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Table 1 Genetic-association studies on susceptibility to pneumococcal disease

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

Name, year, reference Candi-date gene Genetic variants* Country of origin (ethnicity) Patient groups Patient -selection N Controls - selection N Results – Gene, genetic variation, risk allele/genotype: p-value, OR (95% CI) †
Pathogen recognition receptor signalling pathways
Khor, 2007, [29]
Cohort 1
TIRAP 31 variants United Kingdom
(white)
All ages with IPD Blood, CSF, or joint fluid culture 191 Blood donors and cord blood samples 741 rs8177374 heterozygosity: p = 0.013, OR 0.65 (0.44–0.97)
Khor, 2007
Cohort 2
TIRAP 31 variants United Kingdom
(unspecified)
Pleural empyema Empyema culture 36 Healthy adult blood donors 361 rs8177374 heterozygosity: p = 0.08, OR 0.74 (0.32–1.68)
Khor, 2007
Cohort 3
TIRAP 31 variants Kenya
(African)
Children with bacteraemia Blood culture 164 Community-based 423 rs8177374 heterozygosity: p = 0.024, OR 0.30 (0.06–0.99)
Moens, 2007, [30] TLR2 TLR4 rs5743703
rs5743704
rs5743708 rs4986790
Belgium
(white)
All ages with IPD Blood, CSF, or joint fluid culture 99 Family of hospital personnel, university employees 178 NS
Yuan, 2008, [33] TLR2 TLR4
CD14
rs5743708
rs4986790
rs4986791
rs2569190
Australia
(unspecified)
Children with IPD Blood culture 85 Healthy blood donors 409 - TLR4 rs4986790/rs4986791 AG + GG/CT + TT genotypes: P < 0.05, OR 0.3 (0.1–1)
- CD14 rs2569190-CC genotype: P < 0.05, OR 1.7 (1–2.8)
Sanders, 2011, [43] TLR9 rs5743836
rs352140
Netherlands
(white)
Children and adolescents with BM CSF culture 83 Healthy white adults without a known history of BM 392 NS
Van Well, 2013, [57] TLR2
TLR4
NOD1
NOD2 CASP1
rs5743708
rs4986790
rs6958571
rs2066844
rs2066845
rs2066847
rs2282659
Netherlands
(white)
Children with BM CSF culture 82 Ethnically matched healthy controls 1141 NS
Tellería-Orriols, 2013, [59] TLR2
TLR 4 CD14
rs5743708 rs4986790rs2569190 Spain (white) Children with IPD Culture of sterile site, PCR or antigen 114 Healthy White children 66 - TLR2 rs5743708-GA + AA genotypes: p < 0.0001, OR 4.26 (2.19–8.3)
- CD14 rs2569190-CC: p = 0.0167, OR 1.93 (0.95–3.91)
Ellis, 2015, [63] IRAK4
MYD88 IKBKG
233 variants United Kingdom
(white)
All ages with IPD Culture of sterile site 164 Geographically-matched population-based controls 164 IRAK4 rs4251513 variant allele: p = 9.96 × 10− 3, OR 1.50 (1.10–2.04)
Carrasco-Colom, 2015, [65] IRAK4 IRAK1 IRAKM
MYD88
10 variants Spain
(mixed, 92% white)
Children with IPD and SIRS Culture or PCR of sterile site 60 Patients with no previous immunodeficiency or IPD, nor concomitant infectious pathology 120 P-value in article adjusted by false discovery rate: not repoducible by re-calculation
- IRAK1 rs1059701-CC
- IRAK4 rs4251513-CC
- IRAK4 rs1461567-T
- MYD88 rs6853-AA
Gowin, 2017, [74] TLR2 TLR4 TLR9 rs5743708
rs4696480
rs4986790
rs352140
rs5743836
Poland
(White)
Children with BM CSF culture or PCR 14 Family members 49 NS
Gowin, 2018, [76] TIRAP
TLR2 TLR4 TLR9
rs8177374
rs4696480
rs5743708
rs4986790 rs5743836 rs352140
Poland
(white)
Children with bacterial meningitis CSF culture or PCR 14 Family members 49 - TIRAP rs8177374 variant allele carriers: p = 0.0508, OR 4.5 (0.96–21.12)
- TIRAP rs8177374 and MBL2 rs1800451 variant alleles cumulative effect: p = 0.035, OR = 4.9 (1.17–20.48)
Complement system
Roy, 2002, [19] MBL2 rs5030737
rs1800450
rs1800451
rs7096206
United Kingdom (white) All ages with IPD Sterile body site 337 Donors, neonates 1032 MBL2 O/O genotype: p = 0.002, OR 2.59 (1.39–4.83)
Kronborg, 2002 [18] MBL2 rs5030737
rs1800450
rs1800451
rs7096206
Denmark
(mixed, 97.9% white)
