rs7047299 — IFNA21

Regulatory variant upstream of interferon alpha-21 associated with increased susceptibility to herpes zoster (shingles) via reduced type I interferon antiviral signaling

See your personal result for IFNA21

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

IFNA21 rs7047299 — When Your Innate Antiviral Defense Runs Quiet

Herpes zoster — shingles — is not a new infection. It is varicella-zoster virus (VZV) waking up after decades of dormancy in your dorsal root ganglia, the nerve cell clusters flanking your spinal cord. Almost everyone who had chickenpox as a child carries the virus for life. Whether it stays dormant or breaks through depends critically on how well your immune system — and specifically your type I interferon11 type I interferon
A family of cytokines (IFN-alpha and IFN-beta) released within hours of viral detection; they trigger antiviral gene expression in neighboring cells, resist viral replication, and prime adaptive immune responses response — patrols the territory. rs7047299 sits upstream of IFNA21, one of thirteen interferon alpha genes clustered on chromosome 9p21.3, and the A allele at this position is associated with greater susceptibility to shingles.

The Mechanism

IFNA21 encodes interferon alpha-2122 interferon alpha-21
One of 13 IFNA genes clustered on chromosome 9p21.3 encoding subtly distinct IFN-alpha protein isoforms with overlapping but non-identical antiviral potencies; the cluster evolved through repeated gene duplications, a type I interferon secreted primarily by plasmacytoid dendritic cells within hours of detecting viral DNA via TLR9 and other innate sensors. rs7047299 lies approximately 800 bp upstream of the IFNA21 transcription start site — within the proximal promoter/regulatory region — and is annotated as a 2 KB upstream regulatory variant.

Two independent lines of experimental work establish why this matters specifically for VZV. First, IFN-alpha from epidermal cells is the primary barrier to VZV skin spread33 IFN-alpha from epidermal cells is the primary barrier to VZV skin spread
Blocking IFN-alpha receptor in ex vivo human skin increased VZV viral titers approximately tenfold; VZV itself down-regulates IFN-alpha in infected cells to enable focal replication while neighboring uninfected cells still mount a response. Second, IFN-alpha signals through the IFN-α–IRF9 axis44 IFN-alpha signals through the IFN-α–IRF9 axis
IRF9 is an interferon regulatory factor induced by IFN-alpha signaling; it forms the ISGF3 transcription complex that activates hundreds of interferon-stimulated genes; VZV's IE62 protein transcriptionally suppresses IRF9 to escape this response as the first-line delay mechanism against VZV replication. A regulatory variant that reduces IFNA21 promoter activity — or alters expression timing — would blunt this initial barrier, giving the virus an earlier window to replicate before adaptive T cell immunity is mobilized.

The Evidence

The primary association comes from a [large multi-infection GWAS | 23 GWAS studies across

200,000 individuals of European ancestry tested for 23 common infections simultaneously; 59 genome-wide significant loci identified; designed to identify immune-genetic contributions using 23andMe participant cohort data](https://pubmed.ncbi.nlm.nih.gov/28928442/55 https://pubmed.ncbi.nlm.nih.gov/28928442/) by Tian et al. (2017), which identified rs7047299 as a genome-wide significant hit for shingles susceptibility (OR = 1.07; 95% CI, 1.06–1.09; p = 2 × 10⁻⁸). The variant maps to the IFNA21/IFNWP15 chromosomal region, and the biological link to interferon-alpha production is mechanistically coherent. The per-allele OR of 1.07 is modest — comparable to many common GWAS risk alleles — but the genome-wide significance threshold provides high confidence that the association is real, not a false positive.

Complementary human evidence comes from patients with autoimmune polyendocrine syndrome type 1 (APS-1)66 patients with autoimmune polyendocrine syndrome type 1 (APS-1)
APS-1 patients produce high-titer neutralizing autoantibodies against IFN-alpha; this natural human experiment allows researchers to observe the effect of IFN-alpha deficiency on infection susceptibility in a live clinical setting, who produce neutralizing autoantibodies against IFN-alpha and experience significantly higher rates of VZV reactivation — directly confirming that inadequate IFN-alpha signaling is sufficient to allow VZV to break through. These patients also show decreased humoral responses to VZV specifically, pointing to IFN-alpha's role in coordinating both innate and adaptive antiviral defenses.

