The Crazy Version

What if the reason anti-IL17 agents work so well in Maya-mestizo SpA/PsA patients is not a fluke of IMSS formulary — but the echo of a 15,000-year immunological arms race?

The Beringian Migration Theory of IL-17 Superactivation

Step 1: The Crossing (~15,000 years ago) Ancestors of the Maya crossed Beringia from Northeast Asia. They shared a common gene pool with populations that became Japanese, Korean, and Siberian Indigenous groups. This is why:

• CYP3A5 expressor frequencies in Maya (~30%) parallel East Asian populations (~30%) but diverge from Europeans (~10%)
• NUDT15 risk allele: Maya ~10%, East Asian ~10%, European <1%
• TYK2 protective variants: absent in both Maya AND East Asian Indigenous — they were introduced to mestizos by Spanish colonizers

Step 2: The Tropical Pressure Cooker (15,000 → 500 years ago) While their Northeast Asian cousins faced cold-adapted pathogens, Maya ancestors migrated south into Mesoamerica — a tropical paradise of:

• Parasites (helminths, protozoa)
• Fungi (Coccidioides, Histoplasma — endemic in Yucatán)
• Mycobacteria

All of these pathogens are fought primarily by... the IL-17 pathway.

Natural selection CRANKED UP IL-17 signaling in these populations over 15,000 years. The ones with the most aggressive IL-17 response survived malaria, parasites, and fungal infections. The ones without it died.

Step 3: The Autoimmune Tax (modern era) The same supercharged IL-17 pathway that protected against tropical pathogens now ATTACKS SELF in the absence of those pathogens (hygiene hypothesis on steroids):

• SpA/PsA in Maya-mestizo = IL-17 pathway firing at full blast with no parasites to fight
• This explains the FEMALE PREDOMINANCE paradox (65% in our cohort vs 30-40% expected) — estrogen AMPLIFIES IL-17 responses, and in a population with already superactivated IL-17, women cross the autoimmune threshold more easily

Step 4: The Therapeutic Paradox Anti-IL17 agents (secukinumab, ixekizumab) are essentially PRECISION MISSILES against the exact pathway that evolution overactivated:

• In Europeans: IL-17 is moderately activated → anti-IL17 works okay
• In Maya-mestizo: IL-17 is SUPERACTIVATED (15,000 years of selection) → anti-IL17 works SPECTACULARLY because there is MORE target to block

This would explain why secukinumab is the most prescribed individual biologic in our Mérida cohort — clinicians are empirically discovering what evolution already knew.

The Japanese Parallel (Supporting Evidence)

Japanese rheumatologists show similar divergence from Western guidelines:

• Higher tacrolimus use (CYP3A5 parallel with Maya)
• Different biologic preferences
• Shared Beringian ancestry with Indigenous Americans

If this hypothesis is correct, the Japanese SpA/PsA registry data should ALSO show higher-than-expected anti-IL17 efficacy compared to European registries. This is a testable prediction.

The Fungal Connection

Yucatán is endemic for Coccidioides and Histoplasma. IL-17 is the PRIMARY defense against fungal infections. The genes that fight fungi are the SAME genes that cause SpA/PsA:

• CARD9 (FinnGen: p=4.2×10⁻⁶ for erosive arthropathy)
• CLEC7A/Dectin-1 (FinnGen: p=1.7×10⁻⁵ for psoriasis)
• TLR2 (FinnGen: p=9.2×10⁻⁶ for psoriasis)

NONE of these genes have been studied in Mexican populations. But if Maya populations carry gain-of-function variants in these fungal defense genes (selected by millennia of tropical exposure), it would simultaneously explain:

1. Better fungal immunity
2. Higher SpA/PsA susceptibility
3. Superior anti-IL17 response

The Prediction

If the Beringian IL-17 Superactivation hypothesis is correct:

• IL-17A/F serum levels in Maya SLE/SpA patients should be HIGHER than matched European patients
• IL23R, IL12B, TRAF3IP2 gain-of-function variants should be ENRICHED in Maya vs European
• Anti-IL17 ASAS40/ACR50 response rates in Mexican registries should EXCEED European TULIP/MEASURE equivalents
• Japanese SpA registries should show parallel findings
• CARD9/CLEC7A variants should show population-specific frequencies correlating with endemic fungal exposure

Why This Matters

This is not just academic speculation. If 15,000 years of pathogen warfare created an IL-17 superactivated population, then:

• Anti-IL17 should be FIRST-LINE (not second-line) in Maya-mestizo SpA/PsA
• Anti-TNF may be suboptimal for this population (the target pathway is IL-17, not TNF)
• Guideline recommendations based on European genetics are WRONG for 650M+ Latin Americans

The data from IMSS Mérida (n=89) is the first real-world signal. The pharmacogenomics of the IL-17 pathway in Indigenous Americans is a $0 dataset waiting to revolutionize treatment for an entire continent.

Population: 89 SpA/PsA patients, IMSS HGR1 Mérida, Yucatán (65-75% Native American ancestry) Parallel evidence: CYP3A5/NUDT15 Beringian frequencies, FinnGen IL-17 pathway analysis, endemic mycoses References: PMID 31434951, 24926019, 26812836