Adults with IPD Blood culture 140 Blood donors, laboratory personnel 250 NS
Moens, 2006, [27] MBL2 rs5030737
rs1800450
rs1800451
rs7096206
Belgium
(white)
All ages with IPD Blood, CSF, or joint fluid culture 63 Sex-matched hospital employees, urology, and internal medicine outpatients 162 NS
Endeman, 2008, [35] MBL2 rs5030737
rs1800450
rs1800451
rs7096206
Netherlands
(not specified)
Adults with CAP Blood / sputum culture 60 Blood bank donors 223 NS
Garcia-Laorden, 2008, [49] MBL
MASP-2
rs5030737
rs1800450
rs1800451
rs72550870
Spain
(white)
Adults with CAP Clinical symptoms and radiographic findings 195 Healthy control subjects, a control group of patients without relevant infectious diseases 1447, 519 NS
Garcia-Laorden, 2011, [44] SFTPA1
SFTPA2
SFTPD
rs1059047
rs1136450 rs4253527 rs1059046 rs17886395 rs4253527
rs721917
Spain
(white)
Adults with CAP Clinical symptoms and radiographic findings and blood culture 326 Blood and bone marrow donors as well as hospital staff and patients without signs of relevant infectious diseases 1538 Associations below p < 0.05:
- 5 haplotypes of SFTPA1, SFTPA2 and SFTPD
Garcia-Laorden, 2012, [49]
Cohort 1
MBL2 rs5030737 rs1800450 rs1800451 Spain
(white)
Adults with CAP Clinical symptoms and radiographic findings and blood culture 340 Blood and bone marrow donors, hospital staff and patients without signs of relevant infectious diseases 1736 NS
Garcia-Laorden, 2012
Cohort 2
MBL2 rs5030737 rs1800450 rs1800451 Spain
(unspecified)
Adults with CAP Blood, pleural fluid, sputum (+ bacterial recount or positive urinary antigen) culture 84 Healthy controls 91 NS
Brouwer, 2013, [58] MBL2 rs5030737 rs1800450 rs1800451 rs7096206 Netherlands
(white)
Adults with BM CSF culture 299 Partners, non-related proxies 216 MBL2 O/O genotype: p  =  0.017, OR 8.21 (1.05–64.1)
Adriani, 2013, [56] C3 C5 C6 C7 C8B C9 CFH 17 variants Netherlands (mixed, 94% white) Adults with BM CSF culture 299 Partners, non-related proxies 216 NS after correction.
C7 rs13157656 dominant model: p = 0.04 OR 1.46 (1.02–2.09)
C3 rs1047286 recessive model p = 0.03 OR 3.14 (1.08–9.19)
Lundbo, 2014, [62] MBL2 rs5030737 rs1800450 rs1800451 rs7096206 Scandinavia, Germany
(unspecified)
Children with IPD CSF, blood or other sterile site culture 1279 Age- and sex-matched 1263 NS
Mills, 2015, [64] MBL2 rs5030737 rs1800450 rs1800451 rs7096206 United Kingdom
(unspecified)
Sepsis in adults with CAP Not specified 95 Individuals attending general practice surgeries for reasons other than infection 477 NS
Gowin, 2018, [76] MBL2
CFH
CFHR3
rs5030737 rs1800450 rs1800451
rs1065489
rs3753396
Poland
(white)
Children with BM CSF Culture or PCR 14 Family members 49 TIRAP rs8177374 and MBL2 rs1800451 cumulative effect: p = 0.035, OR = 4.9 (1.17–20.48)
Fcγ receptors
Yee, 2000, [17] FCGR2A rs1801274 USA
(mixed)
B-CAP (age not specified) Blood or sputum culture 42 Randomly selected hospital patients 136 R131/R131 genotype: p < 0.05, OR 2.40 (1.18–4.87)
Yuan, 2003, [22] FCGR2A rs1801274 Australia (unspecified) Children with sepsis Blood culture, Ag in blood donors 63, 34 Children from vaccination programme/ Healthy blood donors 20, 57 R131/R131 genotype: P = 0.01, OR 2.81 (1.25–6.32)
Chapman, 2006, [25] PTPN22 rs2476601 UK
(white)
All ages with IPD Culture of sterile body site 286 Ethnically matched 803 T allele: P = 0.004, OR = 1.56 (1.15–2.11)
Moens, 2006, [24] FCGR2A rs1801274 Belgium
(white)
All ages with IPD Blood, cerebrospinal fluid, or joint fluid culture 55 Sex-matched hospital employees, urology, and internal medicine outpatients 100 NS
Yuan, 2008, [33] FCGR2A rs1801274 Australia (unspecified) Children with IPD Blood culture 85 Healthy blood donors 409 R131/R131 genotype: P < 0.001, OR 2.46 (1.49–4.04)
