immunity.py

"""Immunity, autoimmunity & inflammation — curated chip-callable markers."""
from .common import G, C, CHIPS_ALL, PGKB, GWAS, CLIN, CPIC


def register(add):
    add(
        "rs1800795", "IL6", "Interleukin-6 Promoter (-174G>C / Systemic Inflammation)", "7", 22766645,
        ["immunity", "inflammation", "cardio", "fitness"], "strong", "C", "G",
        "IL-6 is a key pro-inflammatory cytokine and exercise-induced myokine. The G allele is associated with higher inducible IL-6 expression in response to stress and exercise.",
        G("Higher Inducible IL-6 (GG)", "notable",
          "Two G alleles. Robust IL-6 inflammatory response.",
          "Higher systemic inflammatory reactivity, but also strong myokine signaling during resistance training.",
          eat=["Anti-inflammatory nutrition: high omega-3s, curcumin, dark berries, and leafy greens."],
          move=["Ensure adequate recovery days between intense training sessions."]),
        G("Intermediate IL-6 (CG)", "typical", "Balanced IL-6 expression.", "Standard baseline."),
        G("Lower Inducible IL-6 (CC)", "advantageous",
          "Two C alleles. Lower baseline IL-6 production.",
          "Associated with lower baseline systemic inflammation and favorable cardiovascular longevity profiles.",
          eat=["Standard healthy anti-inflammatory diet."]),
    )

    add(
        "rs1800629", "TNF", "Tumor Necrosis Factor-Alpha (-308G>A)", "6", 31543031,
        ["immunity", "inflammation"], "strong", "A", "G",
        "TNF-alpha is a central master cytokine driving acute and chronic inflammation. The A allele (-308A) increases TNF-alpha promoter transcription by ~2-fold.",
        G("Typical TNF-Alpha (GG)", "typical", "Standard baseline TNF-alpha transcription.", "Normal inflammatory baseline."),
        G("Elevated TNF-Alpha Expression (AG)", "notable",
          "One A allele. Higher inducible TNF-alpha expression.",
          "Predisposed to stronger inflammatory reactions, post-infection fatigue, and inflammatory joint discomfort.",
          eat=["Incorporate natural TNF-alpha modulators: curcumin, green tea EGCG, ginger, and EPA/DHA omega-3s."]),
        G("High TNF-Alpha Transcription (AA)", "caution",
          "Two A alleles. Markedly higher inducible TNF-alpha.",
          "Significant pro-inflammatory tendency; benefits from proactive lifestyle anti-inflammatory protocols.",
          eat=["Strict whole-food anti-inflammatory diet; avoid industrial seed oils and refined sugars."],
          mind=["Chronic psychological stress elevates TNF-alpha; practice active stress reduction."]),
    )

    add(
        "rs4349859", "HLA-B", "HLA-B*27 Tag SNP (Ankylosing Spondylitis & Reactive Arthritis)", "6", 31324522,
        ["immunity", "autoimmunity"], "strong", "A", "G",
        "rs4349859 is in strong linkage disequilibrium with the HLA-B*27 major histocompatibility complex antigen, the strongest genetic risk factor for axial spondyloarthritis (Ankylosing Spondylitis), uveitis, and reactive arthritis.",
        G("Typical (GG)", "typical", "Negative for HLA-B*27 tag.", "Low baseline genetic risk for HLA-B27 associated arthropathies."),
        G("HLA-B*27 Tag Carrier (AG)", "caution",
          "One A allele. Positive tag for HLA-B*27.",
          "Associated with increased lifetime susceptibility to inflammatory back pain (axial spondyloarthritis), uveitis, and reactive arthritis. Most carriers never develop disease, but early recognition of inflammatory back pain is crucial.",
          move=["Maintain daily spinal mobility, swimming, and postural exercises."],
          recover=["If experiencing chronic inflammatory lower back/sacroiliac pain that improves with exercise but worsens with rest, consult a rheumatologist."]),
        G("HLA-B*27 Tag Homozygote (AA)", "caution",
          "Two A alleles. Positive for HLA-B*27.",
          "Elevated susceptibility to HLA-B27 spondyloarthropathies.",
          recover=["Discuss with a clinician if joint inflammation or eye inflammation (uveitis) occurs."]),
    )

    add(
        "rs2476601", "PTPN22", "Lymphoid Phosphatase (R620W / Multi-Autoimmune Susceptibility)", "1", 114377568,
        ["immunity", "autoimmunity"], "strong", "A", "G",
