = 82), the USA (n = 40), Germany (n = 33), and Spain (n = 22). Based on the number of subjects (cases plus controls) enrolled (ranging from 42 to 18,358, the median number being 720), the 5 most commonly studied variants were as follows: F5 rs6025 (n = 18,358 individuals), TNFA rs1800629 (n = 15,057 individuals), LTA rs909253 (n = 12,185 individuals), MBL2 A/O haplotype (n = 9066 individuals), and IL6 rs1800795 (n = 8630 individuals). TaqMan probes, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), allele-specific amplification, and sequencing were the most common methods used to determine the genotype distribution.
In total, 389 meta-analyses were performed for 76 variants of 44 genes, with at least 3 independent studies for each variant. The major results of the meta-analysis under three different genetic models are listed in Table
1 and Additional file
6: Table S3. Of the 389 meta-analyses, 204 were primary meta-analyses, and 185 were meta-analyses of subgroups defined by ethnicity (white (
n = 64) vs. Asian (
n = 28)) and age (adult (
n = 61) vs. pediatric (
n = 32)).
Table 1
Genetic variants nominally significantly associated with sepsis risk in meta-analyses
TLR1 | rs5743551 | 4 | G | 4 | 1224 | 943 | All/Adult | R | 1.52(1.16–2.00) | 0.002 | 0 | 0.54 | Moderate | BAA |
TLR1 | rs5743551 | 4 | G | 4 | 1224 | 943 | All/Adult | A | 1.17(1.02–1.34) | 0.02 | 0 | 0.42 | Strong | AAA |
TLR1 | rs5743551 | 4 | G | 3 | 978 | 492 | White | R | 1.78(1.18–2.69) | 0.006 | 0 | 0.59 | Moderate | BAA |
TLR1 | rs5743551 | 4 | G | 3 | 978 | 492 | White | A | 1.24(1.04–1.47) | 0.02 | 0 | 0.41 | Weak | BAC |
TLR2 | rs5743708 | 4 | A | 10 | 948 | 1573 | Adult | D | 1.75(1.11–2.75) | 0.02 | 30 | 0.19 | Moderate | BBA |
TLR2 | rs5743708 | 4 | A | 7 | 720 | 695 | Adult | A | 2.04(1.20–3.48) | 0.009 | 0 | 0.45 | Moderate | BAA |
TLR2 | rs5743708 | 4 | G | 4 | 308 | 1087 | Pediatric | D | 0.43(0.20–0.89) | 0.02 | 0 | 0.56 | Moderate | BAA |
TLR2 | rs5743708 | 4 | G | 4 | 308 | 1087 | Pediatric | A | 0.43(0.21–0.90) | 0.03 | 0 | 0.57 | Strong | AAA |
LBP | rs2232618 | 20 | C | 4 | 615 | 1267 | All | D | 1.93(1.49–2.48) | < 0.0001 | 0 | 0.41 | Moderate | BAA |
LBP | rs2232618 | 20 | C | 3 | 501 | 738 | All/Adult | A | 2.10(1.58–2.78) | < 0.0001 | 0 | 0.62 | Moderate | BAA |
RAGE | rs1800625 | 6 | T | 4 | 977 | 1339 | All | D | 0.59(0.48–0.73) | < 0.0001 | 0 | 0.69 | Strong | AAA |
RAGE | rs1800625 | 6 | T | 4 | 977 | 1339 | All | R | 0.47(0.24–0.96) | 0.04 | 0 | 0.79 | Strong | AAA |
RAGE | rs1800625 | 6 | T | 4 | 977 | 1339 | All | A | 0.61(0.51–0.74) | < 0.0001 | 0 | 0.78 | Strong | AAA |
RAGE | rs1800624 | 6 | T | 3 | 662 | 838 | All | A | 0.78(0.63–0.97) | 0.02 | 10 | 0.33 | Strong | AAA |
NOD2 | rs2066844 | 16 | T | 3 | 229 | 943 | All/White | D | 2.25(1.39–3.64) | 0.001 | 0 | 0.55 | Moderate | BAA |
NOD2 | rs2066847 | 16 | insC | 5 | 326 | 1629 | All/White | D | 2.37(1.49–3.75) | 0.0002 | 0 | 0.58 | Moderate | BAA |
