TABLE 1.
Current literature on polymorphisms and RSV disease
| Candidate gene category | Gene | Polymorphism | Association of mutant with primary outcome | Biological significance of polymorphism on RSV pathogenesis | Haplotypee | Trial design (cases and controls) | Reference |
|---|---|---|---|---|---|---|---|
| 384 SNPs in 220 candidate genesa | VDR | Thr1Met | T allele OR,d 1.30; P = 0.0017 | Candidate genes associated with severe RSV were predominantly innate immune genes rather than genes with other functions such airway mucosal responses, chemotaxis, adaptive immunity, allergic asthma; P = 0.046 | ND | 480 children (10 were >12 mo of age) hospitalized for RSV bronchiolitis, parents, and 1,030 randomly chosen people from a different study (The Netherlands) | 66 |
| JUN | G750A | A allele OR, 1.51; P = 0.0093 | |||||
| IFNA5 | C453T | T allele OR, 0.77; P = 0.0093 | |||||
| NOS2A | G2757A | A allele OR, 1.27; P = 0.0031 | |||||
| FCER1A | T-66C | C allele OR, 1.25; P = 0.0113 | |||||
| Surfactantsc | SPA | SP-A1 Val19Ala | 19Ala allele underrepresented; OR, 0.16 (CI, 0.04-0.7); P = 0.007 | Unknown; substitution of glutamine by lysine at amino acid 223 is located in the carbohydrate recognition domain of SPA and may have an impact on its binding and neutralizing capacity for RSV | SP-A1 6A alleleb underrepresented (OR, 0.17; P = 0.01); SP-A2 1A3 allele overrepresented (OR, 10.44; P = 0.006); 1A allele underrepresented (OR, 0.17; P = 0.011); 6A/1Ab haplotypes underrepresented (OR, 0.17; P = 0.011); 6A2/1A3 overrepresented (OR, 10.4; P = 0.006) | 86 infants less than 1 yr of age hospitalized with a diagnosis of RSV bronchiolitis confirmed by antigen testing vs 95 matched healthy control subjects (Finland) | 80 |
| SP-A2 Ala91Pro | 91Pro allele underrepresented (OR, 0.29 [CI, 0.1-0.6]; P = 0.001) | ||||||
| SP-A2 Gln223Lys | 223Lys allele overrepresented; (OR, 1.78 [CI, 1.1-2.9]; P = 0.023) | ||||||
| SPB | −32G/T, T131I, 5781A/C, L176F, R272H | No association | Unknown | −32G/T, T131I, 5781A/C in tight LD, association of haplotypes (P = 0.034) | 131 infants who were hospitalized due to RSV infection and needed supplementary oxygen and/or gavage feeding were compared with 322 children with asthma or 270 randomly chosen adults (Germany) | 103 | |
| SPD | Met11Thr | 11 Met allele overrepresented (OR, 1.63; P = 0.033); 11 Met/Met genotypes overrepresented (OR, 2.29 [CI, 1.09-4.81]; P = 0.028) | Unknown; those authors speculated that differences in hydrophobic properties between methionine verses threonine in the amino-terminal part may have functional consequences such as less opsonization | ND | 86 infants less than 1 yr of age hospitalized with a diagnosis of RSV bronchiolitis confirmed by antigen testing vs 95 matched healthy control subjects (Finland) | 74 | |
| Ala160Thr, Ser270Thr | No association | ||||||
| SPC | Asn138Thr | No association | Unknown | Haplotype 138Thr-186Asn overrepresented (OR, 0.1651 vs 0.0790 vs 0.0845; P = 0.00029) | 131 infants less than 2 yr of age, who were hospitalized due to RSV infection and needed supplementary oxygen and/or gavage feeding were compared with 322 children with asthma or 270 randomly chosen adults (Germany) | 107 | |
| Asn186Ser | |||||||
| Pattern recognition receptors | TLR4 | Asp299Gly | Gly allele overrepresented (OR, 5.1; P = 0.0014) | Cells that are transfected with the polymorphic alleles with Asp299Gly and Thr399Ile fail to translocate TLR4 to cell surface and have reduced NF-κB activity and cytokine production; PBMC of children with variant TLR4 have blunted responses to RSV; the same mutations were previously associated with hyporesponsiveness to LPS; hyporesponsiveness of patient's PBMCs to LPS was a risk factor for intensive care unit hospitalization for RSV | Cosegregation of both mutations (OR, 4.0; P = 0.034) | 99 infants under 12 mo of age hospitalized for RSV | 122 |
| Thr399Ile | Ile allele overrepresented (OR, 4.0; P = 0.01) | ||||||
| Asp299Gly | Genotype underrepresented P = 0.054 (HWE) | 299Asp/399Ile haplotype frequency of −0.0236 in RSV vs 0.0018 in controls (P = 0.001) | 131 infants less than 2 yr of age who were hospitalized due to RSV infection and needed supplementary oxygen and/or gavage feeding were compared with 270 randomly chosen adults (Germany) | 107 | |||