        "PTPN22 (Lyp) regulates T-cell and B-cell receptor signaling thresholds. The A allele (620W) impairs phosphatase inhibition, allowing autoreactive immune cells to escape negative selection, predisposing to multiple autoimmune conditions (Hashimoto's thyroiditis, Type 1 diabetes, rheumatoid arthritis, vitiligo).",
        G("Typical Immune Signaling (GG)", "typical", "Normal T-cell receptor threshold.", "Baseline autoimmune risk."),
        G("Autoimmune Susceptibility Carrier (AG)", "caution",
          "One A allele. ~2x increased risk for autoimmune thyroid and joint conditions.",
          "Lower threshold for autoreactive immune activation.",
          eat=["Prioritize gut barrier integrity: avoid ultra-processed emulsifiers, optimize vitamin D, and maintain a diverse microbiome."],
          recover=["Include thyroid panel (TSH, free T4, TPO antibodies) in annual checkups if autoimmune symptoms arise."]),
        G("High Autoimmune Susceptibility (AA)", "caution",
          "Two A alleles. Significantly increased multi-autoimmune predisposition.",
          "Elevated lifetime vigilance for autoimmune presentations.",
          recover=["Annual autoimmune screening and prompt evaluation of persistent unexplained fatigue or joint pain."]),
    )

    # --- 2.0 expansion: celiac tags, cytokines, asthma/atopy, autoimmune loci, host defense ---
    add(
        "rs2187668", "HLA-DQA1 (DQ2.5 tag)", "Celiac HLA-DQ2.5 Tag SNP", "6", 32605884,
        ["immunity", "autoimmunity", "gut"], "strong", "C", "T",
        "Tag SNP for the HLA-DQ2.5 haplotype that presents gluten peptides to T cells. DQ2.5 is necessary-but-not-sufficient: ~90% of celiac patients carry it, yet most carriers never develop celiac. TAGS ARE IMPERFECT PROXIES for true HLA typing.",
        G("No DQ2.5 tag (CC)", "typical", "DQ2.5 haplotype not indicated by this tag.", "A negative tag does NOT fully exclude celiac-permissive HLA (DQ8 and tag failures exist) — see the celiac compound card."),
        G("One DQ2.5 tag (CT)", "notable", "Celiac-permissive haplotype likely present.", "~2-3% lifetime celiac risk vs ~0.7% baseline. Only relevant with symptoms or family history; never start a gluten-free diet before clinical testing (it invalidates the tests).",
          eat=["If chronic GI/fatigue/anemia symptoms exist, ask about celiac serology WHILE still eating gluten."]),
        G("Two DQ2.5 tags (TT)", "notable", "Homozygous permissive haplotype signal.", "Higher risk tier (~5%+ with family history), still a minority outcome. Same testing rule: serology before any dietary change."),
        tier="well-replicated", transferability="euro-biased",
        effect="DQ2.5 carriage: celiac OR ~6-7; homozygous higher — strong but non-deterministic",
        citations=[C(18509540, "Monsuur 2008, PLoS ONE — HLA tag-SNP validation for celiac"),
                   C(GWAS, "Celiac HLA epidemiology (Sollid reviews)")],
    )
    add(
        "rs7454108", "HLA-DQB1 (DQ8 tag)", "Celiac/T1D HLA-DQ8 Tag SNP", "6", 32681631,
        ["immunity", "autoimmunity", "gut"], "strong", "T", "C",
        "Tag SNP for HLA-DQ8, the second celiac-permissive haplotype (also a type 1 diabetes risk haplotype). Same proxy caveat: tags approximate, they do not type HLA.",
        G("No DQ8 tag (TT)", "typical", "DQ8 not indicated.", "Interpret with the DQ2.5 tag on the celiac compound card."),
        G("One DQ8 tag (CT)", "notable", "DQ8 haplotype likely present.", "Celiac-permissive (weaker than DQ2.5); relevant mainly with symptoms/family history."),
        G("Two DQ8 tags (CC)", "notable", "Homozygous DQ8 signal.", "Same clinical-testing-first rule as DQ2.5."),
        tier="well-replicated", transferability="euro-biased",
        effect="DQ8: celiac OR ~2-3; also T1D-permissive",
        citations=[C(18509540, "Monsuur 2008 — HLA tag validation")],
    )
    add(
        "rs3087243", "CTLA4", "CTLA-4 CT60 (Immune Checkpoint Set-Point)", "2", 204738919,
        ["immunity", "autoimmunity"], "strong", "G", "A",
        "CTLA-4 restrains T-cell activation. CT60 shifts soluble-CTLA4 splicing: the G allele associates with autoimmune thyroid disease, T1D, and other organ-specific autoimmunity — small effects each.",