The evidence level is moderate: the GWAS association is large-scale and genome-wide significant, the biological mechanism is experimentally established, but the specific functional impact of rs7047299 on IFNA21 expression has not been characterized in an eQTL study, and dose-response data for AA vs. AG vs. GG carriers are not available from the 2017 paper.

Practical Actions

The most directly actionable implication of carrying one or two copies of the A allele is that your innate antiviral response to VZV reactivation may be somewhat blunted — not absent, but operating at reduced efficiency. Shingrix (recombinant zoster vaccine, RZV) is specifically designed to compensate for this by building strong T cell memory against VZV glycoprotein E with its AS01B adjuvant system, achieving [≥90% efficacy against herpes zoster | ZOE-70 trial:

90% efficacy in adults 70+; ZOE-50 trial: 97.2% efficacy in adults 50–69; pooled long-term data show efficacy remains high at 10+ years post-vaccination](https://pubmed.ncbi.nlm.nih.gov/27626517/77 https://pubmed.ncbi.nlm.nih.gov/27626517/) even when innate immune responses decline with age. Prioritizing Shingrix vaccination at the earliest eligible age (50 in most guidelines) is the highest-yield intervention.

Beyond vaccination, supporting robust IFN-alpha production involves avoiding immunosuppressive medications that explicitly block interferon signaling (JAK inhibitors, high-dose corticosteroids) when alternatives exist, and discussing shingles prophylaxis with your physician before starting any such treatments.

Interactions

The IFNA gene cluster on 9p21.3 contains thirteen IFNA genes in close proximity. Variants in neighboring interferon genes — particularly those affecting the broader interferon locus haplotype — may compound or buffer the effect of rs7047299. The IFNL3/IFNL4 locus on chromosome 19 (rs11322783, rs12979860) encodes type III interferons (lambda interferons) that act through a parallel pathway targeting epithelial cells; individuals with reduced type III interferon function alongside reduced type I interferon from rs7047299 may have broader antiviral vulnerability. Compound actions for this combination have not been studied, but the convergence of reduced innate signaling across multiple interferon families represents a biologically plausible interaction.

Genotype Interpretations

What each possible genotype means for this variant.

GG Protective Genotype Beneficial

Protective genotype — lower innate interferon-alpha risk profile for varicella-zoster reactivation

GG homozygosity places you in the reference category for rs7047299 — the genotype against which the A-allele risk was measured. This does not eliminate shingles risk, which is primarily age-driven: nearly one in three people develops shingles in their lifetime, regardless of rs7047299 genotype. However, the innate interferon-alpha vulnerability associated with the A allele is not a factor at this locus for GG carriers.

Standard shingles prevention recommendations (Shingrix vaccination at 50+, immune health maintenance) apply to everyone — including GG carriers — because shingles risk from age-related T cell decline is universal and independent of innate IFN-alpha status.

AG Intermediate Shingles Risk Intermediate

One risk allele — slightly elevated shingles susceptibility, well within range of vaccine protection

One copy of the A allele at rs7047299 produces one copy of whatever regulatory signal reduces IFNA21 expression or timing. If the variant operates additively, which the GWAS model supports, the effect is approximately half that of AA homozygosity. Because shingles risk is primarily driven by age-related T cell decline after age 50, the contribution of a single rs7047299 A allele is unlikely to be determinative on its own — but it contributes to the cumulative genetic load affecting VZV immunity.

The key practical implication is the same as for AA carriers: Shingrix vaccination at the earliest eligible age neutralizes the IFN-alpha innate gap by building robust adaptive immune memory that does not depend on IFNA21 expression.

AA Elevated Shingles Risk High Risk

Homozygous risk genotype — modestly elevated susceptibility to varicella-zoster virus reactivation

The OR of 1.07 per A allele means that in an additive model, carrying two A alleles confers approximately 1.07² ≈ 1.14-fold increased odds of developing shingles relative to GG carriers. This is a modest effect at the individual level — it does not predetermine shingles occurrence but shifts probability. Most people who develop shingles do so after age 50, when declining T cell immunity to VZV (not innate IFN-alpha alone) becomes the dominant determinant of reactivation risk.

The importance of this variant lies in its biological context: experimental evidence shows that IFN-alpha is the primary barrier to VZV spread in skin, and that blocking IFN-alpha signaling in human skin explants increases viral titers approximately tenfold. A regulatory upstream variant reducing IFNA21 expression could meaningfully impair this early defense. Combined with normal age-related immune decline, this genotype supports prioritizing Shingrix vaccination as early as possible.