| Thr399Ile | No association | ||||||
| Asp299Gly | No mutations found | ND | 54 children less than 24 mo of age hospitalized for RSV antigen positive bronchiolitis compared with 203 healthy controls who never had wheezing episodes (Japan) | 64 | |||
| Thr399Ile | |||||||
| Asp299Gly | No association | Proinflammatory cytokine production following TLR4 activation of PBMC from subjects was indistinguishable between those who had genotypes that were homozygous (Asp/Asp) those with genotypes that were heterozygous (Asp/Gly) | ND | 136 infants who were hospitalized for RSV versus100 patients with RSV who were monitored as outpatients vs general population control | 100 | ||
| CD14 | −159C/T | No association | Unknown; the SNP at −159C/T is located within a major transcription site and may affect transcription of the CD14 gene; TT genotype is known to have a higher level of soluble CD14 than the CC genotype | ND | 99 infants under 12 mo of age hospitalized for RSV bronchiolitis compared to 82 infants who had mild RSV bronchiolitis and were seen in ambulatory settings or adults (Israel) | 122 | |
| −159C/T | No association | ND | 131 infants less than 2 yr of age who were hospitalized due to RSV infection and needed supplementary oxygen and/or gavage feeding were compared with 270 randomly chosen adults (Germany) | 104 | |||
| −159C/T | No association | Patients with CC genotype had higher serum level of soluble CD14; higher soluble CD14 levels may enhance inflammation and cause severe disease | No association | 54 children less than 24 mo of age hospitalized for RSV antigen positive bronchiolitis compared with 203 healthy controls who never had wheezing episodes (Japan) | 64 | ||
| −550C/T | C allele associated with severe bronchiolitis (OR, 1.78; P = 0.034) | ||||||
| MBL | Combinations of wild-type or variant structural and promoter alleles | No association | Mutation in the promoter region and exon 1 of MBL results in low serum levels of MBL, which is a common immunodeficiency with rates of up to 10% | ND | 55 infants aged 1 to 12 mo, hospitalized for lower respiratory tract infection with RSV vs 113 contemporary matched controls enrolled from immunization clinics | 71 | |
| Cytokine and receptor adhesion molecules | CXC3R1 | Amino acid 280; genotype Met/Met plus Thr/Met | Overrepresented (OR, 2.03 [CI, 1.1-3.9]; P = 0.025) | Unknown; CX3CR1 gene poly-morphisms that substitute valine for isoleucine at position 249 and threonine for methionine at position 280 disrupt CX3CR1 affinity with its ligand fractalkine, which has been shown to be involved in RSV infection | 249Ile-280Met overrepresented (OR, 2.2 [CI, 1.3-3.8]; P = 0.003) | 82 children aged 1-24 mo hospitalized with RSV-positive lower respiratory disease vs 126 sex-matched healthy adults without a history of lower respiratory tract disease (Greece) | 2 |
| IL-4 | T-589C | −589T, −33T, 8375G, 8412A alleles overrepresented (OR, 1.63 [CI, 1.07-2.49]; P = 0.02) (these SNPs are linked) | Unknown; changes in the promoter region of IL-4 at position −589 leads to higher binding affinity to nuclear transcription factors | Common haplotypes with completely linked SNP variants linked SNP variants (OR, 1.53 [CI, 1.07-2.49]; P = 0.02) | 105 children less than 24 mo old hospitalized with RSV disease vs 315 healthy blood donors (South Korea) | 18 | |
| T-33C | |||||||
| G8375A | |||||||
| A8412 | |||||||
| T-1098G | No associations | ||||||
| C-144T | |||||||
| C-590T | T allele overrepresented in case-control (OR, 1.43; P = 0.04); overrepresented in TDT (OR, 1.33; P 0.13) | No association | 207 children hospitalized for RSV and both parents or 447 random individuals (The Netherlands) | 59 | |||
| T-589C | No association | IL-4/IL-13 haplotype associated | 131 infants less than 2 yr of age who were hospitalized due to RSV infection and needed supplementary oxygen and/or gavage feeding were compared with 270 randomly chosen adults (Germany) | 106 | |||
| IL4RA | Ile50Val | No association | The Gln551Arg polymorphism is located in the intracellular domain of the IL-4 receptor in a region known to play an important role in IL-4-induced activation of STAT6 DNA-binding activity | No association | 207 children hospitalized for RSV and both parents or 447 random individuals (The Netherlands) | 59 | |