MBL2 | A/O haplotype | 10 | O | 23 | 3549 | 5517 | All/White | D | 1.25(1.05–1.48) | 0.01 | 63 | < 0.001 | Weak | ACC |
MBL2 | A/O haplotype | 10 | O | 16 | 3353 | 4765 | All/White | A | 1.19(1.04–1.36) | 0.01 | 57 | 0.002 | Weak | ACC |
MBL2 | A/O haplotype | 10 | O | 7 | 307 | 960 | Pediatric | D | 1.61(1.23–2.12) | 0.0006 | 24 | 0.24 | Moderate | BAB |
MBL2 | A/O haplotype | 10 | O | 3 | 176 | 445 | Pediatric | A | 1.40(1.03–1.91) | 0.03 | 0 | 0.72 | Moderate | BAA |
TNFA | rs1799724 | 6 | T | 3 | 502 | 1373 | All/Adult | D | 1.29(1.01–1.64) | 0.04 | 0 | 0.761 | Weak | BAC |
TNFA | rs1800629 | 6 | A | 41 | 5540 | 9709 | All | D | 1.35(1.13–1.62) | 0.001 | 71 | < 0.001 | Weak | ACC |
TNFA | rs1800629 | 6 | A | 33 | 4859 | 8386 | All | R | 1.32(1.05–1.67) | 0.02 | 16 | 0.23 | Moderate | BAA |
TNFA | rs1800629 | 6 | A | 33 | 4859 | 8386 | All | A | 1.21(1.04–1.42) | 0.02 | 66 | < 0.001 | Weak | ACB |
TNFA | rs1800629 | 6 | A | 12 | 1241 | 1715 | Asian | D | 2.16(1.75–2.67) | < 0.0001 | 37 | 0.09 | Moderate | BBA |
TNFA | rs1800629 | 6 | A | 11 | 1209 | 1645 | Asian | R | 2.56(1.44–4.57) | 0.001 | 0 | 0.77 | Weak | CAC |
TNFA | rs1800629 | 6 | A | 11 | 1209 | 1645 | Asian | A | 1.99(1.64–2.42) | < 0.0001 | 30 | 0.16 | Moderate | ABA |
TNFA | rs1800629 | 6 | A | 30 | 4114 | 5983 | Adult | D | 1.51(1.20–1.90) | < 0.0001 | 74 | < 0.001 | Weak | ACC |
TNFA | rs1800629 | 6 | A | 25 | 3515 | 4751 | Adult | R | 1.49(1.12–1.97) | 0.005 | 17 | 0.24 | Moderate | BAA |
TNFA | rs1800629 | 6 | A | 25 | 3515 | 4751 | Adult | A | 1.30(1.06–1.61) | 0.01 | 70 | < 0.001 | Weak | ACA |
TNFA | rs361525 | 6 | A | 5 | 808 | 1457 | All/Adult | R | 4.88(2.19–10.87) | < 0.0001 | 0 | 0.85 | Weak | CAA |
TNFA | rs361525 | 6 | A | 4 | 745 | 903 | Asian | D | 2.05(1.06–3.96) | 0.03 | 65 | 0.04 | Weak | BCC |
TNFA | rs361525 | 6 | A | 4 | 745 | 903 | Asian | A | 1.79(1.39–2.30) | < 0.0001 | 18 | 0.3 | Moderate | BAA |
LTA | rs909253 | 6 | T | 30 | 4662 | 7473 | All | D | 0.83(0.71–0.97) | 0.02 | 64 | < 0.001 | Weak | ACA |
LTA | rs909253 | 6 | T | 27 | 4512 | 6649 | All | A | 0.87(0.79–0.97) | 0.01 | 58 | < 0.001 | Weak | ACA |
LTA | rs909253 | 6 | T | 8 | 946 | 1355 | Asian | R | 0.78(0.63–0.96) | 0.02 | 0 | 0.57 | Weak | BAC |
LTA | rs909253 | 6 | T | 6 | 846 | 1240 | Asian | A | 0.86(0.76–0.97) | 0.02 | 24 | 0.25 | Strong | AAA |
LTA | rs909253 | 6 | T | 27 | 4012 | 6659 | Adult | D | 0.79(0.67–0.94) | 0.007 | 65 | < 0.001 | Weak | ACA |
LTA | rs909253 | 6 | T | 26 | 3962 | 5953 | Adult | R | 0.85(0.75–0.96) | 0.008 | 4 | 0.41 | Strong | AAA |
LTA | rs909253 | 6 | T | 24 | 3862 | 5835 | Adult | A | 0.84(0.75–0.94) | 0.002 | 55 | 0.001 | Weak | ACA |
IL1B | rs143634 | 2 | C | 7 | 1095 | 1168 | All | R | 0.53(0.34–0.82) | 0.004 | 0 | 0.84 | Moderate | AAB |
IL1B | rs143634 | 2 | C | 5 | 969 | 1004 | White | R | 0.51(0.32–0.80) | 0.003 | 0 | 0.82 | Strong | AAA |
IL1B | rs143634 | 2 | C | 5 | 879 | 744 | Adult | R | 0.54(0.33–0.90) | 0.02 | 0 | 0.7 | Strong | AAA |
