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) |