Endeman, 2009, [37] FCGR2A rs1801274 Netherlands (unspecified) Adults with CAP Blood / sputum culture, urine antigen 60 Healthy unrelated Whites from the same geographical area 314 NS
Solé-Violán, 2011, [45] FCGR2A FCGR3A rs1801274
rs396991
Spain
(white)
Adults with CAP and B-CAP Blood culture, urine antigen CAP = 319, B-CAP = 85 Unrelated healthy volunteers and patients without a previous history of relevant infectious diseases 1224 B-CAP FCGR2A– H131/H131 genotype: p = 0.01, OR 1.81 (1.09–2.43)
Bouglé, 2012, [52] FCGR2A rs1801274 France
(white)
Adults with IPD Culture of sterile site 243 ICU patients without infection 2789 NS
NFκβ signalling pathway
Chapman, 2007, [32] NFKBIA NFKBIB NFKBIE 43 variants (very rare excluded) UK
(white)
All ages with IPD Blood, CSF, or joint fluid culture 288 Blood donors and cord blood samples 770 NFKBIA rs3138053 variant allele carriers: p = 0.0003, OR 0.60; (0.45–0.79)
NFKBIA rs2233406 variant allele carriers: p = 0.00001, OR 0.55 (0.42–0.72)NFKBIE rs529948 variant allele carriers, p = 0.001, OR 0.59 (0.43–0.83)
Chapman, 2010, [38]
Cohort 1
NFKBIZ 15 variants, (very rare excluded) UK
(white)
All ages with IPD Culture from sterile site 275 Healthy adult blood donors, cord blood samples 163, 570 3 × 2 Chi-squared comparisons of genotypes, p-values below 0.05:
rs600718: p = 0.01, rs616597: p = 0.001, rs685666: 0.036, rs6441627: 0.011, rs587555: p = 0.05, rs677011: 0.042, rs601225: p = 0.049
Chapman, 2010
Cohort 2
NFKBIZ 15 variants, (very rare excluded) Kenya
(African)
Children with IPD Blood culture 173 Age and sex matched community-based 550 3 × 2 Chi-squared comparisons of genotypes: p-values below 0.05:
rs600718: p = 0.022
Chapman, 2010, [40]
Cohort 1
NFKBIL2 9 variants UK
(white)
All ages with IPD Culture from sterile site 275 Healthy adult blood donors, cord blood samples 163, 570 Both cohorts:
rs760477 heterozygosity: p = 0.0006, OR = 0.67 (0.53–0.84)rs4925858 heterozygosity: p = 0.003, OR = 0.70 (0.55–0.88)
Chapman, 2010
Cohort 2
NFKBIL2 9 variants Kenya
(African)
Children with IPD Blood culture 173 Age and sex matched community-based 550
Sangil 2018, [75] NFKBIA NFKBIE NFKBIL2 NFKBIZ 10 variants Spain
(white)
Adults with IPD Not specified 144 Ethnically matched 280 NFKBIA rs1050851-T: p = 0.04
NFKBIE rs2282151-C: p = 0.02NFKBIZ-CC rs645781: p = 0.02
Cytokines
Schaaf, 2003, [21] IL10
TNF
LTA
rs1800896 rs1800629 rs909253 Germany (white) CAP and IPD
(age not specified)
CSF, blood, pleural fluid, sputum culture 69 Unrelated age and sex-matched orthopaedic patients 50 NS
Schaaf, 2005, [23] IL6 rs1800795 Germany (white) CAP and IPD
(age not specified)
CSF, blood, pleural fluid, sputum culture 100 Age matched 50 NS
Carrol, 2011, [42] IL-1Ra rs4251961 Malawi
(African)
Children with IPD Blood, sputum, CSF culture or Ag test or PCR 299 Healthy controls 933 NS
Martin- Loeches, 2012, [48] IL6 rs1800795 Spain
(white)
Adults with CAP Blood culture, urine antigen 306 953 white Spanish unrelated healthy volunteers, 434 patients without a previous historyof relevant infectious diseases 1387 NS
Savva, 2016, [68] MIF rs5844572 rs755622 Netherlands
(white)
Adults with
BM
CSF culture 405 Partners, non-related proxies 329 NS
Sangil, 2018, [75] IL10
IL12B
IL1A
IL1B ILR1 IL4
33 variants Spain
(white)
Adults with IPD Not specified 144 Ethnically matched 280 IL1R1 rs3917254-CC: p = 0.04
Coagulation and fibrinolysis
Benfield, 2010, [39] FVL rs6025 Denmark
(unspecified)
Adults with IPD Culture of CSF, blood or other sterile site 163 Age matched adults without infectious disease hospitalization 8147 NS
Mook, 2015, [66] CPB2 (TAFI) rs1926447 rs3742264 Netherlands
(white)
