rs3788189 — SLC19A1 SLC19A1 IVS2 variant

SLC19A1 IVS2 — The Antifolate Transport Modifier

SLC19A1, known as the reduced folate carrier (RFC1), is the principal gateway through which folate vitamins and antifolate drugs enter cells. Every cell in your body depends on RFC1 to import the folate it needs for DNA synthesis and methylation. The same transporter is exploited by two major drug classes — antifolate chemotherapies (pemetrexed, methotrexate) and antifolate antibiotics — to enter their target cells. A variant in the second intron of SLC19A1, rs3788189, has emerged in pharmacogenomics studies as a modifier of how well these drugs work and whether side effects are likely.

The Mechanism

rs3788189 sits in intron 2 of SLC19A1 at chromosome position 21:45,516,669 (GRCh38). The gene lies on the minus strand, so the plus-strand T/G polymorphism corresponds to C/A on the coding transcript. This variant has also been annotated in the literature as IVS2(4935) G>A (intron 2, 4,935 bases into the intron). As an intronic variant, rs3788189 does not directly change the amino acid sequence of the RFC1 protein, but intronic variants can alter pre-mRNA splicing¹¹ pre-mRNA splicing
Intronic sequences contain branch points, polypyrimidine tracts, and splice enhancer/silencer sequences that regulate how exons are joined, create cryptic splice sites, affect mRNA stability, or alter transcriptional regulation through intronic enhancer elements. The exact molecular mechanism by which rs3788189 influences RFC1 expression or function has not been characterized, but the pharmacogenomics signal is consistent with functional consequences in folate and antifolate transport.

Note that rs3788189 is distinct from the well-characterized G80A coding variant (rs1051266, p.His27Arg), which is already in the GeneOps database. These are independent variants in the same gene with different functional implications.

The Evidence

The clearest pharmacogenomics signal comes from two small but consistent studies in patients receiving pemetrexed²² pemetrexed
Pemetrexed (Alimta) is an antifolate used for non-small-cell lung cancer and mesothelioma; it enters cells via RFC1 to inhibit folate-dependent enzymes, a modern antifolate chemotherapy that uses RFC1 for cellular uptake.

In a phase II perioperative study of 38 NSCLC patients receiving cisplatin plus pemetrexed, the TT genotype at rs3788189 was associated with improved disease-free survival³³ TT genotype at rs3788189 was associated with improved disease-free survival
Dy et al. J Thorac Oncol 2014 (p=0.0821), suggesting patients with two copies of the reference T allele derived greater benefit from pemetrexed-based chemotherapy.

In a larger pharmacogenomic study of 136 lung cancer and mesothelioma patients receiving pemetrexed/platinum⁴⁴ 136 lung cancer and mesothelioma patients receiving pemetrexed/platinum
Corrigan et al. Pharmacogenomics J 2014, rs3788189 was among three SLC19A1 polymorphisms independently associated with overall survival, supporting the hypothesis that this intronic variant influences RFC1-mediated pemetrexed transport.

A meta-analysis of 16 publications covering 1,510 patients on pemetrexed or gemcitabine identified SLC19A1 IVS2(4935) G>A — corresponding to rs3788189 — as a predictor of grade 3+ leukopenia in American patients⁵⁵ SLC19A1 IVS2(4935) G>A — corresponding to rs3788189 — as a predictor of grade 3+ leukopenia in American patients
Zaïr & Singer, Pharmacogenomics 2016. This hematological toxicity signal suggests that the G allele may be associated with impaired RFC1-mediated pemetrexed transport efficiency or altered folate competition during treatment, leading to differential drug exposure in bone marrow progenitor cells.

The evidence base is limited — most studies are small, the mechanism is not characterized at the molecular level, and no clinical guidelines (CPIC, DPWG) currently exist for this variant. The evidence level is therefore rated emerging.

Practical Actions

For people with GG or GT genotypes who are candidates for pemetrexed or methotrexate treatment, sharing this pharmacogenomic result with their oncologist or rheumatologist provides potentially useful context — particularly given the leukopenia signal in the meta-analysis. Pemetrexed requires standard folic acid and vitamin B12 supplementation before each cycle regardless of genotype (per prescribing protocol), but this variant may influence monitoring intensity.

From a nutritional standpoint, since RFC1 is also the main folate transporter, this variant may modestly affect baseline folate transport efficiency. The G allele may be associated with slightly altered intracellular folate availability, though this has not been studied in nutritional contexts independent of antifolate chemotherapy.

Interactions

The most clinically significant interaction is with the coding variant rs1051266 (G80A, p.His27Arg) in the same gene. rs1051266 reduces RFC1 transport function through a structural change in transmembrane domain 1; rs3788189 may additively affect transport through an independent regulatory mechanism. Carriers of risk alleles at both sites within SLC19A1 may have more pronounced impairment.

The folate pathway interaction extends to MTHFR (rs1801133 C677T, rs1801131 A1298C): if MTHFR activity is reduced AND RFC1 transport is impaired, intracellular methylfolate may be doubly compromised, amplifying the importance of methylfolate supplementation over synthetic folic acid.