rs2231142 — ABCG2 Q141K
Reduces ABCG2 transporter function affecting rosuvastatin levels and uric acid excretion, increasing risk for statin side effects and gout
Details
- Gene
- ABCG2
- Chromosome
- 4
- Risk allele
- T
- Protein change
- p.Gln141Lys
- Consequence
- Missense
- Inheritance
- Codominant
- Clinical
- Risk Factor
- Evidence
- Established
- Chip coverage
- v3 v4 v5
Population Frequency
Ancestry Frequencies
Related SNPs
Category
PharmacogenomicsABCG2 Q141K — Rosuvastatin Response and Gout Risk
ABCG2 encodes breast cancer resistance protein (BCRP), an efflux transporter that pumps drugs and metabolites out of cells.
ABCG2 is expressed in the apical membrane of kidney proximal tubule cells and intestinal epithelium , where it mediates excretion of uric acid, rosuvastatin, and other substrates. The Q141K variant (c.421C>A, rs2231142) is one of the most clinically significant pharmacogenetic variants, earning a CPIC Level A recommendation for rosuvastatin dosing due to 144% increased drug exposure in AA carriers .
The Mechanism
The Q141K mutation causes 53% reduced urate transport rates compared to wild-type ABCG2
. The glutamine at position 141 is highly conserved across species11 highly conserved across species
Q141 is located in the nucleotide-binding domain of ABCG2, right next to the corresponding amino acid F508 in CFTR—a residue commonly mutated in cystic fibrosis patients and sits in the nucleotide-binding domain critical for ATP-dependent transport.
The 141K variant causes instability in the nucleotide-binding domain, leading to decreased surface expression, altered protein trafficking, and increased ubiquitin-mediated proteasomal degradation . The result is reduced functional transporter at the cell membrane.
The Evidence
Gout and Hyperuricemia:
In a population study of 14,783 individuals, the rs2231142 T allele showed highly significant associations with elevated urate levels (P = 10-30 in whites, P = 10-4 in blacks) and gout (adjusted odds ratio 1.68 per risk allele) .
Among 3,923 Japanese participants, the T allele frequency was 31%, and TT carriers had an OR of 4.37 for gout compared to GG carriers .
A meta-analysis found TT genotype conferred OR 4.10 for gout versus GG, with GT showing intermediate risk , establishing a clear codominant effect.
Functional studies in Xenopus oocytes and membrane vesicles confirmed the Q141K variant results in 53% reduced urate secretory capacity .
Rosuvastatin Pharmacokinetics:
Rosuvastatin exposure (AUC) was 144% greater in c.421AA genotype carriers than wild-type CC carriers .
CPIC recommends a rosuvastatin starting dose of ≤20 mg for individuals with ABCG2 poor function; if higher doses are needed, consider alternative statins or combination therapy .
The high prevalence of the Q141K variant in Asian populations (21% AA genotype in Filipinos, 14% in other Asian groups) versus 0.1-1% in non-Asians has important implications for rosuvastatin dosing .
Methotrexate Clearance:
ABCG2 is one of the main determinants for rapid elimination of methotrexate and its toxic metabolite 7-hydroxymethotrexate, working alongside ABCC2 and ABCC3 .
The ABCG2 rs2231142 CA genotype showed statistically significant association with elevated plasma methotrexate levels at 48 hours after high-dose infusion .
Practical Implications
If you're starting a statin: The Q141K variant is the single most important genetic factor for rosuvastatin response. AA carriers have more than double the drug exposure, increasing risk for statin-associated musculoskeletal symptoms22 statin-associated musculoskeletal symptoms
SAMS — muscle pain, weakness, or cramps that prompt many patients to discontinue statins. If you carry two T alleles and your doctor prescribes rosuvastatin, discuss starting at 5-10 mg rather than the standard 10-20 mg dose. Alternative statins metabolized differently (atorvastatin, simvastatin, pravastatin) may be appropriate.