Adults with BM CSF culture 716 Partners, non-related proxies Not shown NS
Other
Roy, 2002, [20] CRP rs3138528 United Kingdom (white) All ages with IPD Blood, CSF, or joint fluid culture 205 Randomly selected local blood donors and transplant donors 345 Common allele: P = 0.001; OR 1.52 (1.18–1.96)
Chapman, 2007, [31] FCN2 rs3124952 rs3124953 rs17514136 rs17549193 rs7851696 United Kingdom
(white)
All ages with IPD Blood, CSF, or joint fluid culture 290 Blood donors and cord blood samples 720 NS
Payton, 2009, [36] NOS2A 9 variants Malawi
(African)
Children with IPD Culture, PCR, antigen tests 229 Age matched 931 NS
Adriani, 2012, [51] ADRB2 rs1042713 rs1042714 Netherlands
(mixed, 94% white)
Adults with BM CSF culture 396 Partners, non-related proxies 376 rs1042714 Gln/Glu genotype: p  =  0.007, OR 1.52 (1.12–2.07)
Brouwer, 2012, [54] GLCCI1 rs37972 Netherlands
(white)
Adults with BM CSF culture 699 Partners, non-related proxies 490 NS
Studies with genes in mixed categories
Lingappa, 2011, [46] 34 genes 326 variants USA (European Americans (EA) and African Americans (AA)) Children with IPD Culture of sterile site EA = 182
AA = 53
Bloodspot collection from new-borns, race/ethnicity and date of birth matched 361, 113 Associations below p < 0.05, none of the variants in both EA and AA):
- In AA: 11 variants in 6 genes (CD46, SFTPB, SFTPD, IL1B, ILIR1, PTAFR)
- in EA: 17 variants in 9 genes (CD46, SFTPA1, SFTPD, IL1B, ILIR1, IL4, IL10, IL12B, FAS)
Lundbo, 2015, [67] NFKBIE
NFKBIA
NFKBIL2
NFKBIZ
TIRAP
PTPN22
rs529948 rs3138053 rs2233406 rs760477 rs616597
rs8177374
rs2476601
Scandinavia, Germany
(unspecified)
Children with BM/ bacteraemia CSF or blood culture 372, 907 Age and sex matched 1273 Pneumococcal meningitis:
NFKBIE rs529948 variant allele carriers, p = 0.0001, OR 1.68 (1.20–2.36) Combined patient groups:
NFKBIE rs529948 variant allele carriers, p = 0.01, OR 1.24 (1.03–1.49)
Other: NS
Hypothesis free studies
Ellis, 2015, [63] Sequencing of IRAK4
MYD88 IKBKG
233 variants United Kingdom
(white)
All ages with IPD Culture of sterile site 164 Geographically-matched population-based 164 IRAK4 rs4251513 variant allele: p = 9.96 × 10−3, OR = 1.50 (1.10–2.04)
Ferwerda, 2016, [72] Sequencing of
46 genes
1854 variants Netherlands
(white)
Adults with BM CSF culture 435 Partners, non-related proxies 416 CARD8 rs2008521-T allele: p = 8.2 × 10−4, OR 1.82 (1.28–2.75) CXCL1 rs56078309-A allele: p = 8.2 × 10− 4, OR 1.96 (1.34–2.87)
Kenyan Bacterae-mia Study Group, 2016, [70] GWAS 787,861 variants,
10 million variants after imputation
Kenya
(African)
Children with bacteraemia Blood culture 429
113
Sex, ethnic group, and geographic area matched controls 2677
1136
17 variants above genome-wide significance (p < 5 × 10−8). Strongest association in discovery cohort: (minor allele = risk allele)
LincRNA rs14081715- additive model: p imputed = 7.25 × 10−9, OR = 2.74
Replication cohort:
LincRNA rs14081715- additive model: p = 0.001, OR 2.72
Kloek, 2016, [71] Exome array analysis 102,097 variants Netherlands
(white)
Adults with BM CSF culture or PCR 469 Population-based controls 2072 COL11A1 rs139064549-G allele: p = 1.51 × 10−6, OR 3.21 (2.05–5.02) EXOC6B rs9309464-G allele: p = 6.01 × 10−5, OR 0.66 (0.54–0.81)
  1. Abbreviations: Ag agglutination, BM bacterial meningitis, B-CAP bacterial-CAP, CAP community acquired pneumoniae, CI confidence interval, CSF cerebrospinal fluid, GWAS genome wide association study, IPD invasive pneumococcal disease, NS not significant, OR odds ratio, PCR polymerase chain reaction, PM pneumococcal meningitis
  2. *Genetic variants: Synonyms of genetic variants can be found in Supplementary Table 1. Results: None of the p-values are corrected for multiple testing