rs316019 — SLC22A2 Ala270Ser

SLC22A2 encodes organic cation transporter 2 (OCT2), the dominant transporter on the basolateral membrane of kidney proximal tubule cells. OCT2 is responsible for the first and rate-limiting step in renal secretion of metformin: uptake from the bloodstream into tubular epithelial cells. Without efficient OCT2 transport, metformin accumulates in plasma at higher concentrations than expected — which may enhance glucose lowering but also risks lactic acidosis in susceptible patients. The same transporter also mediates uptake of cisplatin and oxaliplatin into renal and cochlear cells, making OCT2 genotype a determinant of platinum chemotherapy toxicity.

The rs316019 variant (c.808G>T in coding notation, p.Ser270Ala) substitutes alanine for serine at position 270 of the OCT2 protein. This position sits in a substrate-binding domain, and structural modeling¹¹ structural modeling
Sajib et al. 2018 showed substrates fit better to the Ser270 form than the Ala270 form demonstrates that the Ala270 variant creates a suboptimal binding conformation for its substrates, reducing transport efficiency.

OCT2 operates as an electrogenic uniporter driven by the inside-negative membrane potential of proximal tubule cells. At the molecular level, Ser270 participates in substrate coordination within the transmembrane binding pocket²² transmembrane binding pocket
OCT2 has 12 transmembrane domains; position 270 is in the intracellular loop region near TM5-6, involved in substrate translocation. The Ala270 substitution (a non-polar, smaller side chain replacing a polar hydroxyl group) reduces substrate affinity and transport velocity, resulting in approximately 16% lower metformin renal secretory clearance in carriers.

The same OCT2 reduction in function has a dual consequence for platinum drugs: in cochlear hair cells and renal tubular cells, cisplatin entry depends on OCT2. Carriers with reduced OCT2 activity take up less cisplatin into these sensitive tissues, partially protecting against hearing loss and kidney injury.

Metformin pharmacokinetics:

A clinical pharmacokinetic study of healthy subjects demonstrated that rs316019 carriers had significantly lower metformin renal clearance compared to non-carriers (586 ± 161 vs 699 ± 291 mL/min, p=0.048), with correspondingly higher Cmax and AUC. The same pattern was reported in a Korean healthy volunteer study, where subjects with the c.808G>T variant showed reduced metformin Cmax and altered AUC compared to wild-type GG carriers .

A mechanistic study found that SLC22A2 c.596C>T, c.602C>T, and c.808G>T all showed significant differences in metformin pharmacokinetics³³ all showed significant differences in metformin pharmacokinetics
Song et al. Clin Pharmacol Ther 2008 compared to the reference genotype, with decreased transporter function resulting in reduced renal metformin clearance and consequently increased plasma concentrations.

A critical caveat comes from a controlled interaction study: when rs316019 was analyzed in isolation without co-consideration of MATE1 variants, the effect on metformin clearance was not statistically significant. Only when examining the combined genotype with MATE1 rs2289669 did the OCT2 variant produce significant changes in renal clearance (28.1 to 44.8 L/h, p=0.004)⁴⁴ renal clearance (28.1 to 44.8 L/h, p=0.004)
Christensen et al. Pharmacogenet Genomics 2013, n=50 healthy Caucasians. This gene-gene interaction with the efflux transporter is the primary context in which rs316019 becomes clinically relevant.

Cisplatin toxicity:

In 130 patients (64 pediatric, 66 adult) receiving cisplatin-based chemotherapy, the rs316019 GT heterozygous genotype conferred striking protection against cisplatin-induced ototoxicity⁵⁵ cisplatin-induced ototoxicity
Lanvers-Kaminsky et al. Pharmacogenomics 2015 with OR 0.12 (95% CI 0.02–0.67, p=0.009) — an 88% relative risk reduction for hearing damage versus GG homozygotes.

In a Chinese cohort of 123 cancer patients, the GT/TT genotype was also associated with smaller increases in cystatin C (a sensitive marker of kidney damage) following cisplatin treatment compared to GG carriers (P=0.043). Paradoxically, a separate study reported that rs316019 carriers had higher baseline urinary KIM-1 (kidney injury molecule-1) levels, and elevated KIM-1 at day 3 and day 10 post-cisplatin, suggesting that the relationship between OCT2 genotype and cisplatin nephrotoxicity is more complex than simple protection.

For metformin users: The standalone pharmacokinetic effect of rs316019 is modest (16% clearance reduction) and is amplified substantially when combined with MATE1 variants. Heterozygotes and homozygotes may accumulate slightly higher plasma metformin levels, which becomes clinically relevant mainly in situations of renal impairment, dehydration, iodinated contrast administration, or concurrent use of OCT2 inhibitors such as cimetidine, ranitidine, or trimethoprim.

For oncology patients: If you carry the rs316019 A allele and are scheduled to receive cisplatin-based chemotherapy, this information may be valuable for your oncologist. The reduced cisplatin uptake into cochlear hair cells appears to lower ototoxicity risk, which is particularly relevant in pediatric oncology where hearing preservation is critical for development. This finding should be weighed against the potential for altered cisplatin efficacy.

The most important interaction for metformin response is between OCT2 rs316019 and MATE1 rs2289669. OCT2 mediates metformin uptake from blood into proximal tubule cells (influx), while MATE1 (SLC47A1) mediates the final secretion step from tubular cell into urine (efflux). Christensen et al. demonstrated that the combined genotype at these two loci — not either variant alone — is the primary determinant of renal metformin clearance. A compound action covering both rs316019 and rs2289669 would reflect this documented biology.

OCT2 also interacts with OCT1 (SLC22A1, rs622342) in determining overall metformin handling: OCT1 controls hepatic uptake (determining the glucose-lowering effect), while OCT2 controls renal secretion (determining drug clearance and plasma levels). Combined OCT1+OCT2 poor transporter status would create a complex pharmacokinetic picture: reduced hepatic efficacy and reduced renal clearance simultaneously.