        G("Risk-leaning (GG)", "typical", "Slightly lower checkpoint restraint.", "Small autoimmunity contribution."),
        G("Intermediate (AG)", "typical", "Intermediate.", "Small."),
        G("Protective-leaning (AA)", "typical", "Higher soluble-CTLA4 pattern.", "Small protective association."),
        tier="well-replicated", effect="OR ~1.15-1.3 across organ-specific autoimmunity",
        transferability="multi-ancestry",
        citations=[C(12724780, "Ueda 2003, Nature — CTLA4 and autoimmunity")],
    )
    add(
        "rs231775", "CTLA4", "CTLA-4 A49G (Thr17Ala)", "2", 204732714,
        ["immunity", "autoimmunity"], "moderate", "A", "G",
        "Coding CTLA4 variant traveling with CT60; classic Graves/T1D association literature.",
        G("Reference (AA)", "typical", "Baseline checkpoint.", "Interpret with CT60."),
        G("Intermediate (AG)", "typical", "Intermediate.", "Small."),
        G("Risk-leaning (GG)", "typical", "Autoimmune-thyroid-associated pattern.", "Small effect; thyroid labs if symptoms."),
        tier="replicated", effect="OR ~1.2 thyroid autoimmunity",
        citations=[C(GWAS, "CTLA4 A49G meta-analyses")],
    )
    add(
        "rs361525", "TNF", "TNF-alpha Promoter (-238G>A)", "6", 31543101,
        ["immunity", "inflammation"], "moderate", "G", "A",
        "Second classic TNF promoter variant with small expression effects; disease associations heterogeneous.",
        G("Reference (GG)", "typical", "Typical TNF expression.", "Baseline."),
        G("One A allele (AG)", "typical", "Small expression shift.", "Small."),
        G("Two A alleles (AA)", "typical", "Rare pair.", "Small, heterogeneous literature."),
        tier="tendency", effect="Small, heterogeneous",
        citations=[C(GWAS, "TNF -238 meta-analyses")],
    )
    add(
        "rs1143634", "IL1B", "Interleukin-1β (+3954C>T)", "2", 113590390,
        ["immunity", "inflammation"], "moderate", "C", "T",
        "Classic IL-1β coding-region variant associated with higher IL-1β production in stimulation assays; periodontitis literature is the most consistent.",
        G("Reference (CC)", "typical", "Typical IL-1β output.", "Baseline."),
        G("One T allele (CT)", "typical", "Higher stimulated IL-1β.", "Oral hygiene diligence has evidence here — flossing is anti-inflammatory."),
        G("Two T alleles (TT)", "notable", "Highest-output pattern.", "Periodontitis association is the practical one: dental hygiene and regular cleanings.",
          recover=["Take gum health seriously — IL-1β genotypes show the strongest periodontitis signals."]),
        tier="replicated", effect="OR ~1.3-1.6 periodontitis in meta-analyses",
        citations=[C(GWAS, "IL1B +3954 periodontitis meta-analyses (Kornman 1997 and successors)")],
    )
    add(
        "rs16944", "IL1B", "Interleukin-1β Promoter (-511C>T)", "2", 113594867,
        ["immunity", "inflammation"], "moderate", "G", "A",
        "IL-1β promoter variant forming haplotypes with +3954; broad small-effect literature.",
        G("Reference (GG)", "typical", "Typical promoter.", "Interpret with +3954."),
        G("Intermediate (AG)", "typical", "Intermediate.", "Small."),
        G("Variant pair (AA)", "typical", "Haplotype pole.", "Small effects; interpret with +3954."),
        tier="tendency", effect="Haplotype member",
        citations=[C(GWAS, "IL1B promoter haplotype studies")],
    )
    add(
        "rs1800896", "IL10", "Interleukin-10 Promoter (-1082A>G)", "1", 206946897,
        ["immunity", "inflammation"], "moderate", "T", "C",
        "IL-10 is the major anti-inflammatory brake. The -1082 variant shifts production in stimulation assays (G/C-coded on some arrays; A/T-coded here per dbSNP plus strand).",
        G("Higher-IL10-leaning (TT)", "typical", "Higher anti-inflammatory set-point pattern.", "Baseline."),
        G("Intermediate (CT)", "typical", "Intermediate production.", "Baseline."),
        G("Lower-IL10-leaning (CC)", "typical", "Lower stimulated IL-10 pattern.", "Recovery hygiene (sleep, omega-3s, exercise) supports inflammation resolution for every genotype."),
        tier="tendency", effect="Assay-level production shifts; disease links heterogeneous",
