Gout Genetic Variants — Unified Index Across the Cascade¶
What this page is¶
A unified, cascade-stratified reference catalogue of the genetic variants that drive — or modulate — gout and hyperuricemia. The wiki already does substantial genotype-stratified intervention modeling in uricase-abcg2-genotype-stratification-computational.md, intestinal-abcg2-sex-dimorphism-public-data-mining-computational.md, abcg2-modulators.md §6, androgen-urate-axis.md, and gout-pathophysiology.md §"Genomics and GWAS", but none of those pages link back to a single index of all relevant variants. This page is that index. Downstream stratification analyses should cross-reference this catalogue rather than re-list variants each time.
Audience. PhD-level scientists, clinical translation collaborators, and downstream subagents performing stratified literature scans or computational modeling.
Privacy gradient. This is a public-research reference. No personal genotypes. No clinical data tied to individuals. Anyone reading this page is welcome to do so; nothing here would be inappropriate for an external collaborator.
How to use it. Each variant entry carries an explicit evidence tier per CLAUDE.md §"Evidence Levels". When the source literature disagrees on effect direction, allele frequency, or evidence strength, the disagreement is surfaced in the entry rather than silently resolved — per the multi-source reconciliation discipline encoded in CLAUDE.md §"Pre-commit grep-verify gate." If you are running a stratified subagent task, link to specific table rows by anchor or quote the row inline; do not paraphrase across rows (paraphrasing loses the evidence-tier and cross-source-disagreement information).
Scope discipline. This is a reference index, not a deep-dive page. The mechanism and intervention discussion for each variant lives on the canonical wiki page named in the rightmost column. Long mechanism narrative does not belong here.
Unified summary table — top variants by load-bearing impact¶
The 12 variants below are the ones a downstream stratification subagent or computational-experiment author would touch first. Order is approximate — by depth of evidence × OE-platform relevance — not by raw effect size alone.
| # | Variant | Gene | Cascade step | Effect | Why it matters for OE |
|---|---|---|---|---|---|
| 1 | UOX pseudogenization (codons 33, 187 + splice site) | UOX | Urate degradation (absent in humans) | Universal human loss-of-function → no urate → allantoin clearance | The chokepoint that every OE uricase track (engineered koji, CRISPR uricase, pegloticase analogs) is designed to restore |
| 2 | rs2231142 (p.Gln141Lys, Q141K) | ABCG2 | Renal + intestinal urate secretion | ~50% reduction in transport activity per allele | #1 common genetic risk for gout; rescue lever (HDI, butyrate, fiber, chaperones); large ancestry-frequency gradient |
| 3 | rs2199936 | ABCG2 | Renal + intestinal urate secretion | Intronic; tag SNP for ABCG2 haplotype | Most significant ABCG2 association in 2025 UK Biobank gout GWAS (p = 1.75 × 10⁻⁹⁷; per gout-pathophysiology.md §"Genomics and GWAS") |
| 4 | rs734553 / rs58656183 | SLC2A9 (GLUT9) | Basolateral renal urate exit | Largest per-allele effect on serum urate of any known locus | The other dominant urate transporter; less druggable than URAT1/ABCG2 currently |
| 5 | SLC22A12 W258X (rs121907892) | SLC22A12 (URAT1) | Renal urate reabsorption | LOSS-of-function → urate doesn't get reabsorbed → protective (causes RHUC1) | Validates the URAT1-inhibitor pharmacology class (lesinurad, dotinurad, pozdeutinurad); also the siRNA against URAT1 modality endpoint |
| 6 | HPRT1 LoF (multiple alleles) | HPRT1 (Xq26) | Purine salvage → de novo synthesis dysregulation | LOSS-of-function → Lesch-Nyhan; partial → Kelley-Seegmiller (early-onset gout) | The rare-but-illustrative case of urate overproduction from a genetic source; X-linked |
| 7 | PRPS1 superactivity (multiple alleles, e.g., D52H, A87T, L129I) | PRPS1 (Xq22.3) | De novo purine biosynthesis | GAIN-of-function → ↑ PRPP → ↑ purine flux → early-onset gout | Direct human-genetic anchor for the PRPS chokepoint thesis |
| 8 | NLRP3 CAPS variants (R260W, D303N, T348M, others) | NLRP3 | Inflammasome assembly | GAIN-of-function → constitutive IL-1β release (FCAS / MWS / CINCA-NOMID) | Validates the anti-IL-1β class (canakinumab, anakinra, rilonacept) and the NLRP3-inhibitor class (dapansutrile, oridonin); informs the NLRP3 exploit map |
| 9 | rs10754558 (NLRP3 3′-UTR) | NLRP3 | Inflammasome assembly | Common polymorphism associated with NLRP3 mRNA stability; modest gout-flare-severity signal | Common-variant counterpart to CAPS; informs flare-stratification subagent design |
| 10 | rs16944 (IL1B −511 C/T) | IL1B | Inflammasome output (IL-1β production) | Common promoter variant; T allele associated with ↑ IL-1β production in some studies | Modulates flare amplitude; relevant to anti-IL-1β responder stratification |
| 11 | HLA-B*58:01 | HLA-B (MHC class I) | Pharmacogenetics — allopurinol immunogenicity | Carrier → very high allopurinol SCAR / SJS / TEN risk; OR > 500 in Han Chinese (Hung 2005, PMID 15743917) | ACR 2020 conditional recommendation: test before allopurinol in Southeast Asian / Han Chinese / Korean / Thai ancestry and African American patients; CPIC: allopurinol contraindicated in carriers |
| 12 | rs780094 (GCKR) | GCKR | Comorbidity — fructose / metabolic-syndrome × urate | Common variant linking glucokinase regulation to serum urate via fructose handling | Mechanistic bridge between fructose-connection.md and the urate axis |
Per-category tables and per-variant notes for the load-bearing entries follow below.
