Hypothesis: Indigenous Mexican SLE patients may be superior responders to anifrolumab due to absence of TYK2 protective variants and constitutively elevated type I interferon signaling

Background

Anifrolumab (anti-IFNAR1) targets the type I interferon (IFN-I) pathway in systemic lupus erythematosus (SLE). The TULIP trials demonstrated that patients with high IFN gene signature respond better to anifrolumab. However, no pharmacogenomic data exists for Latin American or Indigenous populations.

Key Evidence

TYK2 protective variants are absent in Indigenous Mexicans (García-Ortiz et al., Sci Rep 2019, PMID 31434951):

• rs12720356: OR=0.308 (p=0.041) — protective against SLE
• rs34536443: OR=0.370 (p=0.034) — protective against SLE
• Both replicated in adult-onset SLE (OR=0.250, p=0.005; OR=0.277, p=0.008)
• These alleles are of European origin and are absent or rare in Indigenous groups
• Implication: Indigenous patients lack a molecular brake on IFN-I signaling

PDCD1 PD.1.3 variant enriched in Mexican SLE (Prokunina et al., Nat Genet 2002, PMID 12402038):

• 7% in SLE vs 2% controls (RR=3.5, p=0.0009)
• Alters RUNX1 binding → dysregulated immune checkpoint → amplified IFN signaling

Native American ancestry correlates with SLE severity (Romero-Hidalgo et al., Sci Rep 2020, PMID 32792643):

• NMO patients: 68.1% Native American ancestry vs 58.6% controls (p=5×10⁻⁶)
• All disease-associated HLA alleles are of Native American origin

The Hypothesis

The same genetic architecture that PREDISPOSES Indigenous/Maya-mestizo patients to severe SLE may PREDICT superior response to anifrolumab:

1. Absent TYK2 protective variants → constitutively higher IFN-I pathway activation
2. PDCD1 PD.1.3 → amplified immune dysregulation → higher IFN signature
3. Higher IFN gene signature = better anifrolumab response (TULIP trial biomarker data)
4. Therefore: Indigenous Mexican SLE patients may derive greater benefit from anti-IFNAR therapy than European patients

Critical Knowledge Gaps

• IFNAR1/IFNAR2 polymorphisms: ZERO data in any Latin American population — this is the literal drug target
• IRF5, IRF7, STAT4: Key IFN-I pathway regulators with no Mexican-specific frequency data
• IFN gene signature by ancestry: No study has measured IFN-I signature stratified by Native American ancestry proportion in SLE patients

Clinical Implications

If confirmed, this hypothesis would:

• Justify prioritizing anifrolumab access in Mexican/Latin American SLE patients
• Add IFNAR1, IFNAR2, TYK2, IRF5, and STAT4 to pharmacogenomic panels for this population
• Potentially explain why SLE is more severe in Indigenous populations — and offer a targeted therapeutic solution

Proposed Validation

Measure IFN gene signature (5-gene panel: IFI27, IFI44, IFI44L, RSAD2, IFI6) stratified by:

• Ancestry proportion (Native American vs European)
• TYK2 genotype (rs34536443, rs12720356)
• PDCD1 genotype (PD.1.3)

In a cohort of Mexican SLE patients (n≥100) from IMSS Mérida, Yucatán (65-75% Native American ancestry).

Population: 607 patients, IMSS HGR1 Mérida, Yucatán, México References: PMID 31434951, 12402038, 32792643, 23511714 Analysis: STORM pharmacogenomic model (rheumascore.xyz/storm.html)