IL6 | rs1800796 | 7 | G | 3 | 298 | 341 | Asian | R | 0.53(0.29–0.96) | 0.04 | 0 | 0.99 | Weak | BAC |
IL6 | rs1800796 | 7 | G | 3 | 478 | 364 | Adult | D | 0.55(0.42–0.74) | < 0.0001 | 63 | 0.07 | Weak | BCA |
IL6 | rs1800795 | 7 | C | 17 | 1903 | 4573 | All/White | A | 1.17(1.01–1.35) | 0.03 | 61 | 0.001 | Weak | ACA |
IL6 | rs1800795 | 7 | C | 11 | 1452 | 2786 | Adult | R | 1.43(1.19–1.73) | < 0.0001 | 42 | 0.06 | Weak | BBC |
IL6 | rs1800795 | 7 | C | 10 | 1405 | 2723 | Adult | A | 1.24(1.06–1.46) | 0.008 | 53 | 0.02 | Weak | ACA |
IL8 | rs4073 | 4 | T | 11 | 1314 | 1605 | All/adult | D | 0.71(0.60–0.84) | < 0.0001 | 43 | 0.06 | Moderate | ABA |
IL8 | rs4073 | 4 | T | 10 | 1224 | 1515 | All/adult | R | 0.71(0.52–0.97) | 0.03 | 47 | 0.05 | Moderate | ABA |
IL8 | rs4073 | 4 | T | 10 | 1224 | 1515 | All/adult | A | 0.76(0.63–0.92) | 0.004 | 60 | 0.008 | Weak | ACA |
IL8 | rs4073 | 4 | T | 7 | 830 | 1074 | White | D | 0.68(0.56–0.84) | 0.0002 | 45 | 0.09 | Moderate | BBA |
IL8 | rs4073 | 4 | T | 7 | 830 | 1074 | White | A | 0.74(0.58–0.95) | 0.02 | 66 | 0.007 | Weak | ACA |
IL10 | rs1800871 | 1 | T | 6 | 686 | 764 | Asian | R | 1.35(1.03–1.76) | 0.03 | 37 | 0.16 | Moderate | BBA |
IFNG | rs2430561 | 12 | T | 5 | 715 | 759 | All/Adult | D | 1.34(1.07–1.68) | 0.01 | 46 | 0.11 | Moderate | ABA |
CXCL1 | rs1429638 | 4 | A | 3 | 589 | 1108 | All/Asian/Adult | R | 0.68(0.56–0.83) | < 0.0001 | 0 | 0.84 | Moderate | BAA |
CXCL1 | rs1429638 | 4 | A | 3 | 589 | 1108 | All/Asian/Adult | A | 0.75(0.64–0.88) | < 0.0001 | 0 | 0.86 | Moderate | AAB |
CXCL12 | rs266087 | 10 | A | 3 | 542 | 1006 | All/Asian/Adult | R | 0.75(0.57–0.99) | 0.04 | 58 | 0.09 | Weak | ACA |
CXCL12 | rs2297630 | 10 | A | 3 | 589 | 1109 | All/Asian/Adult | R | 0.63(0.50–0.79) | < 0.0001 | 0 | 0.9 | Moderate | BAB |
CXCL12 | rs2297630 | 10 | A | 3 | 589 | 1109 | All/Asian/Adult | A | 0.67(0.54–0.82) | < 0.0001 | 0 | 0.89 | Moderate | BAA |
MIF | rs755622 | 22 | G | 4 | 408 | 399 | All | R | 0.42(0.22–0.79) | 0.007 | 52 | 0.1 | Weak | BCC |
FCGR2A | rs1801274 | 1 | G | 8 | 754 | 1307 | All/White | R | 1.65(1.08–2.53) | 0.02 | 68 | 0.003 | Weak | BCC |
FCGR2A | rs1801274 | 1 | G | 8 | 754 | 1307 | All/White | A | 1.25(1.09–1.44) | 0.001 | 44 | 0.09 | Moderate | ABA |
PAI-1 | rs1799768 | 7 | 4G | 11 | 1962 | 1340 | All/White | R | 1.50(1.09–2.06) | 0.01 | 69 | 0.0004 | Weak | BCC |
PAI-1 | rs1799768 | 7 | 4G | 10 | 1277 | 1275 | All/White | A | 1.32(1.01–1.72) | 0.04 | 80 | < 0.0001 | Weak | ACC |
PAI-1 | rs1799768 | 7 | 4G | 4 | 563 | 603 | Pediatric | A | 1.37(1.02–1.85) | 0.04 | 65 | 0.03 | Weak | ACC |
ACE | rs4646994 | 17 | ins | 9 | 1139 | 3107 | All | R | 0.79(0.67–0.92) | 0.003 | 43 | 0.08 | Moderate | ABA |
ACE | rs4646994 | 17 | ins | 4 | 534 | 781 | Adult | R | 0.73(0.58–0.92) | 0.008 | 0 | 0.44 | Moderate | BAA |
ACE | rs4646994 | 17 | ins | 4 | 534 | 781 | Adult | A | 0.81(0.69–0.94) | 0.008 | 43 | 0.15 | Moderate | ABA |
