rs3733585 — SLC2A9

SLC2A9 rs3733585 — An Intronic Tag Variant at the Major Urate Control Locus

Serum uric acid levels are shaped more by a single genomic region — the SLC2A9 gene on chromosome 4 — than by any other locus in the human genome. SLC2A9 encodes GLUT9¹¹ GLUT9
Glucose Transporter 9, a high-capacity electrogenic urate transporter expressed in the renal proximal tubule; despite its name, urate is its primary physiological substrate, the protein responsible for reabsorbing roughly 90% of filtered uric acid back into the bloodstream before it can be excreted in urine. Variants in this gene explain 1.7–5.3% of all variation in serum urate across populations — more than lifestyle, diet, or any other single genetic factor studied to date.

rs3733585 is an intronic SNP in SLC2A9 that serves as a tag marker for one of the regulatory haplotype blocks within this locus. SLC2A9 lies on the minus (reverse) strand of chromosome 4, so the alleles reported by genome sequencing files (A/G on the plus strand) correspond to T/C on the coding strand. The coding-strand T allele (plus-strand A) has been described in association with the urate-raising haplotype, while the coding-strand C allele (plus-strand G) tags the urate-lowering haplotype. Direct association studies specifically naming rs3733585 in the context of serum urate are limited — the strongest published direct signal for this rsid is a gene-environment interaction with tobacco smoke for nonsyndromic cleft palate (PMID 24516586), which is unrelated to uric acid metabolism — but the variant sits within the well-characterised SLC2A9 urate-association LD block and appears to be in linkage disequilibrium with the established urate-controlling haplotypes.

The Mechanism

GLUT9 exists in two isoforms with distinct membrane localisation: GLUT9a (the full-length form) at the basolateral membrane of proximal tubule cells, and GLUT9b (the short isoform, 28 amino acids shorter at the N-terminus) at the apical membrane. Together they coordinate the net reabsorption of urate — GLUT9b pulls urate from the tubular lumen into the epithelial cell, and GLUT9a exports it back into the interstitium and bloodstream. Because urate is passively filtered at the glomerulus but then actively recovered by GLUT9, any genetic change that alters GLUT9 expression or function directly shifts the set-point for serum urate.

rs3733585 is intronic and does not change the amino acid sequence of GLUT9. Its effect on urate transport is regulatory — it is a haplotype tag for the broader SLC2A9 urate-regulatory block, which encompasses both coding variants (Arg265His at rs3733591) and multiple intronic regulatory signals (rs11942223, rs6449213, rs7442295) that together influence SLC2A9 expression and splicing. The intronic signal tagged by rs3733585 is likely mediated through transcriptional regulation, consistent with the finding that the SLC2A9 4p16.1 region is enriched for active enhancers in hepatic and renal cell types ²² Abundant local interactions in the 4p16.1 region suggest functional mechanisms underlying SLC2A9 associations with serum uric acid. Human Mol Genet, 2014.

The Evidence

Foundational SLC2A9 GWAS: Two landmark 2008 Nature Genetics papers (Vitart et al.)³³ (Vitart et al.) and (Döring et al.)⁴⁴ (Döring et al.) simultaneously identified SLC2A9 as the largest-effect urate locus. Intronic SNPs in SLC2A9 introns 4 and 6 explained 1.7–5.3% of serum urate variance, with effect sizes of −0.23 to −0.36 mg/dL per protective allele copy. The effect was 5× stronger in women (6% variance explained) than in men (1.2%), attributed to estrogen's independent stimulation of renal urate excretion.

Sex and BMI modification: A Bruneck Study analysis (Brandstätter et al., 2008)⁵⁵ (Brandstätter et al., 2008) examined four SLC2A9 intronic SNPs and found that each protective allele reduced serum urate by 0.30–0.35 mg/dL on average (p = 10⁻⁹ to 10⁻¹¹), with the association strengthened in high-BMI individuals.

Direct rs3733585 GWAS association: The only published direct signal for this exact rsid is from a genome-wide gene-environment interaction study for nonsyndromic cleft palate in which rs3733585 showed a suggestive interaction with maternal tobacco smoke exposure (P = 2.26×10⁻⁷, OR 2.58 for the C/plus-strand allele). This association with cleft palate is biologically unrelated to urate metabolism and indicates that rs3733585 is a polymorphic marker within the SLC2A9 locus with pleiotropic associations. Its utility for urate prediction rests on inferred LD with established urate signals at this locus.

Overall evidence assessment: No published study has directly tested rs3733585 for serum urate association with adequate statistical power. The evidence level for this specific rsid and urate is emerging — the inference is reasonable given gene membership and genomic position, but has not been independently verified for this variant. For established, replicated SLC2A9 urate associations, see rs11942223, rs3733591, and rs16890979 in the platform.

Practical Actions

Given the limited direct evidence for rs3733585 itself, practical recommendations are drawn from the established SLC2A9 biology and the dietary modulators of urate that have been characterised across this gene's haplotype block. The main levers available regardless of the specific intronic variant:

Fructose is the most potent dietary driver of urate because fructose metabolism in the liver generates urate as a direct by-product and simultaneously reduces renal urate excretion. Purine-rich foods (organ meats, shellfish, anchovies, beer) add substrate load. Low-fat dairy and coffee consistently show inverse associations with gout risk across SLC2A9 haplotype studies.

The sex-specific effect at the SLC2A9 locus is clinically relevant: women carrying risk alleles in the A allele–associated haplotype face up to 5× greater genetic influence on serum urate during reproductive years, with the genetic effect unmasked at menopause when estrogen's uricosuric support is withdrawn.

Interactions

With other SLC2A9 variants: rs3733585 lies within the same SLC2A9 LD block as rs11942223 (independent regulatory signal), rs3733591 (Arg265His missense, the largest-effect coding variant), and rs16890979 (Val282Ile, protective missense). These are partially independent signals with additive effects on serum urate. The combined SLC2A9 genetic burden from multiple risk-haplotype tags is clinically meaningful: two or more risk signals at this locus can raise baseline serum urate by 0.5–1.5 mg/dL.

With ABCG2 rs2231142 (Q141K): ABCG2 mediates intestinal urate secretion — a completely separate route for urate elimination. Carrying risk alleles at both SLC2A9 and ABCG2 creates a double deficit: impaired renal reabsorption regulation AND impaired gut excretion. The combined effect can push mean serum urate above 7 mg/dL in otherwise healthy individuals.

With dietary fructose: A gene-environment interaction between SLC2A9 haplotype and sugar-sweetened beverage consumption has been documented: C allele carriers of related SLC2A9 intronic markers can see their protective effect reversed under high fructose load, increasing gout risk by 12–15% per daily serving of sugar-sweetened beverages.