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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