Category 1 — Urate transporters¶
Renal and intestinal urate handling collectively determine ~95% of inter-individual variance in serum urate at the polygenic level (Tin 2019, Köttgen 2013). The three dominant loci are ABCG2, SLC2A9 (GLUT9), and SLC22A12 (URAT1). Several minor transporters round out the renal handling apparatus.
| Variant | Gene (chr) | Cascade step | Effect direction | Allele frequency | Evidence tier | OE-platform implication | Canonical wiki page |
|---|---|---|---|---|---|---|---|
| rs2231142 (p.Gln141Lys, Q141K) | ABCG2 (chr4q22) | Renal tubular + intestinal urate secretion | Reduces ABCG2 transport activity by ~50% per allele (mild folding/processing defect → reduced plasma-membrane delivery; Saranko 2013, PMID 23800412; independently re-confirmed in Ichida 2024 Japanese urate-transporter review, DOI 10.1248/yakushi.23-00217) → ↑ serum urate |
T allele ~10–15% in European-ancestry cohorts; ~30% in East Asian general population (Japanese, Han Chinese, Korean) — Ichida 2024 gives ~32% for Japanese Q141K; rising to ~50% in Han Chinese gout cohorts (Zhang 2014 PMID 24857923, A allele 49.6% in n=352 male gout patients vs 30.9% in controls); ~3–5% African-ancestry. Within Polynesia: present in Pacific Islanders (OR 2.80 for gout per Phipps-Green 2010 PMID 20858603) but functionally absent in Māori (OR 1.08 — same study). Substantial ancestry stratification — see abcg2-modulators.md §6 for trial-design implications. |
Clinical Trial (GWAS replication across multiple ancestries; Wallace 2018 meta-analysis OR ≈ 2.43 in homozygotes) | Rescue lever stack: HDI-mediated trafficking rescue (butyrate, vorinostat — In Vitro); PPARγ-mediated WT-allele induction (butyrate, fermentable fiber — Animal Model + Clinical Trial); pharmacological chaperone class — comp-032 GREEN 2026-05-16: all four CFTR-corrector positive controls rank in top 11% of 134-molecule library; top wet-lab candidates: lumacaftor, tafamidis, ursodiol/UDCA, diflunisal, TUDCA (Mechanistic Extrapolation; source: abcg2-q141k-chaperone-screen-computational.md). Q141K-stratified butyrate RCT is the canonical computational-experiment design. Q141K is an allopurinol pharmacogenomic stratifier — Wen 2018 meta-analysis (PMID 29342288) OR 2.43 for poor allopurinol response, replicated at genome-wide significance by Roberts 2017 (PMID 26810134, p = 8.06×10⁻¹¹). Q141K is NOT a febuxostat-response stratifier (Stamp 2018 PMID 30274827). In Q141K-positive East Asian patients, febuxostat is the rational first-line ULT modulo cardiovascular comorbidity, independent of HLA-B*58:01 status. | abcg2-modulators.md, uricase-abcg2-genotype-stratification-computational.md |
| rs2199936 | ABCG2 (chr4q22) | Renal tubular + intestinal urate secretion | Intronic; tag SNP for the ABCG2 risk haplotype | Common; LD pattern varies by ancestry | Clinical Trial (GWAS — 2025 UK Biobank gout study, p = 1.75 × 10⁻⁹⁷ per gout-pathophysiology.md) |
Index SNP for genotyping panels that don't include rs2231142 directly; both should be on any gout-relevant array | gout-pathophysiology.md §"Genomics and GWAS" |
| rs2231137 (p.Val12Met, V12M) | ABCG2 (chr4q22) | Renal tubular + intestinal urate secretion; also Jr(a−) blood group phenotype (per UniProt Q9UNQ0) | Modest effect on transport activity; partially LD with Q141K in some populations | T allele ~30–40% in East Asian; lower in European/African | In Vitro + Clinical Trial (GWAS-associated; mechanism less characterized than Q141K) | Secondary ABCG2 marker; complicates pure-Q141K stratification because of LD | abcg2-modulators.md |
| rs734553 | SLC2A9 (chr4p16, GLUT9) | Basolateral renal urate exit | Intronic; one of the most strongly urate-associated common SNPs anywhere in the genome (Vitart 2008, PMID 18327257; Köttgen 2013, PMID 23263486) | Common; major allele frequency varies by ancestry | Clinical Trial (GWAS — replicated across multiple cohorts >100k each) | GLUT9 is the second-strongest GWAS locus but currently the least druggable major urate transporter; relevant to subagent-driven natural-product target screens (GLPP per medicinal-mushroom-complement-track.md) |
gout-pathophysiology.md, fructose-connection.md |
| rs58656183 | SLC2A9 (chr4p16, GLUT9) | Basolateral renal urate exit | Intronic; reported as the most significant SLC2A9 hit in the 2025 UK Biobank gout GWAS (p = 5.52 × 10⁻⁹⁰; per gout-pathophysiology.md) |
Common | Clinical Trial (GWAS) | Same as rs734553 — GLUT9 effect tagging | gout-pathophysiology.md |
| SLC22A12 W258X (rs121907892, p.Trp258Ter) | SLC22A12 (chr11q13, URAT1) | Renal urate reabsorption | LOSS-of-function (stop-gained at residue 258 per dbSNP, UniProt Q96S37) → URAT1 cannot reabsorb urate → renal hypouricemia type 1 (RHUC1) → PROTECTIVE against gout / hyperuricemia but at risk for exercise-induced AKI and urolithiasis (Ichida 2004, PMID 14747400; Sakiyama 2017 J-STAGE DOI 10.6032/gnam.41.143) |
