Table 1 Genetics variants contributing to respiratory disease.
From: Genetic influences on viral-induced cytokine responses in the lung
Gene | Polymorphism | Effect on protein/function | Disease susceptibility virus association, and related host process presented in Fig. 1 (initiation/disease progression) |
|---|---|---|---|
Cytokines, chemokines and receptors | |||
CCR5 | CCR5-Δ32 | 32 bp deletion in CCR5 coding region resulting in partially reduced receptor expression | ↑Influenza A121 Enhancement of cytokines and ISG induction by recruited cells |
IL1A | rs17561 G > T Ser114Ala | Unknown | ↑Influenza A119 Production of cytokines and chemokines |
IL1B | rs1143627 T > C | Possible increased IL1B expression associated with T allele; rs1143627 located on TATA box of IL1B promoter region, may affect TF binding | ↑Influenza A119 Production of cytokines and chemokines |
TNF | rs361525 (TNF −238 A allele) G > A | Decreased TNF transcripts | ↑Influenza A118 Production of cytokines and chemokines Enhancement of cytokines and ISG induction by recruited cells |
IL4 | rs2243250 (IL4 −589T allele) C > T | Increased IL4 transcripts | ↑RSV (embedded within common IL4 haplotype defined at five loci)127 T-cell activation Effector T-cell response |
IL8 | IL8 haplotype: (−251A/+396G/+781T/ +1238delA/+1633T/ +2767T) | Increased IL8 transcripts | ↑RSV130 Production of cytokines and chemokines Enhancement of cytokines and ISG induction by recruited cells |
IL10 | rs1800872 (−592 C/A allele) C > A | Currently not clear whether the C or A allele is associated with higher IL10 expression | ↓RSV with heterozygosity at this allele137 ↑RSV − 592 C allele in children ≤6 months of age137 Enhancement of cytokines and ISG induction by recruited cells T-cell activation |
IL13 | rs1881457 (−1512 C allele) A > C rs1800925 (−1112 C/T allele) C > T | Unknown Altered expression of IL13 and increased binding of nuclear factors to IL13 promoter | ↑RSV with −1512 C allele in the presence of allele 50 Ile in IL4R (rs1801275)128 ↑RSV128 T-cell activation Effector T-cell response |
IL6 | rs1800795 (−174 G/C allele) G > C | −174 CC low producer phenotype | ↑RSV with CC allele132 Production of cytokines and chemokines Enhancement of cytokines and ISG induction by recruited cells T-cell activation |
IFNA5 | rs10757212 C > T | Unknown | ↑RSV135 Production of cytokines and chemokines |
RANTES | rs2280788 (−28 G allele) C > G | Possible enhanced promoter activity | ↑SARS-CoV-1138 Production of cytokines and chemokines |
IFNGR1 | 201-2 A > G | Complete absence of IFN-γ responsiveness observed with homozygosity. Mutation in splice site at end of intron 2, in frame deletion of 34 amino acids, generating a truncated protein of assumed non-function. | ↑RSV112 Enhancement of cytokines and ISG induction by recruited cells T-cell activation Effector T-cell response |
Pattern recognition receptors | |||
TLR3 | rs5743313 T > C | Located in transmembrane signal transduction domain; potentially linked to reduced signalling | ↑Influenza A with CC and CT genotypes144,145 Detection of virus |
DDX58 | rs72710678 G > A Arg71His rs138425677 C > T Pro885Ser | CARD domain; decreased recognition function of RIG-I, impaired antiviral immune responses RNA binding domain; decreased recognition function of RIG-I, impaired antiviral immune responses | ↑Influenza A146 Detection of virus |
TLR8 | rs3761624 A > G | Located in TLR8 promoter region. Increased TLR8 mRNA expression following acute and chronic DNA damage stress in a p53RE SNP-dependent manner. Minor G allele creates a CWWG core in the second decamer of the p53RE within the TLR8 promoter. The A allele in the rs3761624 variant disrupts the CWWG core, reducing p53 binding | ↑RSV with G allele148 Detection of virus |
TLR4 | rs4986790 A > G/A > T Asp299Gly rs4986791 C > T | Located in ectodomain of TLR4; hyper-responsive LPS phenotype Located in ectodomain of TLR4; hyper-responsive LPS phenotype | ↑RSV148 Detection of virus |
TLR2 | rs1898830 C > A rs7656411 G > T | Intron variant Downstream variant 500 kB | ↑Bronchiolitis149 Detection of virus |
TLR9 | rs352162 C > T rs187084 C > T | Unknown Upstream variant 2 kB | ↑Bronchiolitis149 Detection of virus |
IFIH1 | rs35732034 C > T (IFIH1-Δ14) rs35337543 C > G (IFIH1-Δ8) | Minor allele T causes skipping of exon 14, resulting in a frame shift and an early stop codon in exon 15. IFIH1 protein lacks final 153 amino acids, including the C-terminal regulatory domain (CTD), essential for viral dsRNA binding Minor allele G causes skipping of exon 8, removing 39 amino acids at the end of the helicase 1 domain and in the linker part between helicase 1 and helicase 2 Severe disruption of IFIH1 signalling function, enzymatic activity, and protein stability in vitro demonstrated for both IFIH1-Δ8 and IFIH1-Δ14 | ↑RSV8 Detection of virus |
Transcription factors | |||
IRF7 | Two compound heterozygous IRF7 mutations—p.Phe410Val (F410V) and p.Gln421X (Q421X) | F410V: missense substitution predicted to be damaging Q421X: nonsense mutation predicted to generate a premature stop codon Both alleles–lack of IRF7-dependent amplification of type I and III IFN post-influenza exposure | ↑Influenza153 Production of cytokines and chemokines Enhancement of cytokines and ISG induction by recruited cells |
IRF9 | 991 G > A | Mutation in final nucleotide of exon 7 disrupts the essential splice site at the boundary of exon 7 and intron 7, resulting in mRNAs lacking exon 7 and an IRF9 protein probably lacking the IRF association domain (IAD), where STAT proteins bind. Cells with this mutation are impaired in ISG induction | ↑Influenza154 IFN response and ISG induction Enhancement of cytokines and ISG induction by recruited cells |
JUN | rs11688 G > A | Unknown; synonymous variant | ↑RSV135 Production of cytokines and chemokines |
VDR | rs10735810 (also rs2228570) C > T Thr1Met | Initiator codon variant, located at first start codon in exon 2, changes the translation initiation site, resulting in a truncated protein. Truncated protein may have higher activity than the wild type protein | ↑RSV135 Enhancement of cytokines and ISG induction by recruited cells |
Viral restriction factors | |||
IFITM3 | rs12252 T > C rs34481144 C > T | Unknown; synonymous variant Located in the promoter region of IFITM3, repression of IFITM3 expression with A allele, possibly through enhanced CTCF binding to IFITM3 promotor | ↑SARS-CoV-2163 ↑Influenza161 IFN response and ISG induction Enhancement of cytokines and ISG induction by recruited cells |
