Table 1.
Loci reported to be involved in HCMV and related disease susceptibility.
| Phenotype | Gene | Variant/genotype | Location | Sample size | Model | Effect | P-value | Population | Study group | Ref. |
|---|---|---|---|---|---|---|---|---|---|---|
| Humoral immunity | ||||||||||
| IGHG1 | GM 3 | Exon | 131 | Recessive | Reduced anti-HCMV Glycoprotein B Immunoglobulin G (IgG) Antibody level | 0.01 | USA/Europeans | Upper Midwest Health Study | (Pandey et al., 2014c) | |
| IGHG1 | GM 5 | Exon | 131 | Recessive | Reduced anti-HCMV Glycoprotein B Immunoglobulin G (IgG) Antibody level | 0.01 | USA/Europeans | Upper Midwest Health Study | (Pandey et al., 2014c) | |
| AGBL1 | rs2011905 -C Allele |
Intron | 2442 | Allelic | Increased anti-CMV IgG titer | 1.9 x 10−6 | CVD-Finns | 24–39 year old participants (GWAS) | (Kuparinen et al., 2012) | |
| CD53 | rs2885805 -A allele |
Intron | 2442 | Allelic | Decreased anti-CMV IgG titer | 4.6 x 10−6 | CVD-Finns | 24–39 year old participants (GWAS) | (Kuparinen et al., 2012) | |
| EFCAB4B | rs4766152 -G allele |
Intron | 2442 | Allelic | Decreased anti-CMV IgG titer | 5.1 x 10−6 | CVD-Finns | 24–39 year old participants (GWAS) | (Kuparinen et al., 2012) | |
| FREM2 | rs9594293 -A allele |
Intron | 2442 | Allelic | Decreased anti-CMV IgG titer | 6.8 x 10−6 | CVD-Finns | 24–39 year old participants (GWAS) | (Kuparinen et al., 2012) | |
| MCPH1 | rs1707715 - G allele |
Intron | 2442 | Allelic | Increased anti-CMV IgG titer | 7.8 x 10−6 | CVD-Finns | 24–39 year old participants (GWAS) | (Kuparinen et al., 2012) | |
| TTC7B | rs1779382 - A allele |
Intron | 2442 | Allelic | Increased anti-CMV IgG titer | 9.1 x 10−6 | CVD-Finns | 24–39 year old participants (GWAS) | (Kuparinen et al., 2012) | |
| LOC728667 or LINC00596 | rs1288981 - T allele |
Between genes | 1300 | Allelic | Decreased IgG antibody response against HCMV | 8.2 x 10−7 | Mexican Americans in the San Antonio Family Study | 16–94 year old participants (GWAS) | (Rubicz et al., 2015) | |
| Cancer susceptibility | ||||||||||
| IGHG1 | GM 3 | – | 253 (120 case, 133 control) | Recessive | Increased risk of Glioma | 0.04 | Portugal/European | Patients with glioma | (Pandey et al., 2014b) | |
| IGHG1 | GM 3/ GM 17 |
– | 253 (120 case, 133 control) | Genotype | Increased risk of Glioma | 0.02 | Portugal/European | Patients with glioma | (Pandey et al., 2014b) | |
| IGHG1 | GM 3 | – | 258 case–control pair | Additive | Increased breast cancer risk | 0.01 | Brazil/Europeans | Patients with invasive breast cancer | (Pandey et al., 2012) | |
| IGHG1 | GM 3 | – | 251 | Additive and Recessive | Reduced anti-HCMV Glycoprotein B Immunoglobulin G (IgG) Antibody level | 0.01–0.03 | Brazil/Europeans | Breast cancer free controls | (Pandey et al., 2016) | |
| HCMV disease in transplantation | ||||||||||
| Solid organ transplantation | ||||||||||
| TLR2 | R753Q (rs5743708, 2258 G > A) |
Exon | 737 (92 cases, 645 controls) | Recessive | Increased risk of CMV disease after liver transplantation | 0.003 | USA/Europeans | Patients who received liver transplantation at the Mayo Clinic in Rochester, Minnesota | (Kang et al., 2012) | |
| TLR2 | R753Q (rs5743708, 2258 G > A) |
Exon | 92 | Recessive | Increased HCMV viral load and risk of CMV disease after liver transplantation | 0.003–0.04 | USA/Europeans | Patients who received liver transplantation at the Mayo Clinic in Rochester, Minnesota | (Kijpittayarit et al., 2007) | |
| TLR4 | D299G (rs4986790) or T399I (rs498679) |
Exon | 245 | Presence of any of the variants | Increased risk of primary HCMV infection and disease | 0.02 | Spain | Patients who received kidney or kidney-pancreas transplantation | (Cervera et al., 2007) | |
