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Table 2 Genetic-association studies on outcome and phenotype of pneumococcal disease

From: Host genetic variability and pneumococcal disease: a systematic review and meta-analysis

Name, year,
PMID
Candidate gene Genetic variants* Country of origin (ethnicity) Patient groups N Patients- Selection criteria Outcome measures -(% mortality, adverse events) Results – Gene, genetic variation, risk allele/genotype: p-value, OR (95% CI)
Pathogen recognition receptor signalling pathways
Van Well, 2012, [53] TLR2 TLR4 TLR9 NOD1 NOD2 CASP1 TRAIL 11 variants Netherlands
(white)
Children with BM 66 CSF culture Hearing loss (21%) - TLR9 rs5743836 TC and CC genotypes: p  =  0.023, OR 2.5 (1.1–5.4) and p  =  0.017, OR 5.0, (1.4–17.4)Combined carriership:
- TLR2 rs5743708 and TLR4 rs4986790 AG genotype: p   =  0.03, OR 13.9 (1.3–147)- TLR4 rs4986790 and TLR9 rs5743836 mutant alleles: p  =  0.003, OR 6.0 (1.7–21.3)
Garnacho-Montero, 2012, [50] TLR2 TLR4 rs5743708
rs4986790
rs4986791
Spain
(white)
Adults with sepsis 117 Sterile site and BAL/tracheal aspirate culture Septic shock (34%)
In-hospital mortality (18.8%)
90 day mortality (21.4%)
NS
Carrasco-Colom, 2015, [65] IRAK4
IRAK1 IRAKM MYD88
10 variants Spain
(mixed, 92% white)
Children with IPD and SIRS 60 Sterile site culture or PCR Pleuro-pneumonia (7%)
Sequelae (33%)
Mortality (3%)
Serotypes
- Pleuropneumonia: IRAKM rs1624395-G and rs1370128-C; p = 0.0147, OR 1.83 (1.23–2.74) and p = 0.0055, OR 2.06 (1.37–3.11)
- Sequelae: IRAK4 rs4251513-nonGG: p = 0.0010,
OR 7.07 (2.64–18.87)- Death: MYD88 rs6853-nonAA and rs6853-G: p = 0.0054, OR 16.09 (3.34–77.57) and p = 0.0064, OR 8.39 (2.47–28.46)
- Serotypes: NS
Complement system
Kronborg, 2002, [18] MBL2 rs7096206 rs5030737 rs1800450 rs1800451 Denmark
(mixed, 97.9% white)
Adults with IPD 140 Blood culture Outcome (not specified, mortality of 17%) NS
Perez, 2006, [26] MBL-2 rs5030737 rs1800450 rs1800451 Spain
(unspecified)
Adults with CAP 97 Blood or pleural fluid culture/ sputum culture + positive Ag test or quantitative bacterial count Bacteraemia (53%)
Risk class of mortality (Fine scale) I (15%), II (11%), III (17%), IV (42%), V (15%)
- Bacteraemia: MBL2 AA genotype: p = 0.02, OR 2.74 (1.01–7.52)- Risk class mortality: NS
Endeman, 2008, [35] MBL2 rs5030737 rs1800450 rs1800451 rs7096206 Netherlands
(unspecified)
Adults with CAP 60 Blood or sputum culture Outcome - ICU admission (11%), length of hospital stay (median 11 (range 2–153) NS
Garcia-Laorden, 2008, [34] MBL
MASP-2
rs5030737 rs1800450 rs1800451 rs7096206
rs72550870
Spain
(white)
Adults with CAP 195 Clinical symptoms and radiographic findings Severe sepsis (16%), septic shock (14%) ICU admission (22%), MODS (10%), high pneumonia severity index (59%), bacteraemia (8%), ARF (70.9%), ARDS (5%), 90 day mortality (9%) NS
Woehrl, 2011, [47] C3 C5 C6 C7 C8B C9 CFH 17 variants Netherlands
(white)