        citations=[C(GWAS, "IL10 -1082 production studies")],
    )
    add(
        "rs20541", "IL13", "Interleukin-13 (R130Q) — Atopy Axis", "5", 131995964,
        ["immunity", "inflammation"], "strong", "G", "A",
        "IL-13 drives IgE class-switching and airway mucus. R130Q (the A allele) enhances signaling: replicated asthma/atopy associations.",
        G("Reference (GG)", "typical", "Typical IL-13 signaling.", "Baseline atopy odds."),
        G("One 130Q allele (AG)", "typical", "Modestly higher IgE/atopy tendency.", "Small."),
        G("Two 130Q alleles (AA)", "notable", "Replicated asthma/atopy association.", "If allergic symptoms are active, standard triggers (dust-mite covers, air filtration) have evidence.",
          recover=["Bedroom air quality and dust-mite control help atopic genotypes most."]),
        tier="well-replicated", transferability="multi-ancestry",
        effect="OR ~1.2-1.4 asthma/atopy per allele",
        citations=[C(GWAS, "IL13 R130Q asthma meta-analyses")],
    )
    add(
        "rs2243250", "IL4", "Interleukin-4 Promoter (-589C>T)", "5", 132009154,
        ["immunity", "inflammation"], "moderate", "C", "T",
        "IL-4 promoter variant raising expression; Th2/IgE axis partner of IL13 R130Q.",
        G("Reference (CC)", "typical", "Typical IL-4 expression.", "Baseline."),
        G("One T allele (CT)", "typical", "Higher-expression tendency.", "Small."),
        G("Two T alleles (TT)", "typical", "Th2-leaning promoter pair.", "Interpret with IL13; atopy management is environmental."),
        tier="replicated", effect="Small Th2-axis shift",
        citations=[C(GWAS, "IL4 -589 atopy meta-analyses")],
    )
    add(
        "rs1801275", "IL4R", "IL-4 Receptor (Q576R)", "16", 27374400,
        ["immunity", "inflammation"], "moderate", "A", "G",
        "IL-4 receptor variant altering downstream STAT6 signaling; atopy literature with modest effects.",
        G("Reference (AA)", "typical", "Typical receptor signaling.", "Baseline."),
        G("One 576R allele (AG)", "typical", "Modest signaling shift.", "Small."),
        G("Two 576R alleles (GG)", "typical", "Atopy-associated pattern.", "Interpret with IL4/IL13."),
        tier="replicated", effect="Small",
        citations=[C(GWAS, "IL4R Q576R atopy studies")],
    )
    add(
        "rs7216389", "ORMDL3/GSDMB", "Childhood Asthma Locus (17q21)", "17", 38069949,
        ["immunity", "inflammation"], "strong", "C", "T",
        "The 17q21 locus is the most replicated childhood-asthma region; the T allele raises ORMDL3 expression with OR ~1.4 for childhood-onset asthma.",
        G("Reference (CC)", "typical", "Baseline 17q21 contribution.", "Baseline."),
        G("One risk allele (CT)", "typical", "Modest childhood-asthma association.", "Historical information for adults; relevant to family planning conversations."),
        G("Risk pair (TT)", "notable", "OR ~1.7 vs CC for childhood asthma.", "For adults this is mostly explanatory; early-life smoke exposure interacts strongly — keep homes smoke-free."),
        tier="well-replicated", transferability="multi-ancestry",
        effect="OR ~1.4 per allele childhood asthma — the flagship asthma locus",
        citations=[C(17611496, "Moffatt 2007, Nature — ORMDL3 and childhood asthma")],
    )
    add(
        "rs61816761", "FLG", "Filaggrin R501X (Skin Barrier Null)", "1", 152285861,
        ["immunity", "traits"], "strong", "G", "A",
        "Filaggrin builds the skin's moisture barrier. R501X is a true null: carriers have measurably leakier skin — strong eczema association and the classic 'atopic march' gateway.",
        G("Intact barrier gene (GG)", "typical", "No R501X null.", "Other FLG nulls exist that this array misses."),
        G("One null allele (AG)", "notable", "Eczema OR ~3-4; dry-skin tendency.", "Daily emollient habit is genuinely preventive for FLG carriers — cheap and evidence-backed.",
          recover=["Moisturize daily (ceramide-based), especially in winter; treat soaps/hot showers as barrier strippers."]),
        G("Two null alleles (AA)", "caution", "Strong barrier deficiency (rare).", "Ichthyosis-vulgaris-pattern dryness and high eczema risk; dermatology-grade skincare routine pays off.",
