I’m continuing my deep dives into the genetic pathways to get actionable insights as the previous ones have been incredible precise and useful. This time I’m looking at inflammation & immune system genetic pathways.
Here is the general description of the pathways and their variants. I will put the finding about my own genome below it as an example of what useful and actionable insights you can get.
Inflammation_Immune_Genetic_Pathway_Reference.pdf (560.2 KB)
Inflammation & Immune Genetic Report
Highest Priority
1. PTPN22 R620W HOMOZYGOUS (rs2476601 A/A)
Gain-of-function lymphoid phosphatase; strongest common autoimmune risk variant. Population frequency of homozygotes ~1–2%. Action: Request orthogonal clinical confirmation (e.g., validated genotyping platform). Discuss baseline autoimmune vigilance with PCP; consider rheumatology referral for baseline. Mitigator: All three HLA tag SNPs (DRB1 shared epitope, C*06:02, DQ2.5) negative — substantially reduces the HLA-driven RA/celiac/psoriasis risk multiplier.
2. CFH Y402H HOMOZYGOUS (rs1061170 T/T) + second CFH hit
One of the largest common-variant effects in human GWAS. AMD homozygous OR ~4.6. Action: Baseline OCT + fundus imaging with a retina specialist; age-appropriate surveillance thereafter. Discuss AREDS2-style lutein/zeaxanthin if Momentous Multi does not cover.
3. NFE2L2 (NRF2) -617 HOMOZYGOUS (rs6721961 G/G)
Reduced promoter transcription of the entire antioxidant response element program (SOD2, GPX1, NQO1, HMOX1, GCLC, GCLM). Keystone of the glutathione bottleneck that spans 4 reports (NFE2L2 here + CTH in Hcy + AKR1B1/GLO1 in Glycation). Action: Add sulforaphane (10–30 mg/d from stabilized broccoli sprout extract) — the single most impactful supplement addition. Increase NAC/NACET (current 100mg NACET is likely insufficient; target 300–600 mg NACET or 600 mg NAC).
4. Thyroid surveillance (PTPN22 context)
PTPN22 homozygous + absent HLA counterweight specifically for Hashimoto’s and Graves’. Action: Annual TSH, free T4, anti-TPO, anti-thyroglobulin — baseline if not already done. One-time ANA / anti-CCP / RF baseline screen is reasonable.
Moderate Priority
5. Add curcumin (bioavailable form, 500–1000 mg/d)
Dual action: second NRF2 activator (supports the keystone finding) and NF-κB inhibitor (addresses NFKB1 ins/del het + IKBKB het). Meriva / phytosome / BCM-95 forms preferred over standard curcumin.
6. IL6 G/G protective — confirmed across 3 reports
Inflammation, Glucose, and Endothelial reports all show this. Action: Use hs-CRP as your primary inflammatory marker — because genetic baseline is low, any hs-CRP elevation is mechanistically informative and warrants investigation rather than being written off as high genetic set-point. Recommend quarterly if stable.
7. Inflammasome het cluster (IL18 hom + NLRP3 het + IL1B double het + AIM2 het)
Modest upward bias in IL-1β/IL-18 axis. Current regimen already well-aligned: doxycycline 20mg BID (NLRP3 modulation), empagliflozin (NLRP3 inhibition), omega-3 stack (DHA directly inhibits NLRP3). No medication change needed — just note the mechanistic fit when discussing.
8. TGFB1 double homozygous + ALOX15 homozygous (resolution category)
Downstream resolution machinery shifted, but FADS1/FADS2/ELOVL2 all clean — substrate supply for resolvins/protectins is not genetically limited. Current EPA/DHA stack is adequate. Consider slight prioritization of DHA-rich fish oil over pure EPA given the downstream enzyme shifts. Aspirin (already on 81mg) is particularly well-matched here because aspirin-triggered lipoxins provide an alternate pro-resolving pathway bypassing ALOX15.
Monitoring & Lower Priority
9. hs-CRP as the primary inflammatory functional marker
Given the unique combination of IL6 G/G protective + clean TNF + inflammasome hets + CFH complement burden + adhesion molecule signals (from endothelial report), hs-CRP integrates all of these. Target: quarterly if stable, more often if trending. Pair with fibrinogen and neutrophil-to-lymphocyte ratio for integrated inflammatory assessment.
10. Functional glutathione assessment
Given the 4-report glutathione bottleneck convergence, a specialized reduced glutathione / GSSG ratio test would directly measure whether the genetic vulnerability is manifesting clinically and would serve as a biomarker for efficacy of sulforaphane + higher NAC intervention. Not all labs offer this; Doctor’s Data, Genova, and some academic centers do. Optional but mechanistically informative.
Quick alignment summary — what’s already working
HIGHLY FAVORABLE in current regimen:
- Rapamycin (mTOR → broad anti-inflammatory)
- Aspirin 81mg (aspirin-triggered lipoxins)
- Low-dose doxycycline (NLRP3 modulation)
- Omega-3 stack (~2g EPA + 0.4g DHA, substrate-adequate with FADS clean)
- Polyphenol cluster: CacaoVia, olive leaf, d-limonene, ergothioneine (all NRF2 activators)
- Empagliflozin (NLRP3 inhibition)
- Tirzepatide (GLP-1 anti-inflammatory)
Gaps to add:
- Sulforaphane (HIGH priority)
- NAC/NACET dose increase (HIGH priority)
- Curcumin bioavailable form (MODERATE priority)
- Lutein/zeaxanthin if not in Momentous Multi (MODERATE priority)
Monitoring to add:
- Thyroid panel + autoantibodies (HIGH priority — PTPN22)
- Baseline retinal OCT + fundus (HIGH priority — CFH)
- hs-CRP quarterly (primary functional marker)