| TLR9 | rs5743836 – TT genotype | Upstream | 315 | Recessive | Lower incidence of HCMV infection | 0.035 | Spain | Patients received kidney transplantation in the OPERA study | (Fernandez-Ruiz et al., 2015) | |
| DC-SIGN | rs735240 – GG genotype | Upstream | 315 | Recessive | Higher incidence of HCMV infection | 0.008 | Spain | Patients received kidney transplantation in the OPERA study | (Fernandez-Ruiz et al., 2015) | |
| MBL2 | Biochemical deficiency/Null | – | 16 | Recessive | Increased risk of HCMV infection | 0.005 | Univ. Hospital, Lausanne, CH | Patients who received kidney transplantation | (Manuel et al., 2007) | |
| PDCD1/ PD-1 |
rs11568821 - G allele |
Intron | 469 | Recessive | Increased risk of HCMV infection | 0.01 | Univ. Hospital, Tours, France | Patients who received kidney transplantation | (Hoffmann et al., 2010) | |
| PDCD1/ PD-1 |
rs11568821 -A allele |
Intron | 1119 | Dominant | Improved kidney graft survival recipients receiving grafts from CMV-positive donors | 0.002 | Univ. Hospital, Tours, France | Patients who received kidney transplantation | (Forconi et al., 2017) | |
| PDCD1/ PD-1 |
rs11568821 -A allele |
Intron | 181 | Dominant | Improved lung graft survival recipients receiving grafts from CMV-positive donors | 0.006 | University Hospital of Tours, France | Patients who received lung transplantation | (Forconi et al., 2017) | |
| IFNG | +874T/A (rs2430561) -TT genotype |
Intron | 170 | Genotypic | High level of viremia and HCMV disease | 0.001 | USA/Europeans | Patients who received lung transplantation | (Mitsani et al., 2011) | |
| IFNG | +874T/A (rs2430561) -AA genotype |
247 | Genotypic | Increased risk of HCMV infection and disease | 0.01 | USA/Hispanics | Patients who received kidney transplantation | (Vu et al., 2014) | ||
| IFNL3/ IFNL4 |
rs8099917 -G allele |
5’ Upstream region | 38 (17 with CMV replication, 21 no CMV replication) | Dominant | Reduced HCMV replication | 0.04 | University of Alberta, Canada | Patients who received solid organ transplantation | (Egli et al., 2014) | |
| IFNL3/ IFNL4 |
rs368234815 -G allele |
CpG region, 5’ Upstream | 840 | Recessive | Increased risk of HCMV replication and disease | 0.05 | Europeans/Swiss Transplant Cohort Study | Patients who received solid organ transplantation | (Manuel et al., 2015) | |
| IFNL3/ IFNL4/IL28B |
rs12979860 – T allele | Intro | 315 | Allelic | Lower incidence of HCMV infection | 0.03 | Spain | Patients received kidney transplantation in the OPERA study | (Fernandez-Ruiz et al., 2015) | |
| IL-10 | -1082A/G -AA genotype |
5’ Upstream | 408 | Genotypic | Reduced incidence of HCMV infection | 0.03 | Finland | Patients who received kidney transplantation | (Alakulppi et al., 2006) | |
| IL-12B | rs3212227 -C allele (IL-12p40) |
3′-untransla-ted region | 469 | Allelic | Increased risk of HCMV infection | 0.04 | University Hospital of Tours, France | Patients who received kidney transplantation | (Hoffmann et al., 2008) | |
| MICA | rs2596538 | 5’ Upstream region | 181 | Allelic | Protective against HCMV infection and disease | 0.001 | University Hospital Essen, Germany | Patients who received kidney transplantation | (Rohn et al., 2018) | |
| Hematopoietic transplantation | ||||||||||
| IFNL3/ IFNL4 |
rs12979860 -T allele |
Intron | 151 | Genotypic | Protective against HCMV infection | 0.04 | University Clinic Hospital of Valencia, Spain | Patients who received allogeneic stem cell transplantation | (Bravo et al., 2014) | |
| IFNL3/ IFNL4 |
rs12979860 -T allele |
