rs1051298 — SLC19A1 SLC19A1 3'UTR variant (c.*746C>T)

SLC19A1 3'UTR Variant — Folate Transport and Antifolate Drug Sensitivity

SLC19A1, also known as the reduced folate carrier 1 (RFC1), is the primary membrane transporter responsible for moving folate¹¹ folate
Folate: a B-vitamin essential for DNA synthesis, methylation, and one-carbon metabolism and antifolate drugs across cell membranes. Every cell in your body depends on this transporter to import 5-methyltetrahydrofolate (5-MTHF), the active form of folate used in the methylation cycle and nucleotide synthesis. The same transporter that carries folate into cells is also the entry route for antifolate chemotherapy drugs²² antifolate chemotherapy drugs
Antifolate drugs like methotrexate and pemetrexed compete with folate for the RFC1 transporter — they work by flooding the cell and blocking folate-dependent enzymes like methotrexate and pemetrexed.

The Mechanism

The rs1051298 variant (NM_003056.2:c.*746C>T) lies in the 3' untranslated region³³ 3' untranslated region
3'UTR: the segment of mRNA after the protein-coding sequence — it contains regulatory elements that control mRNA stability, degradation rate, and translation efficiency (3'UTR) of SLC19A1. Unlike coding variants that change the transporter protein itself (such as the well-studied G80A/rs1051266 missense variant), this 3'UTR variant does not alter the amino acid sequence. Instead, it may affect mRNA stability, mRNA degradation rate, or the binding of microRNAs⁴⁴ microRNAs
MicroRNAs (miRNAs) are small non-coding RNA molecules that bind to the 3'UTR of target mRNAs and suppress protein production and RNA-binding proteins that regulate how much transporter protein is ultimately produced. Changes in transporter expression level — rather than transporter structure — can shift the balance between folate uptake and antifolate drug accumulation in ways that matter clinically.

The variant is located at position 45,514,912 on chromosome 21 (GRCh38). Because SLC19A1 runs on the minus (reverse) strand, the coding-strand notation c.*746C>T corresponds to a G→A change on the plus strand as reported in genome files. The A allele (plus strand) is the alternate allele associated with altered drug response.

The Evidence

The strongest clinical signal for rs1051298 comes from antifolate pharmacogenomics. Zhang et al. (2019)⁵⁵ Zhang et al. (2019)
Zhang X et al. Discovery of novel biomarkers of therapeutic responses in Han Chinese pemetrexed-based treated advanced NSCLC patients. Front Pharmacol, 2019 studied 203 Han Chinese patients with advanced non-small cell lung cancer receiving pemetrexed monotherapy. Carriers of the rs1051298 T allele (the A allele on the plus strand) showed significantly increased odds of adverse drug reactions: OR 3.14 (p=0.006) over cycles 1–2, and OR 2.24–2.34 (p=0.007) over longer treatment windows. The effect was particularly pronounced for liver injury⁶⁶ particularly pronounced for liver injury
Hepatotoxicity was the most specific ADR signal: OR 3.86 (p=0.006) over cycles 1–4 and OR 3.47 (p=0.007) over cycles 1–6, with odds ratios approaching 4-fold over cycles 1–4.

Corrigan et al. (2014)⁷⁷ Corrigan et al. (2014)
Corrigan A et al. Pharmacogenetics of pemetrexed combination therapy in lung cancer: pathway analysis reveals novel toxicity associations. Pharmacogenomics J, 2014 identified rs1051298 among a group of SLC19A1 polymorphisms (alongside rs3788189 and rs914232) associated with overall survival in 136 patients receiving pemetrexed/platinum combination therapy for lung cancer and mesothelioma.

The pharmacogenomic relevance of SLC19A1 is well-established through its role as the main cellular uptake route for methotrexate and pemetrexed. A PharmGKB pharmacogenomics summary⁸⁸ PharmGKB pharmacogenomics summary
Gong L et al. SLC19A1 pharmacogenomics summary. Pharmacogenet Genomics, 2010 documents the clinical importance of this transporter, noting that genetic variation affecting its expression or function directly influences how much antifolate drug accumulates in tumour cells — affecting both efficacy and toxicity.

The evidence level is moderate: findings are replicated across independent cohorts but come from pharmacogenomics studies in cancer patients; direct mechanistic data on how this 3'UTR variant changes SLC19A1 expression in non-malignant tissue is limited in the published literature.

Practical Actions

For healthy individuals, the rs1051298 variant's most actionable implications concern dietary folate optimization and drug interactions. Because the transporter's expression may be altered, ensuring adequate folate intake — preferably as methylfolate (5-MTHF), which is already in the active form and may have advantages over synthetic folic acid — is a reasonable precaution. The variant should also be flagged to a treating oncologist if pemetrexed-based chemotherapy is ever considered, as the literature suggests elevated toxicity risk — particularly hepatotoxicity — in A-allele carriers.

Interactions

This variant is distinct from the well-characterized SLC19A1 G80A missense variant (rs1051266), which changes the transporter protein structure. The two variants are in the same gene but represent independent sources of variation. Compound effects with MTHFR C677T (rs1801133) are plausible: impaired methylfolate production (MTHFR) combined with altered transporter expression (rs1051298) could amplify folate insufficiency at the cellular level. However, no published study has specifically documented the combined genotype effect of rs1051298 with MTHFR variants in a controlled design.