STAT4 and Systemic Lupus Erythematosus

STAT4 was first implicated in SLE by a common intronic haplotype marked by rs7574865, present on 31% of chromosomes in SLE cases versus 22% in controls (OR 1.55, P = 1.87 × 10⁻⁹) (PMID:17804842). This association was replicated in European and North American cohorts and extended to Asian populations, demonstrating its trans-ethnic relevance.

A Chinese Han GWAS of 1,047 SLE cases and 1,205 controls confirmed STAT4 as a susceptibility locus (P < 5.17 × 10⁻⁴²) alongside seven other loci, underscoring its consistent effect across ancestries (PMID:19838193). A meta-analysis of 2,478 SLE patients and 5,058 controls yielded an overall OR of 1.57 for the rs7574865 T allele (95% CI 1.44–1.71; P < 0.001) (PMID:19479340).

In a Japanese case–control series (308 SLE patients, 306 controls), the rs7574865 T allele frequency was 46.3% versus 33.5% in controls (OR 1.71, P = 4.9 × 10⁻⁶), with stronger effects in nephritis and anti-dsDNA subgroups (PMID:18803832). No evidence has emerged to dispute these findings.

Functional studies demonstrate that STAT4 phosphorylation on Ser721 by the MKK6/p38α pathway is critical for IL-12-driven transcriptional activity. Mutation c.2161T>G (p.Ser721Ala) abolishes IFN-γ production without affecting proliferation, confirming a phosphorylation-dependent mechanism (PMID:10961885; PMID:12213961).

Integration of large genetic cohorts and concordant functional data supports a Strong ClinGen gene-disease association for STAT4 in SLE. Genetic evidence is Moderate (common variants in >15,000 cases across ancestries), and functional evidence is Moderate (mechanistic phosphorylation assays and cellular models).

Key Take-home: STAT4 intronic risk variants confer a reproducible increase in SLE susceptibility by altering Ser721 phosphorylation and downstream Th1/IFN-γ responses, providing a target for stratified risk assessment and potential therapeutic intervention.

References

• Molecular medicine (Cambridge, Mass.) • 2007 • Association of STAT4 with rheumatoid arthritis in the Korean population. PMID:17932559
• The New England journal of medicine • 2007 • STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. PMID:17804842
• Nature genetics • 2009 • Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. PMID:19838193
• Molecular biology reports • 2010 • Association of STAT4 polymorphism with rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis. PMID:19479340
• Arthritis research & therapy • 2008 • Role of STAT4 polymorphisms in systemic lupus erythematosus in a Japanese population: a case-control association study of the STAT1-STAT4 region. PMID:18803832
• Blood • 2000 • Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. PMID:10961885
• Proceedings of the National Academy of Sciences of the United States of America • 2002 • STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. PMID:12213961

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