Pathogenic-rare globally; substantially enriched in East Asian: Japanese MAF 2.23–2.55% (Ichida 2024 review; prior cohorts Iwai 2004, Taniguchi, Tabara 2014, Hamajima 2011, Wakida 2008 PMID 19092327); Korean MAF 0.9–1.4%; markedly lower in China; ~0% null in European / African / South Asian / Ashkenazi Jewish (gnomAD). Roma populations have RHUC1 too but via different mutations (T467M 5.56%, L415-G417del 1.92%) — W258X is genuinely East-Asian-private. Polynesian / Māori / Pacific Island frequency: no published data (the "common in Polynesians" framing in some reviews appears to be a hyperuricemia-prevalence claim, not W258X-specific). Among Japanese RHUC mutations, W258X/c.G774A accounts for ~70% per Ichida 2024 | Clinical Trial (clinical phenotype; OMIM #220150; Japanese case-control cohort) | Human proof-of-concept for the URAT1-inhibitor pharmacology class (lesinurad, dotinurad, pozdeutinurad) and the siRNA against URAT1 modality; the opposite direction — restoring reabsorption — has no clinical use case. Sakiyama 2017 found zero W258X/R90H carriers among 1,993 Japanese male gout patients and a protective hyperuricemia association (P = 0.016, OR = 0.80); one/two variants lowered mean serum urate in Japanese men from 6.2 to 4.0/0.8 mg/dL and in Japanese women from 4.5 to 3.5/0.6 mg/dL. W258X homozygote SUA = 0.75 mg/dL (Japanese males, Sakiyama 2021 PMID 34440216 n=30,685) — ~12% of population mean. Clean knockout phenotype. Ichida 2024 estimates exercise-induced AKI in ~6–7% of renal-hypouricemia patients overall; homozygote-vs-heterozygote lifetime risk remains unquantified. Dosage implication for siRNA-against-URAT1 modality: target ≤50% knockdown to avoid recapitulating homozygote phenotype under exercise stress | sirna-urat1-modality.md, gout-pathophysiology.md |
| SLC22A12 R90H, R434H, V138M, T217M, E298D | SLC22A12 (chr11q13, URAT1) | Renal urate reabsorption | LOSS-of-function missense variants causing RHUC1; reduced or strongly reduced urate transport per UniProt Q96S37 (in vitro transport assays) | Rare; some enriched in specific ancestries (e.g., R90H rs121907896 reported in non-East-Asian RHUC1) | In Vitro + Clinical Trial (functional + clinical RHUC1 phenotype) | Allelic series demonstrating URAT1 is dosage-sensitive and druggable across the whole transport mechanism, not just one binding pocket | sirna-urat1-modality.md |
| GLUT9 missense variants (e.g., p.Arg380Trp, p.Pro412Arg) | SLC2A9 (chr4p16) | Basolateral renal urate exit | LOSS-of-function → renal hypouricemia type 2 (RHUC2); PROTECTIVE against hyperuricemia (Matsuo 2008, OMIM #612076) | Rare | In Vitro + Clinical Trial | Same direction as URAT1 RHUC1 — GLUT9 LoF protects; the analogous URAT1-inhibitor-style approach to GLUT9 has no major program but the human-genetic safety case is established | gout-pathophysiology.md |
| SLC17A1 / SLC17A3 (NPT1 / NPT4) variants | SLC17A1/A3 (chr6p22) | Apical renal urate secretion | Common variants associated with serum urate at modest effect size; some uricosuric-drug interaction | Common | Clinical Trial (GWAS) | Secondary renal-handling layer; less directly druggable in current pipeline | gout-pathophysiology.md |
| PDZK1 variants | PDZK1 (chr1q21) | Transporter scaffolding (URAT1, NPT1, OAT4 anchor) | Common variants modulating renal transporter complex assembly; modest serum urate signal | Common | Clinical Trial (GWAS; mechanism In Vitro) | Scaffold target — pharmacological tractability poor; included for mechanistic completeness | gout-pathophysiology.md |
| LRP2 (megalin) variants | LRP2 (chr2q31) | Receptor-mediated reuptake; broad renal solute handling | Modest serum urate association in some GWAS; mechanism mixed | Common | Mechanistic Extrapolation (GWAS associations; direct urate-specific mechanism less well established than transporter genes above) | Background renal context; not a current OE intervention target | — |
Multi-source disagreement to flag. The Q141K homozygote odds ratio for gout in published meta-analyses ranges from ~2.0 (some European-ancestry cohorts) to ~3.5 (East Asian cohorts), reflecting both real ancestry-related allele-frequency differences and study-design heterogeneity (case definition, ULT-status filtering). Wallace 2018 meta-analysis cites OR ≈ 2.43 (uricase-abcg2-genotype-stratification-computational.md). The "~50% reduction in transport activity" framing is from in-vitro studies (Saranko 2013); the in-vivo serum-urate effect per allele is smaller (~0.2–0.5 mg/dL) because of compensatory renal flux. Both numbers are accurate at their own evidence tier; downstream stratification should specify which one is being invoked.
Per-variant note — Q141K is the load-bearing one. The Q141K rescue thesis is one of the most-developed scope areas in the wiki. The abcg2-modulators.md §6 page documents (a) PPARγ-induction of wild-type ABCG2 by butyrate, (b) HDAC-inhibitor trafficking rescue of the Q141K variant specifically (Basseville 2012, PMID 22472121, In Vitro), and © the pharmacological-chaperone class as a chassis-pending intervention. The genotype-stratified butyrate trial design at abcg2-modulators.md §6 "Q141K × fiber differential response" is the canonical pharmacogenomic-RCT scope for the platform.
Category 2 — Urate-production enzymes¶
The "over-producer" half of gout. Common gout (~90% of patients) is under-excretion; the genetic-overproduction phenotypes are rare but mechanistically illustrative.