          recover=["Consistent emollient use morning/night; dermatologist if eczema is active."]),
        tier="well-replicated", transferability="euro-biased", chips=["23andme_v5"],
        effect="Eczema OR ~3-4 per null allele — strong",
        citations=[C(16550169, "Palmer 2006, Nat Genet — FLG nulls and atopic dermatitis")],
    )
    add(
        "rs3135388", "HLA-DRB1*15:01 tag", "Multiple Sclerosis Major Haplotype Tag", "6", 32413051,
        ["immunity", "autoimmunity"], "strong", "G", "A",
        "Tag for HLA-DRB1*15:01, the strongest MS risk haplotype (OR ~3). Absolute MS risk remains low even for carriers (~0.3-1%). Tag, not true HLA typing.",
        G("No 15:01 tag (GG)", "typical", "Major MS haplotype not indicated.", "Baseline."),
        G("One tag allele (AG)", "typical", "MS OR ~3 relative — absolute risk still ~0.5%.", "Vitamin D sufficiency and not smoking are the modifiable factors in MS epidemiology."),
        G("Two tag alleles (AA)", "notable", "MS OR ~6 relative — absolute risk still low.", "Same modifiables; symptoms (optic neuritis, focal neurology) get standard medical attention regardless of genotype."),
        tier="well-replicated", transferability="euro-biased",
        effect="OR ~3 per haplotype — large relative, small absolute",
        citations=[C(17660530, "Hafler 2007, NEJM — IMSGC MS GWAS"), C(GWAS, "DRB1*15:01 tag validation")],
    )
    add(
        "rs689", "INS", "Insulin Gene VNTR Tag (-23HphI) — T1D Axis", "11", 2182224,
        ["immunity", "autoimmunity", "glucose"], "strong", "A", "T",
        "Tags the insulin-gene VNTR governing thymic insulin expression (immune tolerance). The A allele tags the short VNTR class with higher T1D risk — second only to HLA for T1D.",
        G("Higher-T1D-tag pair (AA)", "typical", "Short-VNTR-class tag.", "T1D is mostly a childhood-onset conversation; adult carriers simply carry history."),
        G("Intermediate (AT)", "typical", "Mixed tag.", "Baseline."),
        G("Protective-tag pair (TT)", "typical", "Long-VNTR-class tag.", "Modest T1D protection association."),
        notes="Palindromic A/T site — reviewed; chips vary in coverage of this SNP.",
        tier="well-replicated", transferability="euro-biased", reviewed=True, chips=["23andme_v5", "myheritage"],
        effect="T1D OR ~2 for susceptible VNTR class",
        citations=[C(GWAS, "INS VNTR T1D literature (Bell 1984; Barratt 2004)")],
    )
    add(
        "rs2240340", "PADI4", "Citrullination Enzyme Variant (RA, East-Asian Axis)", "1", 17672730,
        ["immunity", "autoimmunity"], "moderate", "C", "T",
        "PADI4 citrullinates proteins (the targets of RA's anti-CCP antibodies). Replicated RA association in East-Asian cohorts; weaker in Europeans — a transferability lesson in reverse.",
        G("Reference (CC)", "typical", "Baseline.", "Baseline."),
        G("One risk allele (CT)", "typical", "Small RA association (East-Asian data strongest).", "Not smoking is THE modifiable RA factor."),
        G("Risk pair (TT)", "typical", "Modest RA association.", "Same: smoking triples anti-CCP RA risk and interacts with citrullination biology."),
        tier="replicated", transferability="east-asian-derived",
        effect="RA OR ~1.3 in East-Asian cohorts; weak in European",
        citations=[C(GWAS, "PADI4 RA studies (Suzuki 2003; meta-analyses)")],
    )
    add(
        "rs7574865", "STAT4", "STAT4 Autoimmune Hub (RA/SLE)", "2", 191964633,
        ["immunity", "autoimmunity"], "strong", "G", "T",
        "STAT4 transduces IL-12/IL-23 signals. The T allele is a replicated cross-autoimmunity risk factor (RA OR ~1.3, lupus OR ~1.5).",
        G("Reference (GG)", "typical", "Baseline.", "Baseline."),
        G("One risk allele (GT)", "typical", "Small cross-autoimmune association.", "Small."),
        G("Risk pair (TT)", "notable", "Replicated RA/SLE association pair.", "Context for symptoms, never a prediction; photoprotection and no smoking are rational anyway."),
        tier="well-replicated", transferability="multi-ancestry",
        effect="RA OR ~1.3, SLE OR ~1.5 per allele",
        citations=[C(17804842, "Remmers 2007, NEJM — STAT4 and RA/SLE")],
    )
    add(
        "rs2004640", "IRF5", "Interferon Regulatory Factor 5 (Lupus Axis)", "7", 128578301,
