rs914232 — SLC19A1 RFC1 -43T>C

Regulatory variant that reduces reduced folate carrier protein expression, impairing folate uptake into cells

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SLC19A1 RFC1 -43T>C — The Folate Carrier's Dimmer Switch

Before folate — whether from food or supplements — can do its work inside your cells, it has to get through the cell membrane. That job belongs to SLC19A1, also called the reduced folate carrier (RFC1). Without adequate RFC1 function, even normal blood folate levels can mask cellular deficiency. The -43T>C variant (rs914232) sits in the regulatory region just upstream of the SLC19A1 coding sequence and turns down how much of this transporter your cells actually produce.

The Mechanism

Unlike the well-known G80A variant (rs1051266), which changes the transporter's amino acid sequence, rs914232 is a regulatory polymorphism located in the 5'-flanking sequence near the ATG translation start site. This position influences how efficiently the gene is transcribed. Western blot analysis in a clinical study11 Western blot analysis in a clinical study
Chatzikyriakidou et al. Rheumatol Int, 2007 found that the C allele is associated with reduced RFC protein expression levels, meaning cells with this variant simply build fewer transporter molecules. The three SLC19A1 variants -43T>C, 80G>A (rs1051266), and 696C>T (rs3788189) were found to be in strict linkage disequilibrium in that study, suggesting they often travel together and may act in concert.

The Evidence

Evidence for rs914232 is moderate — several small studies with consistent direction but limited statistical power. Chatzikyriakidou et al. 200822 Chatzikyriakidou et al. 2008
Chatzikyriakidou A et al. Distinct association of SLC19A1 -43T>C with red cell folate levels. Clin Biochem, 2008 studied 64 patients with coronary artery disease and found that the non-wild-type allele of the -43T>C variant was associated with low red cell folate levels. Importantly, that same study showed that MTHFR C677T was associated with low plasma folate rather than red cell folate — two separate compartments — suggesting that SLC19A1 specifically affects folate storage inside red blood cells rather than what circulates in plasma.

In a Korean cohort of 372 colorectal cancer patients, Jang et al. 201433 Jang et al. 2014
Jang MJ et al. Polymorphisms of folate metabolism genes and survival of patients with colorectal cancer. Gene, 2014 found that the RFC1 -43CC genotype was associated with favorable overall survival among rectal cancer patients receiving 5-fluorouracil-based chemotherapy — an observation that may reflect altered folate availability affecting treatment pharmacodynamics. In pemetrexed-treated lung cancer patients (n=136), Berghmans et al. 201444 Berghmans et al. 2014
Berghmans T et al. Pharmacogenetics of pemetrexed combination therapy. Pharmacogenomics J, 2014 reported that SLC19A1 rs914232 was among variants associated with overall survival — though these findings require replication in larger cohorts.

Practical Actions

The C allele reduces RFC1 expression, which translates into less efficient folate entry into cells. For most people with the CT or CC genotype, the practical implication is straightforward: methylfolate (5-MTHF) is already in its bioavailable active form and does not need the same degree of transporter-mediated uptake as synthetic folic acid to exert its effects inside cells. Ensuring adequate dietary folate and supplementing with methylfolate rather than folic acid is the primary mitigation.

Interactions

rs914232 acts in concert with the SLC19A1 G80A coding variant (rs1051266), which alters the transporter's amino acid sequence. The two variants are in linkage disequilibrium, so carriers of the C allele at this position often also carry the risk allele at rs1051266. Layered on top of MTHFR variants (rs1801133, rs1801131), combined transport and conversion impairment can further reduce intracellular folate availability. Red cell homocysteine levels are the most clinically relevant biomarker to monitor when both transport and methylation variants are present.

Nutrient Interactions

folate reduced_absorption

Genotype Interpretations

What each possible genotype means for this variant.

TT Normal RFC Expression Normal

Normal reduced folate carrier expression

You carry two copies of the T allele, the wild-type at this regulatory position. Your SLC19A1 gene produces normal levels of the reduced folate carrier (RFC1), allowing efficient folate uptake into your cells. Approximately 22% of people globally share this genotype.

CT Mildly Reduced RFC Expression Intermediate

One regulatory C allele — modestly reduced RFC1 protein levels

You carry one copy of the C allele, which is associated with somewhat lower RFC1 protein expression. Your folate transport capacity is modestly reduced, meaning cells may import folate slightly less efficiently than average. About 50% of people carry this genotype.

At this heterozygous level the functional impact is mild for most people, but it becomes more relevant when combined with MTHFR variants that also reduce folate availability, or when dietary folate intake is low.

CC Reduced RFC Expression Reduced

Two regulatory C alleles — reduced RFC1 protein levels

The C allele at this regulatory position reduces transcription of the SLC19A1 gene, resulting in fewer RFC1 protein molecules in the cell membrane. A 2007 study (PMID 17404734) confirmed this reduction via Western blot in rheumatoid arthritis patients. A 2008 study (PMID 18053808) specifically found low red cell folate concentrations in CAD patients carrying the non-wild-type allele.

This genotype is particularly consequential if you also carry the SLC19A1 G80A risk allele (rs1051266), because rs914232 and rs1051266 are in linkage disequilibrium — you may have reduced RFC1 quantity (fewer transporters) and reduced RFC1 quality (altered transporter function) simultaneously.