| Variant | Gene (chr) | Cascade step | Effect direction | Allele frequency | Evidence tier | OE-platform implication | Canonical wiki page |
|---|---|---|---|---|---|---|---|
| HPRT1 LoF (multiple alleles) | HPRT1 (Xq26.2-q26.3) | Purine salvage; LoF re-routes hypoxanthine/guanine into degradation → urate | LOSS-of-function → Lesch-Nyhan syndrome (severe, OMIM #300322) or partial-function Kelley-Seegmiller syndrome (early-onset gout, hyperuricemia without neurological features) | Rare; X-linked recessive | Clinical Trial (clinical phenotype) | Validates that purine salvage failure → urate flux is a quantitatively meaningful axis; relevant to allopurinol/febuxostat use in over-producer phenotypes | gout-pathophysiology.md §"Step 1" |
| PRPS1 superactivity (e.g., p.Asp52His, p.Ala87Thr, p.Leu129Ile) | PRPS1 (Xq22.3) | De novo purine biosynthesis (rate-limiting) | GAIN-of-function → ↑ PRPP → ↑ purine flux → early-onset gout + sensorineural deafness in some pedigrees (OMIM #311850) | Rare; X-linked | Clinical Trial (clinical phenotype; In Vitro mechanism) | Direct human-genetic anchor for the PRPS chokepoint thesis — proves PRPP elevation alone drives clinical hyperuricemia | prps-purine-biosynthesis-chokepoint.md |
| XDH (xanthine dehydrogenase / oxidase) variants | XDH (chr2p23) | Hypoxanthine → xanthine → urate (rate-limiting degradation) | LOSS-of-function → xanthinuria (PROTECTIVE against gout but causes xanthine stones, OMIM #278300); common variants modulate XO activity with modest serum urate signal | Common variants ubiquitous; LoF rare | Clinical Trial (xanthinuria — clinical); GWAS — Clinical Trial for common variants | Human proof-of-concept for the XO-inhibitor class (allopurinol, febuxostat); also informs the natural-product XO-inhibition screens (tcm-gout-compound-triage-computational.md, astilbin) |
gout-pathophysiology.md |
| ADA (adenosine deaminase) variants | ADA (chr20q13) | Adenosine → inosine (purine catabolism upstream of XO) | LoF → severe immunodeficiency (ADA-SCID); modulating ADA changes flux entering the XO → urate pipeline (Mechanistic Extrapolation for gout) | LoF very rare; common variants present | Clinical Trial for SCID phenotype; Mechanistic Extrapolation for ADA × gout | Surfaced as a chokepoint candidate by comp-014 (Cordycepin / Cordyceps militaris / pentostatin biology); see gout-pathophysiology.md §"ADA" and medicinal-mushroom-compound-mapping-computational.md |
medicinal-mushroom-compound-mapping-computational.md |
| G6PC LoF (glucose-6-phosphatase) | G6PC1 (chr17q21) | Glycogen metabolism; LoF → von Gierke (GSD type Ia, OMIM #232200) → fructose-1,6-bisphosphate accumulation → ↑ AMP deaminase flux → ↑ urate | LOSS-of-function → secondary hyperuricemia + gout in GSD-I patients | Rare | Clinical Trial (clinical phenotype) | Mechanistic anchor for the fructose → ATP depletion → AMP → urate pathway documented in fructose-connection.md; validates that fructose-driven urate production is real at clinical magnitude |
fructose-connection.md |
Category 3 — UOX (uricase pseudogene) — the universal human variant¶
This is the special case. The human UOX locus is a pseudogene in every human — not a polymorphism but a fixed loss-of-function state shared across the species. Functional uricase persists in most mammals (rats, mice, pigs, cows; reconstructed via CRISPR knock-in) but was inactivated independently in great apes and lesser apes ~15–20 million years ago.
| Variant | Gene (chr) | Cascade step | Effect direction | Allele frequency | Evidence tier | OE-platform implication | Canonical wiki page |
|---|---|---|---|---|---|---|---|
| UOX pseudogenization — nonsense mutations at codons 33 and 187 + aberrant splice site (Wu 1989, PMID 2780565; Oda 2002, PMID 11919282) | UOX (chr1p22.3 in humans) | Urate → allantoin degradation (would be the terminal step in mammals with functional uricase) | LOSS-of-function — fixed in human population | Allele frequency = 1.0 (every human is homozygous pseudogene-carrier) | Clinical Trial (universal human phenotype: serum urate ~4–7 mg/dL vs ~1 mg/dL in uricase-positive mammals) | The root chokepoint every OE uricase track addresses: engineered koji (gut-lumen sink), CRISPR uricase (germline / somatic restoration via ancestral-sequence reconstruction per Gaucher lab 2025), pegloticase / SEL-212 / PRX-115 (pegylated recombinant uricase as systemic enzyme replacement), rasburicase (acute tumor-lysis use of A. flavus uricase in S. cerevisiae background). Cross-references uricase.md and crispr-uricase.md. |
uricase.md, crispr-uricase.md |
Important framing. The "variant" here is not heterogeneous — there is no human population with a functional uricase locus to compare against. The therapeutic target is therefore not stratification but species-level restoration. This makes uricase replacement architecturally different from every other entry on this page: every other variant defines a sub-population for stratified treatment; UOX defines the universal human background that the entire OE platform is engineered against. (See uricase.md §"Evolutionary Loss" and the Johnson fructose-fat-storage hypothesis for the proposed selective pressure that led to the loss.)
Category 4 — Inflammasome assembly / NLRP3¶
The inflammasome arm gates how much IL-1β a person produces in response to a given MSU crystal load. NLRP3 itself harbors both the rare CAPS gain-of-function variants (clinically severe autoinflammatory disease) and several common polymorphisms with modest gout-related signals.
| Variant | Gene (chr) | Cascade step | Effect direction | Allele frequency | Evidence tier | OE-platform implication | Canonical wiki page |
|---|---|---|---|---|---|---|---|
| NLRP3 CAPS variants — p.Arg260Trp, p.Asp303Asn, p.Thr348Met, p.Ala441Pro, p.Tyr570Cys, others | NLRP3 (chr1q44) | Inflammasome assembly | GAIN-of-function → constitutive ASC speck formation → constitutive IL-1β release → cryopyrin-associated periodic syndromes (FCAS, MWS, CINCA/NOMID spectrum, OMIM #606416, autosomal dominant) | Rare; pedigree-specific | Clinical Trial (clinical phenotype; In Vitro mechanism) | Human proof-of-concept that NLRP3 alone is sufficient to drive IL-1β–mediated disease — validates the entire IL-1 inhibitor class (anakinra, canakinumab, rilonacept) and informs the NLRP3-inhibitor class (dapansutrile, oridonin per nlrp3-inhibitor-screen.md) |
nlrp3-inflammasome.md, nlrp3-exploit-map.md |
| rs10754558 (NLRP3 3′-UTR) | NLRP3 (chr1q44) | Inflammasome assembly | C/G common variant in 3′-UTR; G allele associated with altered NLRP3 mRNA stability in some reports; modest effect-size signal for gout-flare severity in mixed-ancestry cohorts (dbSNP "benign" significance flag) | Common; both alleles substantial-frequency in all major ancestries | In Vitro + GWAS — Clinical Trial (modest effect, replication mixed) | Common-variant counterpart to CAPS; relevant for flare-stratification subagent design but not a clinical-grade pharmacogenetic marker on its own | nlrp3-inflammasome.md |
| rs35829419 (NLRP3 p.Gln705Lys, Q705K) | NLRP3 (chr1q44) | Inflammasome assembly | Missense at residue 705 (NP_004886.3:p.Gln705Lys per dbSNP); rare in most populations; reported as a low-penetrance susceptibility allele for several inflammatory conditions; relevance to gout-flare severity uncertain | Rare in most ancestries (T allele MAF <2% in most cohorts) | In Vitro + GWAS — Clinical Trial (mixed; dbSNP "benign, conflicting-interpretations-of-pathogenicity") | Lower-priority than rs10754558 for stratified analysis; included for catalogue completeness | nlrp3-inflammasome.md |
| NLRP1 / AIM2 variants | NLRP1 (chr17p13), AIM2 (chr1q23) | Alternative inflammasome platforms (DNA-sensing AIM2, NLRP1 in epithelial / dendritic cells) | Various; NLRP1 implicated in vitiligo / autoimmune inflammatory diseases; AIM2 implicated in cytosolic dsDNA sensing — relevance to MSU-driven gout is mostly Mechanistic Extrapolation | Common variants present | Mechanistic Extrapolation for direct gout role | Included for catalogue completeness; gout-specific role is upstream-of-evidence | nlrp3-inflammasome.md |
Category 5 — Inflammasome priming + IL-1β output¶
Variants here modulate how much pro-IL-1β is available for the inflammasome to cleave (priming arm) and how strongly downstream TLR4 / MyD88 signaling amplifies the response.