LCE4A | rs4845320 | 1 | C | 3 | 320 | 240 | All | D | 2.75(1.36–5.57) | 0.005 | 0 | 0.47 | Weak | CAA |
LCE4A | rs4845320 | 1 | C | 3 | 320 | 240 | All | A | 2.77(1.41–5.44) | 0.003 | 12 | 0.32 | Weak | CAA |
TAGAP | rs3127214 | 6 | T | 3 | 317 | 239 | All | D | 1.84(1.07–3.17) | 0.03 | 15 | 0.31 | Weak | CAA |
TAGAP | rs3127214 | 6 | T | 3 | 317 | 239 | All | A | 2.01(1.20–3.36) | 0.008 | 21 | 0.28 | Weak | CAA |
VDR | rs2228570 | 12 | T | 4 | 240 | 244 | All | D | 2.94(1.85–4.71) | < 0.0001 | 0 | 0.85 | Moderate | BAA |
VDR | rs2228570 | 12 | T | 3 | 180 | 184 | White | D | 3.15(1.87–5.31) | < 0.0001 | 0 | 0.78 | Moderate | BAA |
VDR | rs2228570 | 12 | T | 3 | 180 | 184 | White | R | 2.96(1.18–4.92) | < 0.0001 | 31 | 0.24 | Weak | CBA |
VDR | rs2228570 | 12 | T | 3 | 200 | 204 | Adult | D | 2.95(1.85–4.71) | < 0.0001 | 0 | 0.69 | Weak | BAC |
MIR608 | rs4919510 | 5 | C | 3 | 502 | 766 | All/Asian/Adult | D | 1.82(1.39–2.38) | < 0.0001 | 0 | 0.85 | Moderate | BAA |
MIR608 | rs4919510 | 5 | C | 3 | 502 | 766 | All/Asian/Adult | R | 1.34(1.03–1.75) | 0.03 | 0 | 0.79 | Moderate | BAA |
MIR608 | rs4919510 | 5 | C | 3 | 502 | 766 | All/Asian/Adult | A | 1.39(1.19–1.63) | < 0.0001 | 0 | 0.81 | Strong | AAA |
Of the 204 primary meta-analyses performed, nominally significant associations (P < 0.05) with the risk of sepsis were found with 26 (34%) variants of 21 genes for at least one genetic model containing TLR1 rs5743551-7202A/G; LBP rs2232618 Phe436Leu; the MBL2 A/O haplotype; RAGE rs1800625-429 T/C and rs1800624-374 T/A; NOD2 rs2066844 Arg702Trp and rs2066847 Leu1007Pro; TNFA rs1799724-857C/T, rs1800629-308G/A, and rs361525-238G/A; LTA rs909253+252 T/C; IL1B rs143634+3594C/T; IL6 rs1800795-174G/C; IL8 rs4073-251 T/A; IFNG rs2430561+874A/T; CXCL1 rs1429638A/C; CXCL12 rs266087A/G and rs2297630A/G; MIF rs755622-173G/C; FCGR2A rs1801274 His131Arg; PAI-1 rs1799768-6755G/4G; ACE rs4646994ins/del; LCE4A rs4845320A/C; TAGAP rs3127214C/T; VDR rs2228570 Met1Thr; and miR-608 rs4919510G/C. The 185 subgroup meta-analyses by ethnicity and age revealed three additive polymorphisms (TLR2 rs5743708 Arg753Gln, IL6 rs1800796-572G/C, and IL10 rs1800896-1082A/G) that were significantly associated with the risk of sepsis. Strong associations with sepsis (ORs ≥ 1.5 or ≤ 0.67) were detected in 14 variants. Moderate associations with sepsis (ORs 1.5–1.15 or 0.67–0.87) were found for the remaining 15 variants. Ten of the 29 positive variants showed a highly significant association with sepsis risk, with p < 0.001; 11 showed an association with sepsis risk with p = 0.001–0.01, and the remaining 8 had p < 0.05.
Of the 389 meta-analyses of all available data, 154 (39.6%) had no or little heterogeneity (I2 < 25%), 92 (23.7%) had a moderate level of heterogeneity (25% < I2 < 50%), and 143 (36.7%) had a high degree of heterogeneity (I2 > 50%). The proportion of studies with a high degree of heterogeneity was significantly lower for the 29 positive variants than the remaining 47variants (30.9% vs. 39.5%, Fisher’s exact p < 0.05).