If you have gout or elevated uric acid:
The Q141K variant is associated with elevated serum urate, unaltered fractional excretion of uric acid (FEUA), and significant evidence of reduced extra-renal (intestinal) urate excretion . TT carriers have 2.5-4 times higher gout risk.
Allopurinol is less effective in Q141K carriers, and DPWG recommends using a higher allopurinol dose or considering alternatives like febuxostat .
Population differences matter:
The 141K allele frequency varies from 1% in Africans to 29% in Southeast Asians , making this one of the most ancestry-differentiated pharmacogenes. About 8% of Europeans, 21% of Filipinos, and 7% of East Asians are homozygous TT, explaining population differences in gout prevalence and statin response.
Interactions
ABCG2 and SLC2A9:
Both ABCG2 rs2231142 and SLC2A9 rs3733591 polymorphisms are associated with serum uric acid levels and exhibit gene dose-dependent and additive effects on uric acid elevation . Individuals carrying risk alleles at both loci have substantially higher gout risk than either variant alone, though the combined effect depends on allele counts at each locus. This represents a documented gene-gene interaction in the urate transport pathway that warrants a compound implication covering both variants.
ABCG2 and SLCO1B1: For rosuvastatin specifically, ABCG2 poor function combined with SLCO1B1 decreased function creates compounded exposure risk.
Selection and dosing of rosuvastatin should consider both ABCG2 Q141K status and Asian ancestry , as the interaction between genetic and demographic factors affects pharmacokinetics. A compound implication covering ABCG2 rs2231142 and SLCO1B1 rs4149056 would capture this clinically relevant interaction for rosuvastatin dosing.
Drug Interactions
Genotype Interpretations
What each possible genotype means for this variant:
Typical ABCG2 transporter activity for drug and uric acid excretion
You have two copies of the common G allele, encoding normal glutamine at position 141 of the ABCG2 protein. Your ABCG2 transporters function at full capacity, efficiently pumping uric acid out through kidneys and intestines, and clearing rosuvastatin and other drug substrates at typical rates. This is the most common genotype in European populations (about 72% of individuals) and provides standard drug response and uric acid handling.
Moderately reduced ABCG2 activity increases rosuvastatin exposure and uric acid levels
The heterozygous state means roughly half your ABCG2 protein is normal and half is the less stable Q141K variant. The practical effect is a moderate reduction in overall transporter capacity—not as severe as homozygous TT, but meaningfully different from normal. For rosuvastatin, this translates to drug levels that are higher than expected at standard doses, though not as dramatically elevated as in TT carriers. For uric acid, you have mildly impaired excretion that may not cause hyperuricemia on its own, but combined with dietary factors, obesity, or other genetic variants (especially SLC2A9), could contribute to elevated levels.
Significantly reduced ABCG2 activity substantially increases rosuvastatin exposure and gout risk
With two Q141K alleles, the majority of your ABCG2 protein undergoes accelerated degradation before reaching the cell membrane. The remaining protein that does reach the surface has impaired ATP-dependent transport activity. This creates a bottleneck for excretion of multiple substrates. For rosuvastatin, reduced intestinal and hepatic efflux leads to substantially elevated blood levels—clinically significant enough that CPIC issued Level A recommendations. For uric acid, impaired intestinal excretion (the "extra-renal" pathway) is the primary mechanism, with kidney function remaining largely intact. Mouse models with the orthologous Q140K variant show severe intestinal ABCG2 deficiency and male hyperuricemia, mirroring human findings. The effect is strong enough that 10% of all gout cases in whites are attributable to this variant alone.
Key References
Functional characterization showing Q141K causes 53% reduced urate transport and is associated with gout
GWAS meta-analysis identifying rs2231142 as causal variant for serum urate and gout (OR 1.74)
CPIC guideline for rosuvastatin: 144% increased exposure in AA genotype, recommend ≤20mg starting dose
Japanese population study showing T allele frequency 31% and OR 4.37 for gout in TT carriers
PAGE Study in 40,000+ individuals confirming T allele increases serum uric acid by 0.24 mg/dL
Meta-analysis showing TT genotype OR 4.10 for gout, with codominant inheritance pattern