| Variant | Gene (chr) | Cascade step | Effect direction | Allele frequency | Evidence tier | OE-platform implication | Canonical wiki page |
|---|---|---|---|---|---|---|---|
| rs16944 (IL1B −511 C/T) | IL1B (chr2q14) | IL-1β priming (transcriptional) | Common promoter variant; T allele associated with ↑ IL-1β production in some LPS-stimulation assays (mixed across studies) | Common; both alleles substantial-frequency in all major ancestries | In Vitro + GWAS — Clinical Trial (mixed replication) | Modulates flare amplitude; relevant to anti-IL-1β responder-stratification logic | nlrp3-inflammasome.md |
| rs1143634 (IL1B +3954 C/T, p.Phe105Phe synonymous) | IL1B (chr2q14) | IL-1β output | Synonymous variant in exon 5; T allele reported in some studies as associated with ↑ IL-1β secretion (mechanism uncertain — likely LD with regulatory variant); inconsistent replication | Common | In Vitro + GWAS — Clinical Trial (inconsistent; dbSNP "association, benign") | Same role as rs16944; the two SNPs together form the historical "IL1B haplotype" used in pre-GWAS-era inflammation studies | nlrp3-inflammasome.md |
| rs4986790 (TLR4 p.Asp299Gly, D299G) | TLR4 (chr9q33) | Inflammasome priming (TLR4 → NF-κB) | Missense; G allele reduces LPS-responsive TLR4 signaling in some in-vitro assays — could in principle dampen NF-κB priming of pro-IL-1β. Direction in gout context is mechanistically ambiguous (less priming might reduce flares, but TLR4 also has roles in clearance) | T allele MAF ~5–10% in European-ancestry; lower in East Asian; ~10% in some African-ancestry cohorts | In Vitro + GWAS — Clinical Trial (mixed for gout specifically) | Inflammasome-priming-axis stratifier; relevant to the complement-c5a-gout track and the TNFSF14 priming amplifier | complement-c5a-gout.md, tnfsf14-gout-target.md |
| rs4986791 (TLR4 p.Thr399Ile, T399I) | TLR4 (chr9q33) | Inflammasome priming | Missense often co-inherited with D299G in European-ancestry populations | Common haplotype with D299G | In Vitro + GWAS — Clinical Trial | Same priming-axis role | complement-c5a-gout.md |
| MyD88 variants | MYD88 (chr3p22) | Inflammasome priming (TLR-axis adapter) | Common variants modest; rare gain-of-function variants (e.g., p.Leu265Pro) drive activated B-cell lymphoma — not gout-relevant | Common common variants; rare oncogenic GoF | Mechanistic Extrapolation for direct gout role | Included for catalogue completeness; not a near-term OE intervention target | — |
| CFH Y402H (rs1061170, p.Tyr402His) | CFH (chr1q31) | Complement-mediated inflammasome priming (alternative-pathway dysregulation → ↑ C5a → ↑ NLRP3 priming via CP1a) | Missense reducing CFH's inhibition of alternative-pathway complement activation; drives ~30–50% of age-related macular degeneration risk; mechanistically implicated in complement-amplified MSU response via elevated CRP (Hecker 2023 PMID 37940657, n=153: CFH 402HH → 38% vs 10% in 3–10 mg/L CRP range, p=0.037) and hypertension-interaction effects on stroke (Volcik 2008 ARIC PMID 18292760, n=15,792: HRR 1.47 in whites, null in African Americans) | gnomAD v4: European 39%, African 37% (parity with European, not lower), South Asian 31%, Latino 18%, East Asian 6%. The "common in European, rare elsewhere" framing in some reviews is wrong — African-ancestry frequency is comparable to European | Clinical Trial (AMD phenotype, GWAS-replicated); Mechanistic Extrapolation (gout-severity link via C5a-NLRP3 priming, no direct gout-cohort effect-size data yet) | Predicted stratification (Speculative, with counter-evidence flag): CFH Y402H carriers should benefit MORE from upstream-of-CFH dietary CP0 blockade (rosmarinic acid at C3 convertase, luteolin at CH50/AP50, Houttuynia cordata multi-target) — same mechanistic logic as Q141K × butyrate. ⚠ Counter-evidence to acknowledge: the closest empirical analog (CFH × dietary supplementation × AMD progression) shows the OPPOSITE direction — Vavvas 2018 reports HR 2.9 (p=0.018) paradoxical worsening for CFH high-risk on AREDS zinc/antioxidant formulation; Merle 2015 / Klein 2008 replicate the direction. Mechanism-dissociation hypothesis (plausible, unverified): AREDS works through CFH-mediated regulation (carriers can't capitalize on the supplementation's CFH-dependent benefit), while comp-018 candidates work upstream of CFH (bypassing the bottleneck) — so the OE prediction can in principle survive the AMD counter-evidence, but the rescue mechanism must be stated explicitly rather than assumed away. Empirically untested as of 2026-05-19 — biobank-mining feasibility: UK Biobank application = £3–9K + 6–12 months; AoU Researcher Workbench ~2–4 weeks free; cheapest practical path = collaboration with existing UKB gout-GWAS groups (Merriman/Otago, Major-Wrigley/Auckland, Choi/MGH). See logs/cfh-y402h-dietary-cp0-biobank-mining-2026-05-19.md for the full lit scan. |
complement-c5a-gout.md §6.3, upstream-complement-modulator-sweep-computational.md |
Category 6 — Pharmacogenetics relevant to gout treatment¶
The HLA-B*58:01 risk allele for allopurinol SCAR is the single most clinically-actionable pharmacogenetic finding in gout management. ACR 2020 conditionally recommends pre-testing in patients of Southeast Asian ancestry (for example Han Chinese, Korean, Thai) and African American patients, while CPIC gives a strong therapeutic recommendation that allopurinol is contraindicated in carriers. Several additional variants modulate response to less-frequently-used drugs.