        ["immunity", "autoimmunity"], "strong", "G", "T",
        "IRF5 splice-site variant creating a functional exon-1B isoform; replicated lupus association through interferon-pathway activation.",
        G("Reference (GG)", "typical", "Baseline interferon tone.", "Baseline."),
        G("One risk allele (GT)", "typical", "Small SLE association.", "Small."),
        G("Risk pair (TT)", "typical", "SLE OR ~1.4-1.6 vs GG.", "Absolute risk remains low; photosensitivity symptoms deserve standard evaluation."),
        tier="well-replicated", transferability="multi-ancestry",
        effect="SLE OR ~1.3 per allele",
        citations=[C(16642019, "Graham 2006, Nat Genet — IRF5 and SLE")],
    )
    add(
        "rs10484554", "HLA-C region", "Psoriasis HLA-C*06:02 Tag", "6", 31274555,
        ["immunity", "autoimmunity"], "strong", "C", "T",
        "Tag for HLA-C*06:02, the major psoriasis haplotype (OR ~2.5-4, early-onset guttate especially). Tag caveat applies.",
        G("No tag (CC)", "typical", "Major psoriasis haplotype not indicated.", "Baseline."),
        G("One tag allele (CT)", "typical", "Psoriasis OR ~2.5 relative — absolute risk modest.", "Skin trauma, strep throat, smoking, and alcohol are the classic triggers."),
        G("Two tag alleles (TT)", "notable", "Strong haplotype signal.", "If plaques appear, dermatology has excellent options now — no need to tough it out."),
        tier="well-replicated", transferability="euro-biased",
        effect="OR ~2.5-4 for C*06:02 carriage",
        citations=[C(GWAS, "Psoriasis GWAS — HLA-C (Nair 2009)")],
    )
    add(
        "rs30187", "ERAP1", "Peptide-Trimming Enzyme (Ankylosing Spondylitis)", "5", 96124330,
        ["immunity", "autoimmunity"], "strong", "C", "T",
        "ERAP1 trims peptides for HLA-B27 presentation. The T allele raises AS risk ONLY in B27-positive people — a clean gene-gene interaction example.",
        G("Reference (CC)", "typical", "Baseline trimming.", "Baseline."),
        G("One risk allele (CT)", "typical", "Small AS contribution (B27-dependent).", "Only meaningful alongside HLA-B27 — see that card."),
        G("Risk pair (TT)", "typical", "AS-associated trimming pattern.", "Interacts with B27 status; inflammatory-pattern back pain gets rheumatology attention."),
        tier="well-replicated", transferability="multi-ancestry",
        effect="OR ~1.3 per allele, conditional on B27",
        citations=[C(GWAS, "ERAP1-HLA-B27 interaction (Evans 2011, Nat Genet)")],
    )
    add(
        "rs179247", "TSHR", "TSH Receptor Intronic (Graves Tendency)", "14", 81558100,
        ["immunity", "autoimmunity"], "moderate", "A", "G",
        "TSHR intronic variant from Graves-disease GWAS; shifts thymic TSHR isoform expression.",
        G("Risk-leaning (AA)", "typical", "Small Graves association.", "Thyroid labs if symptomatic (palpitations, heat intolerance, weight loss)."),
        G("Intermediate (AG)", "typical", "Intermediate.", "Baseline."),
        G("Reference (GG)", "typical", "Baseline.", "Baseline."),
        tier="replicated", effect="OR ~1.3-1.5 Graves per allele",
        citations=[C(GWAS, "TSHR Graves GWAS (Brand 2009)")],
    )
    add(
        "rs1801274", "FCGR2A", "Fc-Gamma Receptor IIa (H131R) — Antibody Handling", "1", 161479745,
        ["immunity"], "strong", "A", "G",
        "FcγRIIa binds IgG2 immune complexes. H131 (A) binds IgG2 well; R131 (G) poorly — affecting encapsulated-bacteria defense and appearing in Kawasaki/infection GWAS.",
        G("Efficient IgG2 binding (AA)", "typical", "H131/H131.", "Typical encapsulated-bacteria handling."),
        G("Intermediate (AG)", "typical", "Mixed binding.", "Baseline."),
        G("Reduced IgG2 binding (GG)", "typical", "R131/R131 pattern.", "Slightly weaker IgG2-mediated clearance — pneumococcal vaccination (standard schedule anyway) is the practical answer."),
        tier="well-replicated", transferability="multi-ancestry",
        effect="Replicated binding difference; modest infection-susceptibility shifts",
        citations=[C(GWAS, "FCGR2A H131R infection/Kawasaki GWAS (Khor 2011)")],
    )
    add(
        "rs1800450", "MBL2", "Mannose-Binding Lectin B Allele (Innate Complement)", "10", 54531235,
