ATIC rs2372536: Methotrexate Response and Rheumatoid Arthritis
The rs2372536 variant is a genetic change located in the ATIC gene, which plays a key role in the body's folate metabolism pathway. Researchers study this variant to understand if it influences how patients with rheumatoid arthritis respond to methotrexate treatment.
What each genotype means
Common ATIC genotype
This is the most common genotype for this variant in many populations. Research into how this specific genotype influences methotrexate response in rheumatoid arthritis has yielded inconsistent results across different ethnic groups, with some studies showing no significant association with treatment efficacy or toxicity. Please discuss your medication response and any concerns about methotrexate dosing with your clinician or pharmacist.
This is the homozygous wild-type genotype and is frequently observed in the majority of individuals across most studied populations.
Heterozygous ATIC genotype
This genotype represents a mix of the common and variant alleles. Studies investigating its role in methotrexate therapy for rheumatoid arthritis have not consistently linked it to specific clinical outcomes, as findings vary significantly by ancestry and study design. Please discuss your medication response and any concerns about methotrexate dosing with your clinician or pharmacist.
This heterozygous genotype is found at varying frequencies depending on the specific ancestral background of the population studied.
Variant ATIC genotype
This genotype involves a substitution of threonine for serine at position 116 of the ATIC protein. Some research has suggested an association between this genotype and methotrexate response in rheumatoid arthritis patients, though results are mixed; for example, some studies in Caucasian populations have linked it to better treatment response, while others have found no significant effect. Please discuss your medication response and any concerns about methotrexate dosing with your clinician or pharmacist.
This is the minor genotype and its frequency is variable, appearing less commonly than the CC genotype in most populations.
Understanding the rs2372536 Variant
The rs2372536 variant is a single nucleotide polymorphism (SNP) located within the ATIC gene. Specifically, this variant involves a change where a cytosine (C) is replaced by a guanine (G) at a specific position in the gene's DNA sequence. This change is located in exon five of the gene and results in a missense mutation, meaning it causes a substitution of the amino acid threonine for serine at position 116 of the resulting protein. Because this change alters the protein's structure, scientists have investigated whether it might affect the function of the ATIC enzyme, which is a critical component of the folate metabolic pathway. This pathway is essential for DNA synthesis and repair, and it is also the primary target for methotrexate, a common medication used to manage autoimmune conditions like rheumatoid arthritis.
The Role of the ATIC Gene
The ATIC gene encodes the bifunctional enzyme 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase. This enzyme is vital for the de novo synthesis of purines, which are the building blocks of DNA and RNA. Methotrexate works in part by inhibiting enzymes involved in folate metabolism, which leads to an accumulation of intermediates that can have anti-inflammatory effects. Because the ATIC enzyme is involved in the final steps of purine synthesis, variations in the ATIC gene are hypothesized to potentially alter the intracellular environment in a way that changes how a patient responds to methotrexate. By studying how the rs2372536 variant affects this enzyme, researchers hope to better understand the biological mechanisms that lead to different clinical outcomes in patients receiving methotrexate therapy.
Research and Clinical Evidence
Research into rs2372536 has produced mixed and sometimes conflicting results regarding its impact on methotrexate efficacy. Some studies have suggested that the G allele or the GG genotype may be associated with a better clinical response or improved remission rates in certain populations. Conversely, other meta-analyses and studies have reported different findings, with some indicating that the major allele or other genotypes might be linked to better clinical benefits. The evidence is currently considered moderate, as the results are often inconsistent across different ethnic groups and study cohorts. Because rheumatoid arthritis is a complex condition influenced by many genetic and environmental factors, it is difficult to isolate the effect of a single SNP. Consequently, this variant is not currently used in routine clinical practice to guide medication dosing or treatment decisions.
Population Frequency
The frequency of the rs2372536 variant varies significantly across different global populations. Data from various studies indicate that the minor allele frequency can differ between groups, such as Malay, Chinese, and Indian populations. Because these frequencies are not uniform, the prevalence of the CC, CG, and GG genotypes will also differ depending on a person's ancestral background. Researchers often observe that allele frequencies reported in public databases may not always align with those found in specific clinical study cohorts, highlighting the importance of considering ancestry when interpreting genetic data.
What This Information Means for You
It is important to understand that genetic variants like rs2372536 are subjects of ongoing scientific research and are not currently used as diagnostic tools. The associations observed in studies are statistical in nature and do not predict how any single individual will respond to a medication. If you are taking methotrexate for rheumatoid arthritis, your treatment plan should be based on your clinical symptoms, blood tests, and the professional judgment of your rheumatologist. Never make changes to your medication regimen based on genetic information without first consulting your healthcare provider or a pharmacist. They are the best resources to help you understand your treatment options and how they relate to your specific health needs.
How common is this variant?
The frequency of the rs2372536 variant is variable across different ancestral populations, with minor allele frequencies often differing between groups such as Malay, Chinese, and Indian cohorts.
Frequently asked questions
Can I use this genetic test to predict if methotrexate will work for me?
No. Current research on rs2372536 is not sufficient to predict individual drug response. Treatment decisions should always be made by your doctor based on your clinical progress.
Is rs2372536 a diagnostic test for rheumatoid arthritis?
No. This variant is studied in the context of pharmacogenomics, which looks at how genes affect drug response. It is not used to diagnose rheumatoid arthritis.
Why do different studies show different results for this variant?
Genetic studies are complex and can be influenced by differences in study design, the ethnic background of participants, and other environmental factors. This is why the evidence for this variant is considered moderate and inconsistent.
Should I ask my doctor about my ATIC genotype?
You can certainly discuss your interest in pharmacogenomics with your doctor. However, be aware that this specific variant is not currently part of standard clinical testing for methotrexate therapy.
Sources & further reading
Educational information only, last refreshed 10/27/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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