SLC22A1 rs28362224: Pharmacogenetics of Metformin Uptake
The rs28362224 variant (historically cross-referenced as rs72552763) is an in-frame trinucleotide deletion in the SLC22A1 gene, resulting in the loss of a methionine residue at codon 420 (p.Met420del). This alteration produces a reduced-function or loss-of-function organic cation transporter 1 (OCT1), which limits the liver's ability to take up cationic medications such as metformin. Pharmacogenomic research links this polymorphism to variability in glycemic response and drug tolerance, though clinical practice guidelines consider the evidence for routine dosing modifications to be limited.
What each genotype means
| Genotype | What the research suggests | Reading |
|---|---|---|
| No Deletion / No Deletion (Normal Function) | Carrying two intact copies of the SLC22A1 allele without the codon 420 deletion represents standard organic cation transporter 1 function. Individuals with this genotype exhibit normal baseline hepatic uptake of cationic medications like metformin. This is considered the typical reference status in global pharmacogenomic assessments. | Favorable |
| No Deletion / Met420del (Heterozygous Reduced Function) | Carrying one functional allele and one deletion allele results in intermediate OCT1 transport capacity. Cellular uptake of metformin and other substrates is moderately attenuated compared to homozygous reference carriers. Most individuals on standard pharmacotherapies do not experience major overt changes in efficacy, though statistical associations show intermediate drug clearance. | Informational |
| Met420del / Met420del (Homozygous Loss of Function) | Carrying two copies of the 3-base-pair deletion leads to a pronounced decrease in OCT1-mediated hepatic substrate transport. Studies report decreased hepatic metformin accumulation and altered systemic pharmacokinetic profiles in homozygous individuals. This status warrants attention if atypical treatment response or intolerance is being evaluated under medical supervision. | Higher attention |
Variant Details and Genomic Context
The variant designated by rs28362224 is located in exon 7 of the SLC22A1 gene on chromosome 6q25.3. It is characterized biologically as c.1260_1262del (or p.Met420del), where the deletion of three base pairs causes the loss of a single methionine amino acid without shifting the remaining reading frame. In clinical genomics literature, this change is frequently referenced alongside rs72552763. The deletion sits within a transmembrane region of the protein structure, altering conformational dynamics necessary for substrate binding and membrane translocation. Because it does not cause early protein truncation, the mutant protein reaches cellular membranes in varying amounts but displays severely impaired capacity to import basic pharmaceutical compounds into the intracellular space.
Biological Function of SLC22A1 and OCT1
SLC22A1 encodes organic cation transporter 1 (OCT1), a membrane transport protein predominantly localized to the basolateral membrane of human hepatocytes, with secondary expression observed in the small intestine and kidneys. OCT1 acts as a cellular gateway, facilitating the uptake of endogenous amines as well as a diverse array of therapeutic agents from the bloodstream into liver tissue. Its primary pharmacologic substrate is metformin, the first-line oral antihyperglycemic medication prescribed for type 2 diabetes. OCT1 is also involved in transporting basic drugs such as tramadol, morphine, tropisetron, and certain kinase inhibitors. Impaired transporter function can prevent drugs from reaching their intended hepatic molecular targets, while potentially altering systemic drug exposure and gastrointestinal concentrations.
Research Associations and Evidence Strength
Pharmacogenomic studies have repeatedly evaluated rs28362224 to determine its impact on diabetes treatment outcomes. In cellular assays and pharmacokinetic evaluations, carriers of the deletion exhibit reduced hepatic uptake of metformin and altered clearance profiles. However, translation into clinical efficacy shows mixed results across large cohort studies such as Go-DARTS. Some clinical cohorts report reduced glycemic response (smaller reductions in HbA1c) and altered susceptibility to gastrointestinal adverse effects among deletion carriers, while other trials find negligible differences in long-term glycemic control. Due to these conflicting clinical findings and the multifactorial nature of diabetes progression, pharmacogenomic consortia classify the evidence strength as limited, and professional guidelines do not currently mandate pre-emptive genotype testing for metformin selection.
Population Frequency and Diversity
The prevalence of the rs28362224 deletion differs dramatically across global ancestral groups. According to population databases such as gnomAD, the deletion allele is common in populations of European and Admixed American (Latino) ancestry, where allele frequencies generally range between 15% and 22%. In contrast, the variant is markedly less frequent in individuals of East Asian ancestry (often below 1%) and is found at lower rates in African lineages (typically around 3% to 5%). These significant ancestral differences mean that reduced hepatic uptake via OCT1 is far more commonly encountered in clinical cohorts of Western European descent, underscoring the importance of diverse genetic mapping in pharmacogenomic research.
Translating Results to Clinical Health
Discovering an rs28362224 deletion in personal direct-to-consumer or exploratory genetic data should not prompt independent changes to medical care. Having one or two copies of the deletion is a statistical factor, not a diagnostic verdict that metformin or any other basic medication will fail. Many carriers manage blood sugar levels effectively on standard metformin regimens due to compensation by alternative organic cation transporters (such as OCT2, OCT3, and MATE transporters) and complementary physiologic mechanisms. Any questions regarding glycemic response, medication side effects, or drug alternatives must be addressed directly with a healthcare provider or licensed clinical pharmacist.
How common is this variant?
The rs28362224 deletion allele is common in European and Admixed American populations with frequencies typically between 15% and 22%, but it is rare in East Asian lineages (under 1%) and observed at lower rates (around 3% to 5%) in African populations.
Frequently asked questions
What is rs28362224 and how does it relate to rs72552763?
Both identifiers refer to the same functional SLC22A1 mutation: an in-frame deletion of codon 420 (p.Met420del, c.1260_1262del). Due to evolution in genomic database nomenclature, older pharmacogenomic literature predominantly cites rs72552763, whereas modern reference catalogs often register this variation under rs28362224.
Does carrying the rs28362224 deletion mean metformin will not work for me?
No. While the variant reduces the transport of metformin into liver cells, clinical studies show variable real-world outcomes. Many patients carrying one or two deletion alleles still achieve good glycemic control through standard treatment and alternative drug transport pathways.
Does this genetic variant cause stomach side effects with metformin?
Research into gastrointestinal side effects has yielded contradictory results. Some researchers suggest decreased hepatic uptake might leave higher drug concentrations in the intestine to trigger nausea or diarrhea, while other clinical studies have found no statistical link or even conflicting patterns. Because evidence is limited, genetics alone cannot predict stomach tolerability.
Should I change my medication dosage if I have this genotype?
You should never alter, pause, or adjust your prescription medication based on personal genomic test results. Major clinical guideline bodies consider the evidence regarding OCT1 variants insufficient for standard dosing protocols; any treatment concerns should be reviewed with your physician or pharmacist.
Are other medications affected by the SLC22A1 gene?
Yes. Beyond metformin, OCT1 transports several basic compounds, including pain therapies like tramadol, morphine, and codeine, as well as certain antiemetics and targeted cancer therapies. However, clinical implementation of genotype-directed dosing remains limited across these drugs as well.
Sources & further reading
Educational information only, last refreshed 9/6/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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