        ["immunity"], "strong", "G", "A",
        "MBL2 structural B allele disrupts lectin-pathway complement activation; low-MBL genotypes associate with modestly higher childhood/mucosal infection frequency.",
        G("Typical MBL (GG)", "typical", "Functional lectin pathway.", "Baseline."),
        G("One B allele (AG)", "typical", "Reduced MBL level.", "Usually silent in healthy adults."),
        G("Two B alleles (AA)", "notable", "Low-MBL genotype.", "Recurrent sinopulmonary infections have one more explanation; worth mentioning to a clinician in that context.",
          recover=["If infections recur unusually often, MBL deficiency is a named, testable entity — raise it."]),
        tier="replicated", effect="Level reduction strong; clinical impact modest",
        citations=[C(GWAS, "MBL2 deficiency literature")],
    )
    add(
        "rs4986790", "TLR4", "Toll-Like Receptor 4 (D299G) — LPS Sensing", "9", 120475302,
        ["immunity", "inflammation"], "moderate", "A", "G",
        "TLR4 senses bacterial LPS. D299G blunts signaling: lower baseline inflammatory response, with mixed infection/atherosclerosis literature.",
        G("Typical LPS sensing (AA)", "typical", "Reference innate response.", "Baseline."),
        G("One 299G allele (AG)", "typical", "Blunted LPS response.", "Mixed literature: slightly calmer innate tone."),
        G("Two 299G alleles (GG)", "typical", "Rare blunted-sensing pair.", "Same mixed evidence; nothing actionable."),
        tier="replicated", effect="Functional blunting; clinical picture mixed",
        citations=[C(GWAS, "TLR4 D299G meta-analyses")],
    )
    add(
        "rs12252", "IFITM3", "Interferon-Induced Antiviral Protein (Influenza Severity)", "11", 320772,
        ["immunity"], "strong", "T", "C",
        "IFITM3 blocks viral membrane fusion. The C allele (common in East Asia, rare in Europe) associates with more severe influenza in hospitalized cohorts.",
        G("Reference (TT)", "typical", "Full-length IFITM3.", "Baseline."),
        G("One C allele (CT)", "typical", "Possible modest severity shift.", "Annual flu vaccination is the practical lever."),
        G("CC pair", "notable", "Severity-associated genotype (East-Asian cohorts).", "Flu vaccination and early antiviral care during confirmed influenza matter a bit more here.",
          recover=["Treat influenza seriously: vaccinate annually; seek care early with high fever + respiratory decline."]),
        tier="replicated", transferability="east-asian-derived",
        effect="Severity OR ~1.4-3 in hospitalized cohorts — moderate, context-limited",
        citations=[C(22446628, "Everitt 2012, Nature — IFITM3 and influenza severity")],
    )
    add(
        "rs8099917", "IFNL3/4 region", "Interferon Lambda Secondary Tag (HCV Axis)", "19", 39743165,
        ["immunity"], "strong", "T", "G",
        "Second IL28B/IFNL tag used in HCV clearance and treatment-response literature; largely historical now that DAAs cure most HCV, but a landmark of host-genetics medicine.",
        G("Favorable-response pair (TT)", "typical", "Higher spontaneous/treatment clearance pattern.", "Historical interest post-DAA era."),
        G("Intermediate (GT)", "typical", "Intermediate.", "Historical."),
        G("Less-favorable pair (GG)", "typical", "Lower interferon-era response pattern.", "Modern antivirals largely erase this difference."),
        tier="well-replicated", effect="Strong in interferon era; historic now",
        transferability="multi-ancestry",
        citations=[C(19749758, "Suppiah 2009, Nat Genet — IL28B and HCV treatment response")],
    )
    add(
        "rs28929474", "SERPINA1", "Alpha-1 Antitrypsin PiZ Allele", "14", 94844947,
        ["immunity", "detox"], "strong", "C", "T",
        "The PiZ allele misfolds alpha-1 antitrypsin: it accumulates in liver and fails to protect lung elastin. PiZZ homozygotes face serious emphysema/liver risk; MZ carriers are mostly fine UNLESS they smoke.",
        G("No PiZ (CC)", "typical", "Typical AAT at this allele.", "PiS and rarer alleles exist — see rs17580."),
        G("PiMZ carrier (CT)", "notable", "One PiZ allele (~2-3% of Europeans).", "Usually healthy — but smoking multiplies COPD risk dramatically for MZ carriers, and heavy alcohol stresses the same liver pathway.",