To assess the cumulative epidemiologic evidence for the 29 positive variants identified through the primary and subgroup analyses, the Venice criteria were applied. According to the Venice criteria, A grades were given to 37, 45, and 58 meta-analyses for the amount of evidence, replication of association, and protection from bias, respectively. B grades were given to 36, 13, and 5 meta-analyses for the same categories, respectively. C grades were given to 7, 22, and 17 meta-analyses for these three criteria, respectively. Next, strong, moderate, and weak levels of evidence of a significant association with sepsis risk were assigned to 4 (TLR1 rs5743551-7202A/G, RAGE rs1800625-429 T/C and rs1800624-374 T/A, and miR-608 rs4919510G/C), 14, and 11 variants, respectively. The details of the nominally significant associations found in the meta-analysis are discussed below.
Polymorphisms in PRRs
Toll-like receptors (TLRs) are a crucial family of pathogen-recognition receptors (PRRs) that provide a major mechanism for innate immune cells to recognize and respond to pathogens [
16]. TLR1/2 is responsible for recognizing cell wall components of gram-positive bacteria (lipopeptides, peptidoglycan, and lipoteichoic acid). TLR4 is responsible for recognizing the lipopolysaccharide of gram-negative bacteria. Increasing evidence indicates that polymorphisms of TLR genes influence susceptibility to various infectious diseases, including sepsis [
6]. According to the primary meta-analysis, four studies (including 1224 cases and 943 controls) were performed to determine the association between TLR1rs5743551-7202A/G and the risk of sepsis. There was a significantly increased risk of sepsis under the recessive (OR = 1.52, 95% CI = 1.16–2.00,
P = 0.002) and allelic models (OR = 1.17, 95% CI = 1.02–1.34,
P = 0.02). When subgroups were considered, data from three white populations revealed more significant associations (OR = 1.78, 95% CI = 1.18–2.69,
P = 0.006 for the recessive model and OR = 1.24, 95% CI = 1.04–1.47,
P = 0.02 for the allelic model). However, the level of evidence was intermediate due to the study sample size. For rs5743708 Arg753Gln in the TLR2 gene, there was no significant association found in the overall analysis of 14 studies. However, the association between Arg753Gln and the risk of sepsis was significant in the adult population (OR = 1.75, 95% CI = 1.11–2.75,
P = 0.02 for the dominant model and OR = 2.04, 95% CI = 1.20–3.48,
P = 0.009 for the allelic model). In contrast, there was a marginally significantly decreased risk of sepsis associated with Arg753Gln in pediatric studies (OR = 0.43, 95% CI = 0.20–0.89,
P = 0.02 for the dominant model and OR = 0.43, 95% CI = 0.21–0.90,
P = 0.03 for the allelic model), which may be due to differences between the adult and pediatric populations.
