rs12720270 — TYK2 TYK2 Intron 7 Splicing Variant

TYK2 Intron 7 Splicing Variant — Regulating the Exon 8 Switch in Autoimmune Signaling

The TYK2 gene encodes a Janus kinase that sits at the junction of the IL-12, IL-23, and type I interferon signaling pathways — the three cytokine cascades most consistently implicated in autoimmune disease. Most protective TYK2 variants studied in depth are coding-sequence changes that impair kinase domain activity directly. rs12720270 operates differently: it is an intronic variant that appears to regulate pre-mRNA splicing¹¹ pre-mRNA splicing
Pre-mRNA splicing is the process by which introns are removed and exons joined to produce mature mRNA; regulated alternative splicing can include or exclude specific exons depending on sequence signals in the surrounding intron/exon context, affecting how TYK2 protein is assembled before it ever reaches the cytoplasm.

The Mechanism

rs12720270 lies in intron 7 of TYK2, positioned 36 nucleotides upstream of the intron 7/exon 8 splice acceptor boundary. Li et al. (2020)²² Li et al. (2020) demonstrated that the minor A allele of rs12720270 (together with rs2304256 in exon 8) promotes the inclusion of exon 8³³ exon 8
Exon 8 of TYK2 encodes part of the FERM domain, which mediates TYK2 binding to cytokine receptor subunits including IFNAR1 and IL-12Rβ1; without exon 8, TYK2 cannot couple properly to these receptors in the mature TYK2 transcript. The G-to-A substitution is predicted in silico to disrupt a potential branch point⁴⁴ branch point
A branch point is an adenosine nucleotide near the 3' end of an intron that initiates the lariat-formation step of RNA splicing; disrupting the branch point sequence can alter the efficiency with which the intron is removed, affecting whether the adjacent exon is included or skipped consensus sequence in intron 7, which would alter the efficiency of exon 8 recognition by the spliceosome.

Exon 8 is not dispensable: it contributes critical residues to the TYK2 FERM domain that mediate receptor binding. Without exon 8, TYK2 cannot efficiently couple to the IL-12 receptor beta-1 subunit (IL-12Rβ1) or the type I interferon receptor chain IFNAR1. Paradoxically, enhancing exon 8 inclusion — and therefore optimizing TYK2 receptor coupling — appears to reduce net autoimmune signaling output, possibly through enhanced regulatory feedback mechanisms or more precisely calibrated cytokine threshold responses.

The rs12720270 A allele and rs2304256 A allele are in strong linkage disequilibrium⁵⁵ linkage disequilibrium
Linkage disequilibrium (LD) is the non-random co-inheritance of alleles at nearby genomic positions; when two variants are in strong LD (high r²), they tend to be co-inherited as a haplotype and it can be difficult to determine which variant drives an observed association in Europeans (r² ≈ 0.83), meaning they are commonly co-inherited. The Li et al. study found that the independent effect of rs12720270 on TYK2 expression disappears after statistically accounting for rs2304256, suggesting the two variants tag the same functional haplotype in European populations. In East Asian populations, allele frequencies and LD patterns differ, which may explain why disease associations are less consistent in Asian cohorts.

The Evidence

The foundational SLE association for rs12720270 comes from two European population studies. Cunninghame Graham et al. (2007)⁶⁶ Cunninghame Graham et al. (2007) studied 380 UK SLE families and found significant under-transmission of the A allele to affected offspring (P = 0.004), placing rs12720270 among the original TYK2 variants implicated in SLE genetics. The location near an intron/exon boundary was noted at the time as mechanistically suggestive of a splicing effect, though the molecular confirmation waited for Li et al. (2020).

The Finnish SLE study⁷⁷ Finnish SLE study (277 patients, 356 controls) by Voss et al. (2009) found significant association at rs12720270 (p = 0.0031), with the G allele conferring risk (OR 1.57, 95% CI 1.16–2.21). This G allele risk framing is the reciprocal of the A allele's protection: carriers of the A allele are protected; carriers of GG lack this protection.

The most comprehensive assessment comes from the Pellenz et al. (2021) systematic review and meta-analysis⁸⁸ Pellenz et al. (2021) systematic review and meta-analysis of 34 studies, which pooled data from 2,792 SLE cases and 5,184 controls specifically for rs12720270. The A allele conferred SLE protection under the allele contrast model in Caucasian populations (FEM OR 0.84, 95% CI 0.72–0.98, P = 0.022), but the effect was not significant in Asian populations and was not evaluated for other autoimmune conditions beyond SLE. This contrasts with the co-associated rs2304256, which has been assessed across eight autoimmune conditions including RA, T1D, and MS.

Practical Implications

For users of European ancestry, the A allele frequency is approximately 18%, meaning about 33% of Europeans carry at least one A allele (AG or AA). The protective signal observed for rs12720270 in SLE is generally attributed to the same exon 8 splicing haplotype as rs2304256, and the two variants should be interpreted together where possible. When a user carries the A allele at both rs12720270 and rs2304256, the evidence is strongest — they carry the complete protective haplotype across both the intronic splicing signal and the exonic Val362Phe variant.

The variant is relevant in the same clinical contexts as other protective TYK2 alleles: autoimmune disease workup interpretation, biologic therapy prescribing context, and family history counseling for SLE and related conditions. As with rs2304256, if a TYK2 inhibitor such as deucravacitinib is prescribed, the A allele at this locus contributes to a genetic background of partially modulated TYK2 signaling.

Interactions

rs12720270 and rs2304256 (Val362Phe) are in strong linkage disequilibrium in Europeans and were identified together in the same functional splicing study. They promote exon 8 inclusion through complementary intronic and exonic splicing signals, respectively — the intronic branch point effect of rs12720270 and the exonic splicing enhancer effect encoded by the Val362Phe substitution of rs2304256. Carriers of the A allele at rs12720270 are very likely to also carry the A allele at rs2304256.

The splicing/expression arm of TYK2 protection (rs12720270 and rs2304256) is mechanistically independent from the kinase-domain-impairment arm (rs34536443 P1104A, rs12720356 I684S, rs35018800 A928V). Individuals who carry the exon 8 splicing haplotype (rs12720270/rs2304256 A alleles) together with coding protective alleles at the other TYK2 loci have multiple independent layers of TYK2 attenuation through distinct structural mechanisms.

Beyond TYK2, this variant acts within the same type I interferon pathway as IRF5 (rs10954213), where functional interaction between TYK2 and IRF5 variants on SLE risk has been documented in Finnish and other European population studies.