Adults with BM 217 CSF culture Outcome - unfavourable (24%) vs favourable (76%, GOS 5) C5 rs17611-GG genotype: p = 0.002, OR 2.25 (1.33–3.81)
Garcia-Laorden, 2012, [49] MBL2 rs5030737 rs1800450 rs1800451 rs7096206 Spain
(white)
Adults with CAP 346 Clinical symptoms and radiographic findings and blood culture Severity sepsis, ICU admission (38%), acute renal failure (33%), MODS (21%), high pneumonia severity index (56%), bacteraemia (28%), ARF (72%), ARDS (8%), 90 day mortality (7%) NS
Garnacho-Montero, 2012, [50] MBL-2 rs1800450 rs1800451 rs5030737 Spain
(white)
Adults with sepsis 117 Culture of sterile site Septic shock (34%)
In-hospital mortality (19%)
90 day mortality (21%)
MBL2 AO/OO variants:
- Septic shock: aHR 15.3 (3.5–36.5)- In hospital mortality: aHR 3.2 (1.01–9.8)
- 90 day mortality: aHR 2.2, (1.1–8.1)
Brouwer, 2013, [58] MBL2 rs5030737 rs1800450 rs1800451 rs7096206 Netherlands
(white)
Adults with BM 299 CSF culture Septic shock, systemic complications
Mortality (8%), - unfavourable outcome: GOS 1–4 (28%)
Serotypes
NS
Lundbo, 2014, [62] MBL2 rs5030737 rs1800450 rs1800451 rs7096206 Scandinavia, Germany
(unspecified)
Children with IPD 1279 CSF, blood or other sterile site culture Mortality (2%) and serotypes NS
Muñoz-Almagro, 2014, [61] MBL2 rs5030737 rs1800450 rs1800451 rs7096206
rs11003125
rs7095891
Spain
(mixed)
All ages with IPD 147 CSF, blood, sterile body site culture or PCR Serotypes, children < 18 years (69%) vs adults (31%) - Children < 2 years vs other MBL2 O/O and XA/O: p = 0.031- Children < 2 years vs other (opportunistic or low-attack-rate serotypes only) MBL2 O/O and XA/O: p = 0.02
Mills, 2015, [64] MBL2 rs5030737 rs1800450 rs1800451 rs7096206 United Kingdom
(unspecified)
Sepsis in adults with CAP 245 Not specified 28-day mortality from CAP sepsis (19%) NS
Kasan-moentalib, 2017, [73] MASP-2 rs2273346 rs12711521 rs12142107 rs139962539 Netherlands (white) Adults with BM 397 CSF Culture Unfavourable outcome: GOS scale 1–4 (32%) NS
Fcγ receptors
Solé-Violán, 2011, [45] FCGR2A FCGR3A rs1801274
rs396991
Spain
(white)
Adults with CAP and B-CAP CAP:319, B-CAP:85 Blood culture, urine antigen Acute renal failure (32%), ARDS (8%), severe sepsis (41%), 28 (4%) and 90 day (6%) mortality Bacteraemic vs non-bacteraemic CAP: FCGR2A-H/H: p = 0.00016, OR 2.9 (1.58–5.3)
B-CAP and CAP:
- Acute renal failure FCGR2A-H/H: p = 0.004, OR 2.32
- Acute respiratory stress syndrome FCGR2A-H/H: p = 0.047, OR 2.17- Severe sepsis FCGR2A-H/H: p = 0.037. OR 1.8
Garnacho-Montero J, 2012, [50] FCGR2A rs1801274 Spain
(white)
Adults with sepsis 117 Culture of sterile site Septic shock (34%)
In-hospital mortality (19%)
90 day mortality (21%)
NS
Bouglé, 2012, [52] FCGR2A rs1801274 France
(white)
Adults with IPD 243 Culture of sterile site Hospital mortality (31%) Hospital mortality FCGR2A-H/H: p = 0.004, OR 0.251 (0.098–0.645)
NFκβ signalling pathway
Chapman, 2010, [38]
Cohort 1
NFKBIZ 15 variants, (very rare excluded) UK
(white)
All ages with IPD 275 Culture from sterile site Outcome (not specified) NS
