Two genes do most of the inherited work here, and both of them are plumbing: one moves urate out through the kidney, the other out through the gut. Neither is a reason to test, and one of them is a reason to be careful with a drug.
Gout is arthritis caused by a crystal. When urate — the end product of purine breakdown — rises past what blood can hold, it can come out of solution as needle-shaped crystals in a joint. The immune system attacks the crystals, and the result is one of the most violently painful things a joint can do: usually the base of the big toe, usually overnight, red and hot and untouchable.
It has a reputation as a disease of excess, and diet does matter. It matters less than most people are told, and rather less than inheritance does.
Urate is not made in an unusual way in people who get gout. It is removed in an unusual way. Both major genes here are transporters — proteins that carry urate across a membrane and out.
rs4475146 is in SLC2A9, which reabsorbs urate in the kidney: it decides how much of what is filtered out gets pulled back in. It has the largest effect on blood urate of any common variant known, in either direction.
rs1481012 is in ABCG2, which pumps urate out into the intestine. When it works less well, a route of disposal narrows.
The scale of these effects is unusual for common variants. In a 2008 study, the missense variant in SLC2A9 reached a p-value of 7 × 10⁻¹⁶⁸ for blood urate and was associated with gout at an odds ratio of 0.59 per copy of the protective allele; the missense variant in ABCG2 was associated with gout at OR 1.74. Those are not the fractional shifts common-variant genetics usually delivers.
A 2013 study of more than 140,000 people found 28 loci affecting blood urate — 18 of them new — and checked each one against gout itself and against how much urate the kidney excretes. Effects were of similar size in several non-European groups, which is not something that can be assumed.
The pathways the analysis pointed at were not only transport: glucose metabolism turned up too, which is part of why gout keeps company with obesity, diabetes and high blood pressure rather than arriving alone.
High urate is necessary for gout and nowhere near sufficient: most people with raised urate never have an attack. And of the variation in blood urate between people, diet accounts for a strikingly small share compared with these transporters.
That is not permission, and it is not blame either. It is a correction to a story in which gout is something a person did to themselves.
Not these two. A different position, in HLA-B, does: the allele HLA-B*58:01 raises the risk of a rare but severe skin reaction to allopurinol, the most-prescribed urate-lowering drug. Prescribing guidance recommends testing before starting allopurinol in the populations where that allele is common — see the allopurinol page.
That is the reverse of the usual direction. It is not a genotype telling somebody to take something; it is a genotype telling a prescriber to look before they do.
Sources. Köttgen et al. (Nat Genet 2013) combined data from more than 140,000 individuals of European ancestry within the Global Urate Genetics Consortium and identified and replicated 28 genome-wide significant loci for serum urate concentration, 18 of them novel. The loci were further characterised for association with gout, for transcript expression and for the fractional excretion of urate; associations for many were of similar magnitude in individuals of non-European ancestry. Network analysis implicated inhibin–activin signalling and glucose metabolism in systemic urate control. This is the study the collector recorded as the source for both positions listed on this page.
Effect sizes at the two major loci. Dehghan et al. (Lancet 2008), in genome-wide analyses of the Framingham and Rotterdam cohorts with replication in ARIC, reported the missense variant rs16890979 in SLC2A9 at p = 7.0 × 10⁻¹⁶⁸ for serum urate in white participants and OR 0.59 per T allele (95% CI 0.52–0.68) for gout, and the missense variant rs2231142 in ABCG2 (Q141K) at p = 2.5 × 10⁻⁶⁰ for urate and OR 1.74 (95% CI 1.51–1.99) for gout, direction-consistent in black participants. Those two missense positions are not in our variant table; the positions listed here are the SLC2A9 and ABCG2 signals recorded under the gout trait by the collector. They mark the same two genes, not the same two markers.
Diagnosis. Definitive diagnosis is the identification of monosodium urate crystals in synovial fluid under polarised light. Serum urate measured during an acute attack can be normal and does not exclude the diagnosis. No genotype is used diagnostically.
Pharmacogenomics. HLA-B*58:01 is associated with allopurinol-induced severe cutaneous adverse reactions, including Stevens–Johnson syndrome, toxic epidermal necrolysis and DRESS. CPIC published a guideline for HLA-B genotype and allopurinol dosing in 2013 and confirmed in its 2015 update that the recommendation was unchanged. Allele frequency is markedly population-dependent, and testing recommendations are framed accordingly.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Gout comes down to these specific, well-studied positions — not a diagnosis.
Research-derived gene–drug associations only — not a prescription, dosing guide, or medical advice. Always follow your prescriber's guidance.
| Gene | Drug | What the research shows |
|---|---|---|
| HLA-B | Allopurinol | The HLA-B*58:01 allele is associated with a substantially increased risk of severe cutaneous adverse reactions to allopurinol — Stevens–Johnson syndrome, toxic epidermal necrolysis and DRESS. CPIC published a guideline for HLA-B genotype and allopurinol dosing and confirmed in its 2015 update that the original recommendation stands. Allele frequency varies widely between populations, which is why testing guidance is population-specific rather than universal. This is a safety check before prescribing, not a dosing adjustment and not something to act on from a raw data file. (CPIC guidelines for HLA-B genotype and allopurinol dosing: 2015 update (Clin Pharmacol Ther 2016, PMID 26094938).) |
Diet contributes and does not explain most of it. The variation in blood urate between people is dominated by how urate is transported out of the body — through the kidney and through the gut — and those transporters are inherited. High urate is also necessary but not sufficient: most people with raised urate never have an attack.
No. Neither position is used to diagnose gout, to predict an attack or to choose a treatment. Gout is diagnosed by finding urate crystals in joint fluid. If you have had an attack, that is a conversation with a doctor, and your genotype will not be part of it.
That one is real and it is a safety check rather than a result to act on alone. Carrying the allele raises the risk of a severe skin reaction to allopurinol, and prescribing guidance recommends testing beforehand where the allele is common. It is ordered by the prescriber, from a clinical laboratory — a consumer raw data file is not the right instrument for it.
Partly because the same pathways turn up. The 2013 analysis of urate loci implicated glucose metabolism as well as transport, which is one reason gout tends to arrive in company rather than on its own.
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