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 |
TellerÃa-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) |