| Gln551Arg | |||||||
| IL-5 | −746 | No association | Unknown | ND | 105 children less than 24 mo old hospitalized with RSV disease vs 315 healthy blood donors (South Korea) | 18 | |
| IL-9 | A-345G | No association | Unknown | ND | 207 children hospitalized for RSV and both parents or 447 random individuals (The Netherlands) | 58 | |
| IL-13 | C-1112T | T allele overrepresented (wild-type allele frequency for cases of 0.713 vs 0.784; P = 0.026) | SNP in the promoter sequence at position −1112 of the IL-13 gene has been shown to alter the binding of nuclear transcription | Haplotype analysis including 3 IL-13 and 1 IL-4 polymorphism associated with RSV disease (P = 0.0008) | 131 infants less than 2 yr of age who were hospitalized due to RSV infection and needed supplementary oxygen and/or gavage feeding were compared with 270 randomly chosen adults (Germany) | 106 | |
| Arg110Gln | No association | factor and expression of IL-13 | |||||
| −1512 | No association | No association | 105 children less than 24 mo old hospitalized with RSV disease vs 315 healthy blood donors (South Korea) | 18 | |||
| −1112 | |||||||
| G2044A | |||||||
| IL-10 | −1082 | Genotypes stratified as “high, intermediate, and low phenotype producers” correlated with development of pneumonia (0%, 11%, and 27%, respectively; P = 0.02) | Stratification of genotype to high, intermediate, and low phenotypes has not been validated in context of RSV infection | ND | 77 infants hospitalized for RSV vs 107 randomly selected adults (United States) | 41 | |
| C-592A | No association overall C allele overrepresented in children <6 mo old (OR 1.61 [CI, 1.10-2.35]; P = 0.014) | Genetic interaction of IL-10-592A allele with IL4Ra Q551R allele (OR, 2.03; P = 0.01) | 207 children hospitalized for RSV and both parents or 447 random individuals (The Netherlands) | 58 | |||
| 5876, 4949, 1547, 919, −627, −854, −1117, −3585 | No association overall; −1117 and −3585 alleles associated with need for mechanical ventilation | SNPs in the promoter studied (−1117, −854, and −627) have been associated with altered transcriptional regulation of IL-10 | No association | 580 infants <12 mo of age who had RSV bronchiolitis and who required gavage feeds, intravenous, or oxygen vs 580 infants born consecutively (United Kingdom) | 138 | ||
| IL-18 | A-607C, G-137C, T133G, C127T, A5304G, G133C | G-133C associated with severe RSV (P = 0.043) | SNP in the promoter at position −133C/G potentially creates a new binding site for STAT | Haplotype analysis (P < 0.00001) | 134 infants less than 2 yr of age who were hospitalized due to RSV infection and needed supplementary oxygen and/or gavage feeding were compared with 270 randomly chosen adults (Germany) | 105 | |
| IL-6 | G-174C | “Higher-producer” genotype −174G/G; G/C associated with shorter hospital stay (P = 0.009) | IL-6 genotype was not related to IL-6 levels in experimentally infected adults (42 adults) | ND | 77 infants hospitalized for RSV vs 107 randomly selected adults (United States) | 41 | |
| TNF-α | G-308A | No association | Unknown | Genetic interaction of TNF-α −308A allele with IL4RA Gln551Arg contributing to OR of 0.40 (P = 0.01) | 207 children hospitalized for RSV and both parents or 447 random individuals (The Netherlands) | 58 | |
| G-308A | No association | ND | 77 infants hospitalized for RSV vs 107 randomly selected adults (United States) | 41 | |||
| TGFB1 | Haplotype for codons 10 and 25 | Stratification of genotype to high, intermediate, and low phenotypes has not been validated in context of RSV infection | Associated with oxygen score at presentation (P = 0.008) | 77 infants hospitalized for RSV vs 107 randomly selected adults (United States) | 41 | ||
| IFN-γ | 874 | “High-producer” genotype tended to have more severe disease as measured by physical exam score (P < 0.001; intensive care unit stay P = 0.021) | Stratification of genotype to high, intermediate, and low phenotype has not been validated in context of RSV infection | ND | 77 infants hospitalized for RSV vs 107 randomly selected adults (United States) | 41 | |