Chapman, 2010
Cohort 2
NFKBIZ 15 variants, (very rare excluded) Kenya
(African)
Children with IPD 173 Blood culture Outcome (not specified) NS
Chapman, 2010, [40]
Cohort 1
NFKBIL2 9 variants UK
(white)
All ages with IPD 275 Culture from sterile site Mortality (10%) NS
Chapman, 2010
Cohort 2
NFKBIL2 9 variants Kenya
(African)
Children with IPD 173 Blood culture Mortality (28%) NS
Geldhoff, 2013, [55] CARD8 NLRP1
NLRP3
rs2043211 rs11621270
rs35829479
Netherlands
(white)
Adults with BM 531 (72% PM) CSF culture Mortality (18%), unfavourable outcome: GOS 1–4 (38%), systemic complications, neurological complications CARD8 rs2043211-TT genotype:
- Unfavourable outcome: p = 0.018, OR 2.19 (1.15–4.81)
- Systemic complications: p = 0.016, OR 2.48 (1.29–4.7)
- Neurological complications: p = 0.022, 3.03 (1.34–6.85)
NLRP1 rs11651270-TT genotype:
- Mortality: p = 0.047, OR 1.97 (1.02–3.85)
Cytokines
Schaaf, 2003, [21] IL10
TNF
LTA
rs1800896 rs1800629 rs909253 Germany (white) CAP and IPD
(age not specified)
69 CSF, blood, pleural fluid, sputum culture Septic shock (19%), complications (48%), mortality (7%) IL10-GG genotype:
- severity (development of septic shock): p = 0.008, OR 6.1 (1.4–27.2)
- complications and mortality: NS (re-calculated)
Schaaf, 2005, [23] IL6 rs1800795 Germany (white) CAP and IPD
(age not specified)
100 CSF, blood, pleural fluid, sputum culture Bacterial dissemination (25%) GG genotype: p = 0.04, OR 0.26 (0.07–0.94)
Carrol, 2011, [42] IL-1Ra rs4251961 Malawi
(African)
Children with IPD 299 Blood, sputum, CSF culture or Ag test or PCR Mortality (22%) NS
Doernberg, 2011, [41] MIF rs5844572rs755622 USA, Germany
(white)
Adults with IPD 30, 89 Culture from sterile body site Disease phenotype: meningitis (14%) Meningitis vs no meningitis:
- rs5844572–77 and 7X genotypes: p = 0.02, OR = 3.34 (1.34–8.35)
Martin- Loeches, 2012, [48] IL6 rs1800795 Spain
(white)
Adults with CAP 306 Blood culture, urine antigen ARDS (7%), septic shock (20%), multiple organ dysfunction syndrome (18%), hospital mortality (6%) GG genotype: - ARDS: p = 0.002, OR = 0.25 (0.07–0.79)
- septic shock: p = 0.006, OR = 0.46 (0.18–0.79)
- multiple organ dysfunction syndrome: p = 0.02, OR = 0.53 (0.27–0.89)- survival (adjusted for age, gender, comorbidity, hospital of origin, and PSI): p = 0.048, OR = 0.27 (0.07–0.98)
Savva, 2016, [68] MIF rs5844572 rs755622 Netherlands
(white)
Adults with
BM
405 CSF culture Unfavourable outcome- GOS 1–4 (33%), mortality (7%) Unfavourable outcome:
- rs5844572–77 and 7X: p = 0.005, OR 1.89 (1.21–2.96)
- rs755622- GC and CC: p = 0.003, OR 1.9 (1.24–2.92)
Mortality:- rs5844572–77 and 7X: p = 0.03, OR 2.27 (1.07–4.83)
- rs755622 - GC and CC: p = 0.01, OR 2.6 (1.01–3.78)
Coagulation and fibrinolysis
Benfield, 2010, [39] FVL rs6025 Denmark
(unspecified)
Adults with IPD 163 Culture of CSF, blood or other sterile site Mortality (15%),
ICU admission
NS
Brouwer, 2014, [60] SERPINE1 (PAI-1) rs1799889 Netherlands