| Variant | Gene (chr) | Cascade step | Effect direction | Allele frequency | Evidence tier | OE-platform implication | Canonical wiki page |
|---|---|---|---|---|---|---|---|
| HLA-B*58:01 | HLA-B (chr6p21, MHC class I) | Pharmacogenetics — allopurinol immunogenicity | Carrier → very high allopurinol-induced SCAR (SJS / TEN / DRESS) risk via oxypurinol-restricted T-cell activation; OR > 500 in Han Chinese (Hung 2005, PMID 15743917) | Carrier frequency varies substantially within "East Asian": Taiwanese ~20% carrier (Ko 2015 PMID 26399967, n=2,910); Han Chinese ~10–15% allele; Korean ~12% allele; Hong Kong ~14% allele; Thai ~12% allele; Vietnamese 6–8.4% allele (Kinh cord blood n=3,750 = 7.65%); Indonesian ~11%; Filipino 7.9% carrier (NMDP); Indian ~15% allele; Japanese ~6% allele (low end of East Asian range); ~1–2% European-ancestry; ~3–4% African-ancestry. The ACR 2020 "East Asian" lumped framing spans a ~3× range across these sub-populations. | Clinical Trial (PharmGKB Level 1A; ACR 2020 conditional testing recommendation for Southeast Asian and African American patients; CPIC strong carrier-avoidance recommendation; FDA label warning) | Pre-test in Southeast Asian / Han Chinese / Korean / Thai ancestry and African American patients before allopurinol initiation per ACR 2020; alternative ULT (febuxostat, pozdeutinurad, dotinurad) for carriers per CPIC/DPWG. As of 2026: mandatory or universal screening implemented in Taiwan (post-2014), Korea (public insurance), Thailand (public insurance), and Hong Kong (March 2023 — electronic-prescribing-system prompt) per Yi 2025 JOGH PMC12372636. Singapore tertiary-center only; Malaysia uncommon. Taiwan national cohort (Ko 2015): zero SCAR cases in B*58:01-negative allopurinol recipients vs ~7 historically expected (p = 0.0026). The OE engineered-koji / CRISPR uricase tracks sidestep this pharmacogenetic constraint entirely because neither requires XO inhibition. | gout-pathophysiology.md, gout-clinical-pipeline.md |
| TPMT variants (e.g., *2, *3A, *3B, *3C) | TPMT (chr6p22) | Pharmacogenetics — azathioprine metabolism | LoF variants → reduced thiopurine S-methyltransferase activity → ↑ azathioprine toxicity (myelosuppression) | TPMT*3A ~5% in European-ancestry; *3C more common in Asian / African | Clinical Trial (PharmGKB Level 1A) | Relevant only to mixed-comorbidity patients on azathioprine (e.g., gout + IBD); not a frontline gout pharmacogenetic | — |
| CYP2C9 variants (*2, *3) | CYP2C9 (chr10q24) | Pharmacogenetics — sulfinpyrazone, some uricosurics, warfarin co-medication | Reduced metabolism of substrate drugs | Common | Clinical Trial (PharmGKB) | Modulates dose-response for older uricosurics; less relevant to current pipeline (pozdeutinurad / dotinurad have different metabolism) | — |
| G6PD deficiency (multiple alleles) | G6PD (Xq28) | Pharmacogenetics — pegloticase, rasburicase | LOSS-of-function → severe hemolysis on uricase-class drugs (rasburicase contraindicated; pegloticase relative contraindication) | Variable; ~10% in some Mediterranean / African-ancestry populations | Clinical Trial (FDA boxed warning on rasburicase) | Hard contraindication for systemic recombinant uricase (rasburicase, pegloticase, SEL-212, PRX-115). The engineered-koji gut-lumen approach is plausibly safer for G6PD-deficient patients because the uricase acts in the intestinal lumen rather than the bloodstream — but this is an explicit open question that has not been empirically tested. Cross-reference crispr-uricase.md for the systemic-uricase G6PD framing and engineered-koji-protocol.md for the gut-lumen track. |
crispr-uricase.md |
Multi-source disagreement to flag. The HLA-B*58:01 prevalence within "East Asian" spans ~3×: Japanese ~6%, Vietnamese 6–8%, Korean ~12%, Thai ~12%, Hong Kong ~14%, Han Chinese 10–15%, Taiwanese ~20% carrier. The ACR 2020 lumped recommendation does not distinguish; sub-population-specific cost-benefit analyses will diverge accordingly. Universal screening programs (Taiwan, Korea, Thailand, Hong Kong 2023+) have moved past the recommendation tier to mandatory pre-allopurinol genotyping. Febuxostat is the default substitution but B*58:01-positive prospective cohort safety data for febuxostat is sparser than the allopurinol-screening evidence — flag as residual uncertainty in carrier management.
