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Diseases/Lupus/Genes/TYK2

SLE gene evidence

TYK2

Tyrosine kinase 2

Evidence summaryStrong and consistently replicated association with SLETwo independent genetic signals

Overview

A central immune-signalling gene

TYK2 is one of the strongest and most consistently replicated genetic risk genes for systemic lupus erythematosus.

TYK2 encodes a Janus kinase involved in signalling downstream of type I interferons, IL-12 and IL-23. This places it at the centre of innate and adaptive immune responses—systems strongly implicated in lupus biology.

Key findingTwo independent association signals have been identified at the TYK2 locus, both with strong statistical evidence of association with SLE.

Genetic association with SLE

Two distinct signals

The odds ratios below are less than one, indicating that the measured alleles are associated with protection from SLE rather than increased susceptibility.

Signal 01Stronger functional evidence
Likely causal variant

rs34536443

Ala1104Pro

Protein-altering variant
Odds ratio0.53
95% CI0.47–0.59
P-value9.8 × 10⁻²⁶

The strongest candidate causal variant for the primary TYK2 association signal.

Proposed mechanism

The protective allele reduces TYK2 kinase activity and impairs signalling through type I interferon, IL-12 and IL-23 pathways.

Signal 02Mechanism less certain
Likely causal variant

rs34725611

Correlated with rs2304256 (Val362Phe)

Likely regulatory variant
Odds ratio0.80
95% CI0.77–0.83
P-value3.8 × 10⁻²⁷

A second association signal that is independent of the primary protein-altering signal.

Proposed mechanism

Evidence suggests that rs2304256 and linked variants affect TYK2 expression and transcript processing, although the functional mechanism is less certain.

Current understanding

Different variants, converging effects on TYK2 activity

01

Protein function

Signal 1 is most likely driven by rs34536443, a missense variant that alters TYK2 protein function.

02

Regulation and splicing

Signal 2 is likely driven by regulatory variation, with rs2304256 and linked variants affecting TYK2 splicing and expression.

03

Interferon signalling

Together, these variants alter TYK2 activity and contribute to differences in interferon signalling, a major biological pathway implicated in SLE.

Key reference

Evidence source