Intron | 142 | Recessive | Protective against HCMV infection | 0.05 | University Clinic Hospital of Valencia, Spain | Patients who received allogeneic stem cell transplantation | (Corrales et al., 2017) | |
| IFNL3/ IFNL4 |
rs12979860 -T allele; rs368234815-ΔG allele |
Intron; Exon | 99 | Compound Genotypic | Increased risk of HCMV activation | < 0.05 | Italian cohorts | Patients who received allogeneic stem cell transplantation | (Annibali et al., 2018) | |
| IL-10 | rs1800893 -G allele |
5’ Upstream | 154 (83 HCMV activation, 71 control) | Additive | Increased risk of HCMV disease | 0.009 | Multinational/Europeans | Patients who received allogeneic stem cell transplantation | (Loeffler et al., 2006) | |
| IL-10 | rs1800896 -G allele |
5’ Upstream | 154 (83 HCMV activation, 71 control) | Additive | Increased risk of HCMV disease | 0.001 | Multinational/Europeans | Patients who received allogeneic stem cell transplantation | (Loeffler et al., 2006) | |
| IL-10 | rs1878672 -G allele |
Intron | 154 (83 HCMV activation, 71 control) | Additive | Increased risk of HCMV disease | 0.003 | Multinational/Europeans | Patients who received allogeneic stem cell transplantation | (Loeffler et al., 2006) | |
| IL-10 | rs3024492 -T allele |
Intron | 154 (83 HCMV activation, 71 control) | Additive | Increased risk of HCMV disease | 0.04 | Multinational/Europeans | Patients who received allogeneic stem cell transplantation | (Loeffler et al., 2006) | |
| IL-7 | rs6897932 -T allele |
Exon | 460 | Genotypic | Increased risk of HCMV infection | 0.007 | Copenhagen University, Denmark | Patients who received allogeneic stem cell transplantation | (Kielsen et al., 2018) | |
| CCL2 (MCP1) | rs1024611 -T allele |
5’ Upstream | 154 (83 HCMV activation, 71 control) | Additive | Increased risk of HCMV reactivation | 0.03 | Multinational/Europeans | Patients who received allogeneic stem cell transplantation | (Loeffler et al., 2006) | |
| CCL2 (MCP1) | rs13900 -T allele |
Exon | 154 (83 HCMV activation, 71 control) | Additive | Increased risk of HCMV reactivation | 0.02 | Multinational/Europeans | Patients who received allogeneic stem cell transplantation | (Loeffler et al., 2006) | |
| CCR5 | rs17141079 -T allele |
Intron | 154 (83 HCMV activation, 71 control) | Additive | Increased risk of HCMV disease | 0.02 | Multinational/Europeans | Patients who received allogeneic stem cell transplantation | (Loeffler et al., 2006) | |
| CCR5 | rs1800023 -G allele |
5’ Upstream | 154 (83 HCMV activation, 71 control) | Additive | Increased risk of HCMV disease | 0.01 | Multinational/Europeans | Patients who received allogeneic stem cell transplantation | (Loeffler et al., 2006) | |
| CCR5 | rs1800023 -A allele |
5’ Upstream | 102 | Additive, Recessive | Increased CMV DNAemia and DNA peak | 0.02, 0.05 | Spanish cohort | Patients who received allogeneic stem cell transplantation | (Corrales et al., 2015) | |
| CCR5 | rs2734648 -T allele |
5’ Upstream | 154 (83 HCMV activation, 71 control) | Additive | Increased risk of HCMV disease | 0.01 | Multinational/Europeans | Patients who received allogeneic stem cell transplantation | (Loeffler et al., 2006) | |
| CD209 (DC-SIGN) |
rs2287886 -T allele |
5’ Upstream | 194 (70 HCMV reactivation, 59 HCMV disease, 65 control) | Allelic | Increased risk of development of HCMV reactivation and disease | 0.003 | Germany/Europeans | Patients who received allogeneic stem cell transplantation | (Mezger et al., 2008) | |
| CD209 (DC-SIGN) |
rs735240 -A allele |
5’ Upstream | 194 (70 HCMV reactivation, 59 HCMV disease, 65 control) | Allelic | Increased risk of development of HCMV reactivation and disease | 0.01 | Germany/Europeans | Patients who received allogeneic stem cell transplantation | (Mezger et al., 2008) | |