The lipopolysaccharide-binding protein (LBP) is an enhancer of the host response to lipopolysaccharides that acts by facilitating the transfer of lipopolysaccharides to CD14 membrane-bound TLRs that ultimately activate signaling transduction pathways and the production of cytokines [
17]. The primary meta-analysis of LBP rs2232618 Phe436Leu included four studies (615 cases and 1267 controls). There was a significantly increased risk of sepsis associated with this variant in the dominant model (OR = 1.93, 95% CI = 1.49–2.48,
P < 0.0001). Furthermore, through the subgroup analysis, strong associations were found in three adult populations (OR = 2.10, 95% CI = 1.58–2.78,
P < 0.0001 for the allelic model).
The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin protein family of cell surface molecules and has been shown to bind a diverse set of ligands, and this binding leads to the activation of several pro-inflammatory signaling pathways [
18]. Two variants located in the promoter region of RAGE were significantly associated with the risk of sepsis. In total, four studies on RAGE rs1800625-429 T/C were conducted by Zeng et al [
19] and Shao et al [
20]. The primary meta-analysis of the four studies showed significant associations between the risk of sepsis and RAGE rs1800625-429 T/C in all three genetic models (OR = 0.59, 95% CI = 0.45–0.73,
P < 0.001 for the dominant model, OR = 0.47, 95%CI = 0.24–0.96,
P = 0.04 for the recessive model, and OR = 0.61, 95%CI = 0.51–0.74,
P < 0.0001 for the allelic model) with a high level of evidence. Moreover, in vitro LPS-induced RAGE expression and TNF-α production were significantly lower in the variant C allele patients than in those with the wild-type T allele [
21]. With regard to another RAGE variant, rs1800624-374 T/A, a significant association was observed only in the allelic model (OR = 0.78, 95% CI = 0.63–0.97,
P = 0.02) in three studies.
NOD2/CARD15 is a member of a superfamily of genes, the NBS-LRR proteins (for nucleotide-binding sites and leucine-rich repeats), which are involved in the intracellular recognition of microbes and their products [
22]. Three studies (including 229 cases and 943 controls) determined the association between NOD2 rs2066844 Arg702Trp and the risk of sepsis. There was an increased risk of sepsis associated with NOD2 rs2066844 Arg702Trp in the dominant model (OR = 2.25, 95% CI = 1.39–3.64,
P = 0.001). For an additional variant, rs2066847 Leu1007Pro, five studies (326 cases and 1629controls) were included in our meta-analysis. A significant association between rs2066847 Leu1007Pro and the risk of sepsis was confirmed in the dominant model (OR = 2.37, 95% CI = 1.49–3.75,
P = 0.0002). Mannose-binding lectin (MBL) is a soluble pattern recognition molecule that binds microorganisms, thereby activating the lectin or additional complement pathways [
23]. Three polymorphisms in the MBL2 gene result in three variant structural alleles (B, C, and D), which are referred to collectively as O, while A is the wild-type allele. Twenty-three studies analyzed the MBL2 A/O haplotype. The overall results showed a significant association between MBL2 A/O and the risk of sepsis (OR = 1.25, 95% CI = 1.05–1.48,
P = 0.01 for the dominant model; OR = 1.19, 95% CI = 1.04–1.36, P = 0.01 for the allelic model). The significant association was stronger when the meta-analysis was restricted to pediatric sepsis (OR = 161, 95% CI = 1.23–2.12,
P = 0.0006 for the dominant model; OR = 1.40, 95% CI = 1.03–1.91,
P = 0.03 for the allelic model).