Category 7 — Comorbidity-coupled loci¶
Variants here are not direct urate-cascade actors but modulate metabolic, lipid, or fructose-handling pathways with downstream urate consequences. These are the loci that link gout to metabolic syndrome.
| Variant | Gene (chr) | Cascade step | Effect direction | Allele frequency | Evidence tier | OE-platform implication | Canonical wiki page |
|---|---|---|---|---|---|---|---|
| rs780094 (GCKR intron) | GCKR (chr2p23) | Metabolic-syndrome × fructose × urate | Common variant in glucokinase regulatory protein; T allele associated with ↑ serum urate, ↑ triglycerides, ↓ fasting glucose (mixed lipid / glucose / urate pattern). Mechanism likely via altered hepatic fructose handling → AMP → urate flux | Common; both alleles substantial-frequency in all major ancestries | Clinical Trial (GWAS — Tin 2019, Köttgen 2013; multi-trait pleiotropy) | Mechanistic bridge between fructose-connection.md and the urate axis; relevant to dietary-fructose-stratification subagent design |
fructose-connection.md |
| APOA1/C3/A4/A5 cluster variants | APOA1-A5 (chr11q23) | Metabolic syndrome × triglycerides | Modest serum urate signal at GWAS scale; shared genetic architecture with hypertriglyceridemia | Common | Clinical Trial (GWAS) | Background-comorbidity loci; not a near-term OE intervention target | — |
| PNPLA3 p.Ile148Met (rs738409) | PNPLA3 (chr22q13) | NAFLD risk / lipid droplet biology | G allele strongly associated with NAFLD; modest serum urate signal in some GWAS | G allele ~20–25% in European-ancestry; ~50% in Hispanic-ancestry; ~10% in African-ancestry | Clinical Trial (GWAS for NAFLD; modest for urate) | Comorbidity stratifier; relevant when gout intersects with NAFLD treatment | — |
| MLXIPL (ChREBP) variants | MLXIPL (chr7q11) | Carbohydrate-responsive transcription | Common variants associated with serum urate at GWAS scale; mechanism via carbohydrate-responsive lipogenic flux | Common | Clinical Trial (GWAS) | Background fructose-metabolism context | fructose-connection.md |
| HNF1A / HNF4A variants | HNF1A (chr12q24), HNF4A (chr20q13) | Hepatic transcription / MODY | Common variants associated with serum urate at modest effect size; rare LoF cause MODY (maturity-onset diabetes of the young) | Common common variants; rare MODY-causing | Clinical Trial (GWAS + MODY phenotype) | Background; relevant to mixed gout + early-diabetes phenotypes | — |
The Tin et al. 2019 Nature Genetics meta-analysis (PMID 31578528, ~1M participants, 351 loci) and the 2025 UK Biobank gout GWAS (N=150,542, 13 gout-diagnosis loci with marked sex-specific architecture per gout-pathophysiology.md) are the canonical meta-analytic anchors for the comorbidity-coupled tail. Most of the 351 loci are individually small-effect and not catalogued individually here — they are best treated as a polygenic-risk-score input rather than a per-variant intervention target.
How to test — testing tiers at a glance¶
| Tier | What it covers | Approximate cost (USD, 2026 pricing) | When useful |
|---|---|---|---|
| Single-SNP clinical PCR (Quest, LabCorp, equivalent) | One named SNP (e.g., rs2231142 for Q141K, HLA-B*58:01 typing) | ~$40–150 per SNP / typing | Pre-allopurinol HLA-B*58:01 screen (ACR 2020 recommendation); Q141K stratification at clinical-trial enrollment per abcg2-modulators.md §6 |
| Consumer SNP array (23andMe, AncestryDNA) | ~600k–1M tagged common SNPs across the genome | ~$100–200 one-time | Personal exploration only; NOT clinical-grade — known accuracy issues at lower-frequency variants and rare alleles. The CLIA-certified clinical PCR is the right tool for any trial-grade or clinical-decision context. |
| Whole exome sequencing (WES) | Coding sequence across ~20,000 genes | ~$300–1,000 clinical / ~$500 research | Rare-variant catalog (Lesch-Nyhan, PRPS1 superactivity, RHUC1, NLRP3 CAPS); useful when family history suggests Mendelian etiology |
| Whole genome sequencing (WGS) | Coding + regulatory + intronic + structural | ~$500–2,000 clinical / ~$200–600 research | Most complete; useful for research panels and rare-disease workups; overkill for routine gout stratification |
| Targeted gout panel (where offered) | Curated ABCG2 + SLC2A9 + SLC22A12 + NLRP3 + HLA-B + GCKR | Variable; not yet standard of care | Useful when commercially available; depends on local lab offerings |
Key practical note. For most gout-relevant downstream work, the highest-value single test is the HLA-B*58:01 pre-allopurinol screen in Southeast Asian / Han Chinese / Korean / Thai ancestry and African American patients — ACR 2020 conditional testing recommendation, CPIC strong carrier-avoidance recommendation, single-test cost, prevents life-threatening SCAR. The Q141K (rs2231142) clinical PCR is the next-highest-value if pharmacogenomic stratification of butyrate / fiber / HDI interventions is being considered (per abcg2-modulators.md §6 RCT design).
Consumer SNP data-quality caveat — canonical statement¶
Consumer SNP arrays (23andMe, AncestryDNA, MyHeritage, etc.) are NOT recommended for any gout-stack-design or precision-pharmacogenomics decision. Reasons:
- Uneven raw SNP data quality for the variants gout stack design depends on — ABCG2 Q141K (rs2231142), SLC2A9 / GLUT9 variants, SLC22A12 / URAT1 variants (including W258X rs121907892), HLA-B*58:01 typing, CFH Y402H (rs1061170). Consumer chips are optimized for common-variant genome-wide imputation, not for the specific pharmacogenetic loci where a miscall changes a clinical decision.
- HLA typing is particularly weak on consumer arrays. HLA-B*58:01 confirmation for allopurinol prescribing decisions must be done via CLIA-certified clinical PCR or sequencing — never trust a consumer-array imputed HLA call for a prescribing decision that could result in Stevens-Johnson syndrome.
- Terms-of-service and data-governance risks (23andMe 2023 credential-stuffing breach, 2024-25 financial wobble + sale uncertainty, GSK pharma partnership monetizing user data without per-user compensation) compound the technical reasons not to route clinical decisions through consumer panels.
The right tools, in order of clinical-decision-grade:
| Use case | Right tool | Approximate cost |
|---|---|---|
| Single named variant (Q141K, HLA-B*58:01 typing, CFH Y402H, individual URAT1 variants) | CLIA-certified clinical PCR ordered via rheumatologist or direct-to-consumer clinical service | $40–150 per SNP / typing |
| Rare-variant catalogue (Lesch-Nyhan, PRPS1 superactivity, RHUC1, NLRP3 CAPS, full SLC22A12 series) | CLIA-certified whole exome (WES) | $300–1,000 |
| Complete catalogue + regulatory + structural | Physician-routed CLIA whole-genome sequencing (WGS) | $1,000–3,000 |
| Personal exploration only (ancestry, broad traits, gout interest but not gout decisions) | Consumer SNP array | $100–200 |
This caveat is the canonical statement. Other wiki pages (gout-action-guide.md, personal-genome-protocol.md, genotype-informed-supplement-workflow.md) cross-reference this section rather than repeat the warning. Updates to consumer-SNP-quality discipline land here first; downstream pages link to it.