| SDC2 | rs1042381 -T allele |
Exon | 194 (70 HCMV reactivation, 59 HCMV disease, 65 control) | Allelic | Increased risk of development of HCMV reactivation and disease | 0.04 | Germany/Europeans | Patients who received allogeneic stem cell transplantation | (Mezger et al., 2008) | |
| KIR2DS4 | KIR1D+ (deletion) haplotype | – | 165 | Recessive | Increased risk of HCMV reactivation | 0.002 | Chinese cohort | Patients with hematopoietic stem cell transplantation | (Wu et al., 2016) | |
| STAT4 | Rs7574865 -T allele |
Intron | 161 | Recessive | Increased risk of HCMV infection | 0.01 | Seoul National University, Korea | Patients with hematopoietic stem cell transplantation | (Wun et al., 2017) | |
| FOXP3 | Rs3761548 -C allele |
Intron | 171 | Recessive | Increased risk of HCMV infection | 0.01 | Seoul National University, Korea | Patients with hematopoietic stem cell transplantation | (Piao et al., 2016) | |
| HCMV disease in HIV infection | ||||||||||
| IL-10 | rs3024496 -C Allele |
3’ UTR | 534 (110 cases, 424 controls) | Dominant | Susceptible to CMV-Retinitis | 0.05 | USA/African Americans | Patients with AIDS | (Sezgin et al., 2010) | |
| IL-10 | rs3024500 -C Allele |
3’ UTR | 534 (110 cases, 424 controls) | Dominant | Susceptible to CMV-Retinitis | 0.02 | USA/African Americans | Patients with AIDS | (Sezgin et al., 2010) | |
| IL-10R1 (IL10RA) | rs2228055 -G allele |
Exon | 750 (200 cases, 550 controls) | Haplotypic | Susceptible to CMV-Retinitis | 0.04 | USA/Europeans | Patients with AIDS | (Sezgin et al., 2010) | |
| IL-10R1 (IL10RA) | rs2229114 -T allele |
Exon | 750 (200 cases, 550 controls) | Allelic | Protective against CMV-Retinitis | 0.03 | USA/Europeans | Patients with AIDS | (Sezgin et al., 2010) | |
| CCR5 | rs1799988 | 5’ UTR, CCR5 P1 Promoter Haplotype | 117 | Haplotypic | Increased risk of CMV-Retinitis progression | 0.007 | USA/African Americans | Patients with AIDS | (Sezgin et al., 2011) | |
| CCR5 | rs1799988 | 5’ UTR, CCR5 P1 Promoter Haplotype | 203 | Haplotypic | Increased risk of mortality in patients with CMV-Retinitis | 0.05 | USA/African Americans | Patients with AIDS | (Sezgin et al., 2011) | |
| CXCL12 (SDF1) | rs1801157 -A allele |
3′-untranslat-ed region | 117 | Dominant | Increased risk of CMV-Retinitis progression | 0.008 | USA/African Americans | Patients with AIDS | (Sezgin et al., 2011) | |
| TNF | 4-1-G-2-2-1 | 5’ Upstream | 222 (52 CMV-retinitis, 170 control) | Haplotypic | Susceptible to CMV-Retinitis | 0.03 | Brazilian cohort (mixed race) | Patients with AIDS | (Deghaide et al., 2009) | |
| TNF | TNFc1 | 5’ Upstream | 222 (52 CMV-retinitis, 170 control) | Allelic | Protective against CMV-Retinitis | 0.04 | Brazilian cohort (mixed race) | Patients with AIDS | (Deghaide et al., 2009) | |
| IFNL3/ IFNL4 |
rs368234815 -G allele |
CpG region, 5’ Upstream | 1134 | Recessive | Increased risk of CMV-retinitis | 0.007 | Europeans/Swiss HIV Cohort Study | Patients with HIV infection | (Bibert et al., 2014) | |
| HCMV disease in vertical transmission | ||||||||||
| TLR2 | rs1898830 -AG genotype |
Intron | 170 (87 case, 83 control) | Genotypic | decreased risk of congenital HCMV infection | 0.03 | Japanese cohort | Children with congenital HCMV infection | (Taniguchi et al., 2013) | |
| TLR2 | rs1898830 -GG genotype |
Intron | 83 (33 case, 50 control) | Recessive | Protection against HCMV transmission | 0.008 | Israeli cohort | Pregnant women with HCMV infection | (Eldar-Yedidia et al., 2017) | |
| TLR2 | rs3804100 (1350 T > C) -CC genotype |