Polymorphisms in cytokines
Cytokines released from immune cells are major players in the inflammatory response to infection. Primary pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1), induce secondary pro- and anti-inflammatory mediators such as IL-6 and IL-10 [
24]. Genetic variants of these cytokines have been shown to play key roles in determining susceptibility to sepsis [
6].
Forty-one studies investigated the association between TNFA rs1800629-308G/A and the risk of sepsis (5540 cases and 9709 controls). In the primary meta-analysis, significant associations between the -308G/A polymorphism and the risk of sepsis were found under all three genetic models. Furthermore, through stratified analysis according to ethnicity and age, the associations were more significant in the adult and Asian populations than in the overall populations, suggesting that this SNP might be specifically linked to the adult and Asian populations. In our study, data on the second TNFA variant (rs1799724-857C/T) from three studies (502 cases and 1373 controls) were meta-analyzed. The overall results showed that there was a significant association between this variant and the risk of sepsis under the dominant model (OR = 1.29, 95% CI = 1.01–1.64, P = 0.04) with a low level of evidence. Associations between a third TNFA variant (rs361525-238G/A) and the risk of sepsis were investigated in nine studies. The primary meta-analysis indicated a highly significant association between the TNFA rs361525-238G/A variant and the risk of sepsis under the recessive model (OR = 4.88, 95% CI = 2.19–10.87, P < 0.0001). Furthermore, in the analysis stratified by ethnicity, only Asian individuals with this variant had a higher risk of sepsis than individuals with the wild-type allele under the dominant and allelic genetic models. The LTA rs909253+252 T/C variant was analyzed in 32 studies with 4762 cases and 7588 controls and was significantly associated with the risk of sepsis under the dominant and allelic models; however, there was a low level of evidence due to between-study heterogeneity. The associations were also significant in the analyses stratified by ethnicity and age.
Seven studies investigated the IL1B rs143634+3594C/T variant. The result of the overall comparison suggested that the association of this variant with sepsis susceptibility was significant under the recessive genetic model (OR = 0.53, 95% CI = 0.34–0.82, P = 0.034). Meanwhile, the stratified analysis showed that there was a significant association between this variant and the risk of sepsis in the white population (OR = 0.51, 95% CI = 0.32–0.80, P = 0.003 for the recessive model) and the adult population (OR = 0.54, 95% CI = 0.33–0.90, P = 0.02 for the recessive model). With regard to rs1800796-572G/C, which is located in the IL-6 promoter region, there was no significant association with the risk of sepsis in the primary meta-analysis. However, three studies in Asian populations indicated a significant association between -572G/C and the risk of sepsis (OR = 0.53, 95% CI = 0.29–0.96, P = 0.04 for the recessive model). In the adult population, the association between this variant and the risk of sepsis was also confirmed under the dominant model. A significantly increased risk of sepsis was found to be associated with another variant, rs1800795-174G/C, in the allelic model (OR = 1.17, 95% CI = 1.01–1.35, P = 0.03) through the primary meta-analysis of 17 studies and the subgroup analysis of adults (OR = 1.43, 95% CI = 1.19–1.73, P < 0.0001 for the recessive model and OR = 1.24, 95% CI = 1.06–1.46, P = 0.008 for the allelic model). For IL-8rs4073-251 T/A, the association between the variant and the risk of sepsis were confirmed under all genetic models in the primary analysis and the subgroup analysis according to ethnicity. For the IL10 rs1800871-819C/T variant, a significant association with the susceptibility to sepsis was only confirmed in the Asian population (OR = 1.35, 95% CI = 1.03–1.76, P = 0.03 for the recessive model).
