rs2413775 — SLC28A2

SLC28A2 rs2413775 — A Promoter Switch on the CNT2 Nucleoside Gate

Every cell in your body depends on a continuous supply of nucleosides — the molecular building blocks of DNA and RNA — and specialized transport proteins ferry these molecules across cell membranes. One such transporter, CNT2¹¹ CNT2
Concentrative Nucleoside Transporter 2, encoded by SLC28A2 on chromosome 15; the "concentrative" label reflects that it moves nucleosides against their concentration gradient, powered by co-transported sodium ions, sits at a critical junction in the intestinal wall and kidney tubules, governing how efficiently purines and certain nucleoside-based drugs enter and leave the body. The rs2413775 variant sits 146 base pairs upstream of the SLC28A2 coding sequence, inside the gene's proximal promoter, and alters how much CNT2 protein the liver and kidney produce.

The Mechanism

The variant creates a T-to-A change at position −146 relative to the SLC28A2 transcription start site, directly within a binding site recognized by hepatic nuclear factor 1²² hepatic nuclear factor 1
HNF1α and HNF1β are transcription factors that control gene expression in liver, kidney, and intestine; they bind specific DNA sequences and recruit the RNA polymerase machinery (HNF1). The A allele enhances HNF1α and HNF1β binding affinity at this site — demonstrated by electrophoretic mobility shift assays showing superior binding of -146A oligonucleotides at all competitor concentrations tested. The result is a gain-of-function³³ gain-of-function
The A allele increases, not decreases, CNT2 expression; this is the globally predominant allele (~62% globally), so "higher expression" is the population norm effect: Yee et al. (2009)⁴⁴ Yee et al. (2009)
Yee SW et al. Identification and characterization of proximal promoter polymorphisms in the human concentrative nucleoside transporter 2 (SLC28A2). J Pharmacol Exp Ther. 2009;328(3):699-707 showed that constructs carrying the A allele drove 1.8-fold greater luciferase activity than T-allele constructs in HepG2 hepatoblastoma cells (p < 0.001), with the effect confirmed in renal and colorectal cell lines and in mouse liver in vivo. Individuals carrying the T allele — the GRCh38 reference base but the global minor allele — produce less CNT2 protein per cell.

The Evidence

The foundational functional work was published in 2009 by the Pharmacogenomics of Membrane Transporters consortium⁵⁵ Pharmacogenomics of Membrane Transporters consortium
PMT — a UCSF-led consortium dedicated to characterizing how genetic variation in drug transporters affects pharmacokinetics in diverse populations. Yee et al. (2009)⁶⁶ Yee et al. (2009) sequenced the SLC28A2 promoter in 272 individuals across five ethnic groups and identified rs2413775 as the only promoter variant with an allele frequency exceeding 20% in all populations studied. In a parallel analysis, Hesselson et al. (2009)⁷⁷ Hesselson et al. (2009)
Hesselson SE et al. Genetic variation in the proximal promoter of ABC and SLC superfamilies: liver and kidney specific expression and promoter activity predict variation. PLoS ONE. 2009;4(9):e6942 confirmed that the T allele was associated with lower promoter activity in hepatic tissue across a broader survey of SLC family promoter variants.

The clinical pharmacogenomic relevance of SLC28A2 expression level has been demonstrated in studies of ribavirin, a purine nucleoside analog used to treat hepatitis C. CNT2 mediates intestinal absorption and renal tubular reabsorption of ribavirin; higher CNT2 expression translates to greater intracellular drug accumulation. A multicenter study by Ampuero et al. (2015)⁸⁸ Ampuero et al. (2015)
Ampuero J et al. Role of ITPA and SLC28A2 genes in the prediction of anaemia associated with protease inhibitor plus ribavirin and peginterferon in hepatitis C treatment. J Clin Virol. 2015;68:8-13 found that the related SLC28A2 variant rs11854484 TT genotype independently predicted clinically significant ribavirin-induced anemia (OR 2.33, 95% CI 1.10–4.95, p = 0.027) — demonstrating that SLC28A2 expression differences have measurable hematological consequences during nucleoside analog therapy.

Beyond drug transport, SLC28A2 plays a role in purine nucleoside homeostasis. Zhou et al. (2019)⁹⁹ Zhou et al. (2019)
Zhou Z et al. Common variants in the SLC28A2 gene are associated with serum uric acid level and hyperuricemia and gout in Han Chinese. Hereditas. 2019;156:7 identified multiple SLC28A2 variants significantly associated with serum uric acid levels and gout risk in 4,015 Han Chinese participants, confirming CNT2's role in purine clearance and urate homeostasis.

Clinical translation of rs2413775 specifically awaits prospective pharmacokinetic/pharmacodynamic studies — the existing evidence is mechanistically compelling but direct outcome data for this exact promoter variant remain limited, warranting an emerging evidence classification.

Practical Actions

For individuals receiving nucleoside analog drugs that are CNT2 substrates — primarily ribavirin and didanosine — the T allele may signal reduced transporter expression and potentially lower intracellular drug accumulation. This could affect both therapeutic efficacy (less drug reaching target cells) and tolerability (potentially less drug accumulation in red blood cells, which drives ribavirin- induced hemolytic anemia). The clinical significance for any individual patient depends on the specific drug, dose, and co-administered agents.

For general health, CNT2 also transports dietary purine nucleosides across the intestinal epithelium. Reduced CNT2 expression in T-allele carriers may modestly affect purine absorption from high-purine foods (red meat, organ meat, shellfish, beer), though the magnitude of this effect on serum uric acid has not been characterized for rs2413775 specifically.

Interactions

CNT2 works alongside the equilibrative nucleoside transporters ENT1 (SLC29A1) and ENT2 (SLC29A2) and the concentrative transporter CNT3 (SLC28A3) to govern nucleoside flux. Studies of ribavirin pharmacogenomics consistently include SLC29A1 variants alongside SLC28A2, as the two transporter families serve partly overlapping substrates in different tissue compartments.

The coding-region variant rs11854484 in SLC28A2 has been more extensively studied in clinical cohorts for ribavirin-induced anemia and treatment outcomes than rs2413775 itself, and these variants are not in strong linkage disequilibrium — they tag independent aspects of CNT2 biology (promoter expression level vs. protein function).