Exon | 170 (87 case, 83 control) | Genotypic | Increased risk of congenital HCMV infection | 0.01 | Japanese cohort | Children with congenital HCMV infection | (Taniguchi et al., 2013) | |
| TLR2 | Arg677Trp (rs121917864, 2029 C > T) |
Exon | 229 (151 case, 78 control) | Allelic | Reduced risk of infection only in adults | < 0.001 | Polish cohort | HCMV-infected children and adults | (Jablonska et al., 2014) | |
| TLR4 | D299G (rs4986790) |
Exon | 229 (151 case, 78 control) | Allelic | Reduced risk of infection only in adults | 0.02 | Polish cohort | HCMV-infected children and adults | (Jablonska et al., 2014) | |
| TLR2 | R753Q (rs5743708, 2258 G > A) |
Exon | 51 (20 case, 30 control) | Genotypic | increased risk of congenital HCMV infection | 0.02 | Polish cohort | HCMV-infected fetuses and neonates | (Wujcicka et al., 2017a) | |
| TLR9 | rs352140 (2848 G > A) - A allele |
Exon (synonymous change) | 131 (66 case, 65 control) | Dominant | Reduced risk of HCMV infection in pregnant women | 0.03 | Polish cohort | HCMV-infected pregnant women | (Wujcicka et al., 2017b) | |
| TLR9 | rs352140 (2848 G > A) -TC genotype |
Exon (synonymous change) | 142 (72 case, 70 control) | Genotypic | Increased risk of HCMV infection in infants | 0.02 | Polish cohort | Congenitally HCMV-infected infants | (Paradowska et al., 2016) | |
| TLR9 | Rs187084 (-1486 T > C) -C allele |
Upstream |
142 (72 case, 70 control) | Dominant | Increased risk of HCMV infection in infants | 0.02 | Polish cohort | Congenitally HCMV-infected infants | (Paradowska et al., 2016) | |
| IL1A | -889 C > T | 5’ Upstream | 51 (20 case, 31 control) | Allelic | increased risk of congenital HCMV infection and onset of related symptoms | < 0.0001 | Polish Mother’s Memorial Hospital, Poland | Fetuses and Neonates with HCMV infection | (Wujcicka et al., 2017c) | |
| IL1A | -889 C > T | 5’ Upstream | 129 (65 case, 64 control) | Recessive | Decreased risk of HCMV infection | 0.05 | Polish Mother’s Memorial Hospital, Poland | Pregnant women | (Wujcicka et al., 2017d) | |
| IL1B | rs1143634 (+3954 C > T) -T allele |
Exon | 51 (20 case, 31 control) | Allelic | increased risk of congenital HCMV infection and onset of related symptoms | < 0.0001 | Polish Mother’s Memorial Hospital, Poland | Fetuses and Neonates with HCMV infection | (Wujcicka et al., 2017c) | |
| IL1B | rs16944 -T allele |
5’ Upstream | 470 (72 case, 398 control) | Genotypic | increased risk of intrauterine HCMV infection | 0.03 | Infants enrolled at the Children’s Memorial Health Institute in Warsaw, Poland | Infants with HCMV infection | (Kasztelewicz et al., 2017) | |
| IL6 | -174 G > C | 5’ Upstream | 129 (65 case, 64 control) | Recessive | Decreased risk of HCMV infection in their offspring | 0.02 | Polish Mother’s Memorial Hospital, Poland | Pregnant women | (Wujcicka et al., 2017d) | |
| CCL2 (MCP1) | rs13900 -T allele |
Exon | 470 (72 case, 398 control) | Genotypic | increased risk of hearing loss at birth | 0.03 | Infants enrolled at the Children’s Memorial Health Institute in Warsaw, Poland | Infants with HCMV infection | (Kasztelewicz et al., 2017) | |
| TNF | rs1799964 -T allele |
5’ Upstream | 470 (72 case, 398 control) | Genotypic | increased risk of intrauterine HCMV infection | 0.03 | Infants enrolled at the Children’s Memorial Health Institute in Warsaw, Poland | Infants with HCMV infection | (Kasztelewicz et al., 2017) | |
All values and information are based on the cited paper. Whenever case–control status or disease-specific divisions of patients were available, they are reported under the sample size column.
IGHG1: Immunoglobulin GM γ chain marker.
CVD-Finns: Cardiovascular risks in young Finns study.