Five studies of the IFNG rs2430561-874A/T variant were included in the meta-analysis. The results of the overall comparison suggested that the association of this variant with the risk of sepsis was significant under the dominant genetic model (OR = 1.34, 95% CI = 1.07–1.68, P = 0.01). The rs1429638A/C variant of the CXCL1 gene and the rs2297630A/G and rs266087A/G polymorphisms of the CXCL12 gene were found to be associated with altered susceptibility to traumatic sepsis in Wang’s study (accepted by Journal of Trauma Acute Care Surg). Four studies of MIF-173G/C were included in the meta-analysis. A significant association between this variant and the susceptibility to sepsis was found under the recessive model (OR = 0.42, 95% CI = 0.22–0.79, P = 0.007).
Polymorphisms in other genes
Eleven studies determined the association between PAI-1-675 5G/4G and the risk of sepsis in white populations. There was a significantly increased risk of sepsis associated with this variant in the recessive model (OR = 1.50, 95% CI = 1.09–2.06, P = 0.01) and the allelic model (OR = 1.32, 95% CI = 1.01–1.72, P = 0.04). Furthermore, in the subgroup analysis stratified by age, a significant association was also found in the pediatric population (OR = 1.37, 95% CI = 1.02–1.85, P = 0.04 for allelic effect). The rs4646994ins/del polymorphism in the ACE gene was significantly associated with the risk of sepsis in the recessive model (OR = 0.79, 95% CI = 0.67–0.92, P = 0.003) according to a primary meta-analysis of nine studies; this association was stronger in the adult population than in the pediatric population. Three studies evaluated the association between the LCE4A rs4845320 polymorphism and the risk of sepsis. There were significant associations between this variant and an increased risk of sepsis under the dominant (OR = 2.75, 95% CI = 1.36–5.57, P = 0.005) and allelic models (OR = 2.77, 95% CI = 1.41–5.44, P = 0.003). For the TAGAP rs3127214C/T variant, there was a significantly increased risk of sepsis under the dominant (OR = 1.84, 95% CI = 1.07–3.17, P = 0.03) and allelic models (OR = 2.01, 95% CI = 1.20–3.36, P = 0.008). For the VDR rs2228570 Met1Thr variant, a statistically significant association with an increased risk of sepsis was found under the dominant model (OR = 2.94, 95% CI = 1.85–4.71, p < 0.0001) according to the primary meta-analysis of four studies; this association was also identified in the white and adult populations in the subgroup analyses. Finally, three studies evaluated the association between the miR-608 rs4919510G/C variant and the risk of sepsis, and the meta-analysis results showed that the association was significant under all three genetic models.
Polymorphisms not included in the meta-analysis
In this study, 329 polymorphisms could not be meta-analyzed because fewer than three studies investigated them. We systematically reviewed the associations between these polymorphisms and the risk of sepsis, and nominally statistically significant associations with the susceptibility to sepsis were found for 63 polymorphisms in 48 genes (
p < 0.05) (Additional file
7: Table S4). The samples sizes ranged from 80 to 1895. These functional genes encoded PRRs (
n = 10), signaling molecules (
n = 5), transcription factors (
n = 3), cytokines (
n = 11), and other molecules (
n = 19). Furthermore, most of these genetic variants were located in the promoter region (
n = 16), introns (
n = 23), and 3′UTR (
n = 7); 13 variants were missense. Furthermore, some genetic variants (
n = 10) were also confirmed to be functional variants. For example, the TLR4 rs10116253-2242C allele enhances the transcriptional activities and expression of TLR4, and trauma patients with the variant C allele have a greater capacity to produce the pro-inflammatory cytokines TNF-α and IL-6 than those with other alleles [
26]. After exposure to LPS, TOLLIP expression levels from homozygotes for the rs5743867C allele were significantly higher than those from other genotypes. Moreover, the concentrations of TNF-α and IL-6 were significantly lower in the culture supernatants from subjects with the rs5743867CC genotype than in those from subjects with the CT and TT genotypes [
27]. Genetic variants in the miRNA region also affected the risk of sepsis. Patients with the rs2910164 GG/GC genotypes had higher levels of mature miR-146a than those with the rs2910164 CC genotype, which was related to the excessive inflammation in patients with severe sepsis [
28]. Therefore, further studies are needed to investigate the functional roles of these polymorphisms in the pathophysiology of sepsis and to validate these encouraging results in independent cohorts.