(white)
Adults with BM 400 CSF culture Unfavourable outcome- GOS 1–4 (33%), mortality (8%), cerebral infarction 14%), haemorrhages (2%) 5G/5G genotype (low expression):
- Unfavourable outcome: p = 0.035, OR 1.69 (1.03–2.78)
- Mortality: p = 0.039 OR 2.23 (1.02–4.86)
- Cerebral infarction: p = 0.011, OR 2.20 (1.19–4.07)
- Haemorrhages: p = 0.005, OR 9.94 (1.89–52.17)
Mook, 2015, [66] CPB2 (TAFI) rs1926447 rs3742264 Netherlands
(white)
Adults with BM 716 CSF culture Unfavourable outcome – GOS 1–4 (29%), death (7%), systemic complications (31%) Unfavourable outcome and death: NSSystemic complications:
- rs3742264 -AA allele vs common allele: p = 0.008, OR 0.40 (0.20–0.79)
Other
Eklund 2006, [28] CRP rs1800947 rs2794521
rs1130864
Finland
(white)
Patients with bacteraemia 42 Blood culture Mortality (19%) rs2794521- GG homozygotes: p = 0.03, OR 9.6 (1.3–72.5) recalculated
Payton, 2009, [36] NOS2A 9 variants Malawi
(African)
Children with IPD 229 Culture, PCR, antigen tests Mortality (22%) NS
Adriani, 2012, [51] ADRB2 rs1042713 rs1042714 Netherlands
(mixed, 94% white)
Adults with BM 396 CSF culture All BM unfavourable outcome: GOS 1–4 (23%), mortality (7%) NS
Brouwer, 2012, [54] GLCCI1 rs37972 Netherlands
(white)
Adults with BM 699 CSF culture Treatment effect dexamethasone (mortality) NS
Studies with genes in mixed categories
Lundbo, 2015, [67] NFKBIE
NFKBIA
NFKBIL2
NFKBIZ
TIRAP
PTPN22
rs529948 rs3138053 rs2233406 rs760477 rs616597
rs8177374
rs2476601
Scandinavia, Germany (unspecified) Children with BM / bacteraemia 372, 907 CSF or blood culture 30 day mortality (2%) NS
Hypothesis free studies
Valls Seron, 2016, [69] Exome array analysis 24,000 variants Netherlands
(white)
Adults with BM 472 CSF culture Unfavourable outcome: GOS 1–4 (32%), mortality (8%) - AKT3 rs10157763 –A allele: p = 9.9 × 10− 5, OR 1.88 (1.4–2.6) - RAET1E rs3798763 and rs6925151 –G allele: p = 9.4 × 10− 5, OR 1.9 (1.4–2.6)- DCTN4 rs11954652 and rs6869603 –G allele: p = 2.4 × 10− 5, OR 5.6 (2.4–12.9)
Ferwerda, 2016, [72] Sequencing of 46 genes 1385 variants Netherlands
(white)
Adults with BM 435 CSF culture Unfavourable outcome: GOS 1–4 (34%), mortality (8%) - IRAK4 rs4251552 –G allele: p = 4.8 × 10− 4, OR 2.86 (1.58–5.18)- NOD2 rs2067085 –G allele: p = 5.1 × 10− 4, OR 2.16 (1.40–3.34)
  1. Abbreviations: Ag agglutination, aHR adjusted Hazard ratio, ARDS acute respiratory stress syndrome, ARF Acute respiratory failure, BM bacterial meningitis, B-CAP bacterial-CAP, CAP community acquired pneumoniae, CI confidence interval, CSF cerebrospinal fluid, GOS Glasgow Outcome Scale, GWAS genome wide association study, ICU Intensive care unit, IPD invasive pneumococcal disease, MODS Multiple organ dysfunction syndrome, NS not significant, OR odds ratio, PCR polymerase chain reaction, PM pneumococcal meningitis
  2. *Genetic variants: Synonyms of genetic variants can be found in Additional file 1: Table S1. † Results: None of the p-values are corrected for multiple testing