| IL-8 | T-251A | A allele associated with higher-than-expected rate of transmission of 78% (CI, 62-93%; P = 0.004) | Unknown | ND | 83 infants admitted for RSV bronchiolitis vs their parents (United Kingdom) | 62 | |
| T-251A | No association | No association | 131 infants less than 2 yr of age who were hospitalized due to RSV infection and needed supplementary oxygen and/or gavage feeding were compared with 270 randomly chosen adults (Germany) | 108 | |||
| C-781T | |||||||
| IL8RA | Met32Arg | No association | Unknown | No association | 131 infants less than 2 yr of age, who were hospitalized due to RSV infection and needed supplementary oxygen and/or gavage feeding, were compared with 270 randomly chosen adults (Germany) | 108 | |
| Ser276Thr | |||||||
| Arg335Cys | |||||||
| CCR5 | −2554T | T allele OR, 1.25 (P = 0.01) | SNP in the promoter at position −2459 is associated with both enhanced and decreased expression of CCR5 | −2554T and −2459G in complete linkage disequilibrium | 580 infants <12 mo of age who had RSV bronchiolitis and who required gavage feeds, intravenous, or oxygen vs 580 infants born consecutively (United Kingdom) | 61 | |
| −2459G | G allele OR, 1.21 (P = 0.02); homozygosity enhanced association slightly | ||||||
| Delta21 | No association | ||||||
| −1835 | |||||||
| −2733 | |||||||
| RANTES | C-28G, G-403A, TIn1.1C | No association | SNP variants −28G and −403A in the promoter region of RANTES; upregulate RANTES transcription | −28C/C−403G/Ain1.1T/T combined genotype (OR, 2.3; P = 0.035) | 106 children aged 1-24 mo hospitalized with RSV-positive lower respiratory disease vs 126 sex-matched healthy adults without a history of lower respiratory tract disease (Crete) | 1 | |
| ICAM-1 | Lys469Glu | No association | Unknown | No association | 134 infants less than 2 yr of age who were hospitalized due to RSV infection and needed supplementary oxygen and/or gavage feeding were compared with 270 randomly chosen adults (Germany) | 72 | |
| A20788G | |||||||
| VCAM-1 | −C833T | No association | Unknown | ND | 134 infants less than 2 yr of age who were hospitalized due to RSV infection and needed supplementary oxygen and/or gavage feeding were compared with 270 randomly chosen adults (Germany) | 72 | |
| E-selectin | Ser128Arg | No association | Unknown | ND | 134 infants less than 2 yr of age who were hospitalized due to RSV infection and needed supplementary oxygen and/or gavage feeding were compared with 270 randomly chosen adults (Germany) | 72 | |
| HIs468Tyr | |||||||
| Others | HLA | HLA A, HLA B | No association | ND | 65 | ||
| IGHG | IGHG2 genotype −n/−n | Overrepresented (OR, 2.3; P = 0.004) | IGHG2(−n) allele and IGHG2(−n/−n) genotype were previously shown to be correlated with low antibody response to bacterial agents, immunodeficiencies, and nonatopic phenotype of childhood asthma | 49 children from Finland hospitalized for RSV infection during a single season vs 430 healthy Caucasian children from Sweden | 7 | ||
| IGHG allele bf-n | Overrepresented (OR, 1.7; P = 0.025) |
a
Genes that had associations at both the allele level and genotype level are shown here.
b
The SP-A gene consists of two functional genes, SP-A1 and SP-A2, with five and four polymorphic sites, respectively. Nineteen alleles were identified for SP-A1 (denoted 6An), and 15 alleles were identified for SP-A2 (denoted 1An).
c
Some surfactant proteins, especially SP-A, are also classified as pattern recognition receptors.
d
OR, the frequency of an allele in the diseased population divided by the frequency of this allele in the control (nondiseased) population. An OR of >1 would mean that the allele is associated with a worse outcome, and an OR of <1 would mean that the allele protects against severe RSV disease.
e
A haplotype is a combination of alleles on each chromosome that tend to be inherited together. Thus, a haplotype, in the context of polymorphism analysis, is a combination of SNPs within the candidate gene of interest. Haplotype analysis compares the frequency of the occurrence of the different haplotypes in populations having different disease severities. Haplotype analysis has the advantage of assessing the influence of a block of SNPs (or genes), which fall in proximity to the SNP being analyzed. ND, not determined.