          recover=["Absolute smoking avoidance is THE actionable item for PiZ carriers; mention carrier status if liver enzymes ever run high."]),
        G("PiZZ pattern (TT)", "caution", "Alpha-1 antitrypsin deficiency genotype.", "This warrants real clinical follow-up (AAT level testing, lung/liver baseline) — one of the few array findings with concrete medical value. Confirm clinically first.",
          recover=["Ask a clinician for serum AAT level confirmation; never smoke; limit alcohol."]),
        tier="well-replicated", transferability="euro-biased",
        effect="PiZZ: high emphysema risk (smoking-dependent); MZ: modest, smoking-conditional",
        citations=[C(CLIN, "SERPINA1 PiZ pathogenic (AATD)"), C(GWAS, "AATD epidemiology reviews")],
    )
    add(
        "rs17580", "SERPINA1", "Alpha-1 Antitrypsin PiS Allele", "14", 94847262,
        ["immunity", "detox"], "strong", "T", "A",
        "The PiS allele mildly reduces AAT levels; problematic mainly in SZ compound heterozygotes.",
        G("No PiS (TT)", "typical", "Typical at this allele.", "Interpret with PiZ."),
        G("PiMS carrier (AT)", "typical", "One PiS allele.", "Benign in isolation."),
        G("PiSS pattern (AA)", "typical", "Moderately reduced AAT.", "Usually clinically silent; combined with PiZ (SZ) it matters — see the compound context."),
        notes="Palindromic A/T site — reviewed.",
        tier="well-replicated", transferability="euro-biased", reviewed=True,
        effect="Mild level reduction; matters in SZ combinations",
        citations=[C(CLIN, "SERPINA1 PiS annotations")],
    )
    add(
        "rs2569190", "CD14", "CD14 Promoter (-159C>T) — Innate Sensing Set-Point", "5", 140012916,
        ["immunity", "inflammation"], "moderate", "A", "G",
        "CD14 co-receptors LPS with TLR4. The promoter variant shifts soluble CD14 and appeared throughout the 'hygiene hypothesis' atopy literature with environment-dependent directions — an honest example of gene-environment complexity.",
        G("Pole 1 (AA)", "typical", "Higher soluble-CD14 pattern.", "Direction of atopy effects depends on microbial environment in studies."),
        G("Intermediate (AG)", "typical", "Intermediate.", "Baseline."),
        G("Pole 2 (GG)", "typical", "Lower soluble-CD14 pattern.", "Same environment-dependence caveat."),
        tier="tendency", effect="Environment-dependent, direction-flipping literature",
        citations=[C(GWAS, "CD14 -159 atopy/hygiene literature")],
    )
    add(
        "rs909253", "LTA", "Lymphotoxin-Alpha (TNF Cluster Haplotype)", "6", 31540313,
        ["immunity", "inflammation"], "moderate", "A", "G",
        "LTA sits beside TNF in the MHC class III cluster; this variant forms the classic TNF-region haplotype studied across inflammatory conditions.",
        G("Reference (AA)", "typical", "Baseline haplotype.", "Interpret with TNF -308."),
        G("Intermediate (AG)", "typical", "Intermediate.", "Small."),
        G("Variant pair (GG)", "typical", "Alternate haplotype pole.", "Small, cluster-level effects."),
        tier="tendency", effect="Haplotype member",
        citations=[C(GWAS, "LTA/TNF haplotype literature")],
    )
    add(
        "rs1990760", "IFIH1", "Interferon Sensor MDA5 (A946T)", "2", 163124051,
        ["immunity", "autoimmunity"], "strong", "C", "T",
        "IFIH1 (MDA5) senses viral RNA. The T (946T) allele raises baseline interferon tone: slightly better antiviral posture, slightly higher T1D/autoimmune-thyroid risk — a clean trade-off variant.",
        G("Reference (CC)", "typical", "Lower baseline interferon tone.", "Baseline."),
        G("Intermediate (CT)", "typical", "Intermediate tone.", "Small effects both directions."),
        G("Higher-tone pair (TT)", "typical", "Higher baseline interferon tone.", "Modest autoimmunity association (T1D OR ~1.2) with hints of stronger antiviral response — evolution's trade-offs in one SNP."),
        tier="well-replicated", transferability="multi-ancestry",
        effect="T1D OR ~1.15-1.2 per allele — modest",
        citations=[C(16699517, "Smyth 2006, Nat Genet — IFIH1 and type 1 diabetes")],
    )