Open questions / coverage gaps¶
These are the gaps the OE corpus has noted but does not yet have evidence depth for. Each is a candidate for a future literature-scan subagent pass or computational-experiment design.
- Comprehensive SLC22A12 (URAT1) allelic series across non-East-Asian RHUC1 cases. Most published URAT1 LoF variants are characterized in Japanese cohorts (Ichida 2004, Enomoto 2002). The full allelic series in European, South Asian, and African-ancestry RHUC1 patients is less well documented; gnomAD provides exome-frequency data that could anchor a more complete catalogue.
- Common-variant NLRP3 polymorphisms and gout-flare severity. rs10754558 and rs35829419 (Q705K) have mixed replication for gout-flare-severity stratification. A dedicated meta-analysis across published gout-flare cohorts would help establish whether these variants justify being a NLRP3-inhibitor responder-stratification marker (relevant to dapansutrile, oridonin development per
nlrp3-inhibitor-screen.md). - Polygenic risk score (PRS) calibration for gout across ancestries. The 351 loci of Tin 2019 are predominantly European-ancestry-derived. Cross-ancestry PRS portability for serum urate is documented as moderate at best; the East Asian Biobank GWAS (Boocock 2020 and successors) would be the natural anchor for an East-Asian-calibrated PRS. The platform's stratification-mining computational experiments would benefit from PRS rather than single-variant indexing for some questions.
- Q141K homozygote PK / PD response to systemic vs gut-lumen uricase. comp-019 modeled this at the flux level (Q141K homozygotes show the smallest gut-lumen-sink response among typical genotypes but get a synergy bonus from rescue interventions). The empirical question — does this carry to the clinic? — is open and waits on actual genotype-stratified uricase trial data (currently absent from the literature).
- GLUT9 druggability. SLC2A9 has the largest per-allele effect on serum urate of any locus, yet no clinical-grade GLUT9-targeted drug exists. Whether this is a tractability problem (structural / selectivity) or a clinical-priority problem (URAT1 was a richer initial substrate) deserves a dedicated chassis-pending entry.
- G6PD deficiency × gut-lumen uricase safety. Stated open question above in Category 6: whether the engineered-koji gut-lumen approach is safer for G6PD-deficient patients than systemic recombinant uricase is mechanistically plausible but empirically untested. Worth queuing as a peer-track open question.
-
East-Asian-cohort Q141K × dietary-fiber RCT. Per the multilingual scan 2026-05-19 (see
logs/multilingual-east-asian-gout-cohort-scan-2026-05-19.md), no Q141K-stratified fiber or butyrate-supplementation RCT has been published in any database (PubMed, citation-chain through Chinese/Japanese cohorts). The Han Chinese / Japanese cohorts (Q141K frequency ~30% in general population, ~50% in gout patients) are the natural recruitment substrate for the canonical Q141K × fiber trial design atabcg2-modulators.md§6. The empirical question remains genuinely untested in 2026. -
W258X-homozygote lifetime EI-AKI risk. Despite W258X being intensively studied across ~31,000 Japanese individuals (Iwai, Taniguchi, Tabara 2014, Hamajima 2011, Wakida 2008), the lifetime exercise-induced AKI incidence in homozygotes vs heterozygotes is not quantified in any published source. This is a tractable Japanese-cohort epidemiology study and a load-bearing constraint for the URAT1-siRNA modality safety case at
sirna-urat1-modality.md. -
HLA-B*58:01-positive febuxostat prospective safety cohort. The substitution recommendation has strong mechanistic backing but no large prospective cohort tracks B*58:01-positive febuxostat-takers for SCAR incidence. The Taiwan / Korea / Hong Kong universal-screening programs are now generating exactly this cohort by construction — published outcomes data from these programs (2025+) should be re-scanned in the next sweep.
-
East-Asian-literature deep dive on TCM-era gout cohorts. Per
CLAUDE.md§"Global-multilingual research by default", direct CNKI / WanFang / J-STAGE / CiNii queries (requiring authenticated browser sessions) likely surface additional Chinese / Japanese cohort papers — particularly regional sub-cohort breakdowns and TCM-context intervention studies — not surfaced by the 2026-05-19 multilingual scan. A dedicated session with database credentials would close this gap.
Cross-references¶
- gout-pathophysiology.md — the full cascade in which these variants act (§"Genomics and GWAS" is the partner section)
- abcg2-modulators.md — Q141K rescue lever stack; §6 is the canonical Q141K dossier
- uricase-abcg2-genotype-stratification-computational.md — comp-019 flux modeling, Q141K-stratified gut-lumen uricase predictions
- intestinal-abcg2-sex-dimorphism-public-data-mining-computational.md — comp-017 intestinal-ABCG2 sex-dimorphism scan
- androgen-urate-axis.md — sex-hormone × ABCG2 axis (interacts with Q141K stratification)
- uricase.md — UOX pseudogene background; ancestral-sequence reconstruction context
- crispr-uricase.md — UOX restoration via CRISPR; ancestral sequence reconstruction (Georgia State / Gaucher lab 2025)
- nlrp3-inflammasome.md — NLRP3 biology
- nlrp3-exploit-map.md — NLRP3 chokepoint map
- prps-purine-biosynthesis-chokepoint.md — PRPS1 superactivity as the human-genetic anchor for the PRPS chokepoint
- fructose-connection.md — fructose → AMP → urate pathway (G6PC, GCKR, MLXIPL relevance)
- sirna-urat1-modality.md — URAT1 LoF (RHUC1) as the human-genetic anchor for URAT1-targeted siRNA
- chassis-pending-interventions.md — pharmacological-chaperone class for Q141K (§7)
- gout-clinical-pipeline.md — current drug pipeline; informs which variants are clinically actionable now
Index page; no inline mechanism deep-dives. Variant-specific mechanisms, rescue strategies, and intervention design belong on the canonical wiki pages linked in the "Canonical wiki page" column of each table.