rs3918290 — DPYD *2A

DPYD*2A — The Most Critical Pharmacogenomic Variant

DPYD encodes dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme¹¹ rate-limiting enzyme
DPD catabolizes 80-90% of administered 5-fluorouracil into inactive metabolites responsible for breaking down fluoropyrimidine chemotherapy drugs. The DPYD*2A variant (also known as IVS14+1G>A) is a ²² G-to-A transition at the invariant splice donor site of intron 14, causing complete skipping of exon 14 splice site mutation that results in complete loss of enzyme function. This is the single most important pharmacogenomic variant to test before starting fluoropyrimidine-based cancer treatment.

The Mechanism

The DPYD gene spans 950 kb on ³³ chromosome 1p22 with 23 coding exons encoding the 1025 amino acid DPD enzyme chromosome 1. The *2A variant occurs at the ⁴⁴ The +1 position of the splice donor site — the invariant GT dinucleotide essential for proper mRNA splicing splice donor site immediately after exon 14, disrupting the normal splicing machinery. Without the correct splice signal, the entire exon 14 (165 base pairs) is ⁵⁵ RT-PCR analysis on patient RNA demonstrated complete exon 14 skipping resulting in an in-frame deletion of 55 amino acids skipped during mRNA processing, producing a truncated, catalytically inactive protein.

Functional studies⁶⁶ Functional studies
Patient fibroblasts homozygous for *2A showed undetectable DPD enzyme activity; heterozygotes had approximately 50% activity have confirmed that homozygous *2A carriers have zero measurable DPD activity, while heterozygous carriers retain approximately 50% of normal enzyme function. Without sufficient DPD to metabolize fluoropyrimidines, these drugs accumulate to toxic levels, causing severe bone marrow suppression, gastrointestinal toxicity, and in 2-4% of variant carriers receiving standard doses, ⁷⁷ death.

The Evidence

The clinical significance of DPYD*2A is ⁸⁸ supported by CPIC Level 1A evidence: variant-specific prescribing guidance in current clinical guidelines with PharmGKB Level 1A annotation thoroughly established across multiple lines of evidence. A 2021 meta-analysis⁹⁹ A 2021 meta-analysis
Pooled data from 13,929 patients showing carriers had 25.6-fold increased risk of treatment-related death (95% CI 12.1-53.9) of 13,929 cancer patients found that *2A carriers receiving standard-dose fluoropyrimidines had a 25.6-fold increased risk of treatment-related death compared to non-carriers. Without dose adjustment, heterozygous *2A carriers experience severe toxicity in ¹⁰¹⁰ 73-77% of cases, compared to 20-30% in the general population.

Prospective implementation trials¹¹¹¹ Prospective implementation trials
Henricks et al. 2018 study of 1,103 patients with pre-treatment DPYD genotyping and dose adjustment have proven that genotype-guided dosing solves this problem. In a landmark 2018 study of 1,103 patients, preemptive 50% dose reduction in *2A carriers reduced severe toxicity from 73% to 31% — nearly normalizing risk to that of non-carriers. Critically, ¹²¹² matched pair analysis showed no difference in overall survival or progression-free survival between dose-reduced carriers and full-dose non-carriers survival outcomes remained equivalent: dose-reduced *2A carriers had the same overall survival and progression-free survival as non-carriers receiving full doses.

Based on this evidence, the Clinical Pharmacogenetics Implementation Consortium¹³¹³ Clinical Pharmacogenetics Implementation Consortium
CPIC 2017 guideline with 2018 update recommending 50% dose reduction for intermediate metabolizers (CPIC) issued Level A guidelines in 2017 (updated 2018) for DPYD-guided fluoropyrimidine dosing. The ¹⁴¹⁴ European Medicines Agency mandated DPD testing before fluoropyrimidine treatment in 2020; UK NHS implemented national DPYD testing in 2020 European Medicines Agency (2020) and UK National Health Service (2020) now mandate or strongly recommend pre-treatment DPYD testing.

Practical Implications

If you are being prescribed 5-fluorouracil (5-FU), capecitabine (Xeloda), or tegafur for cancer treatment, DPYD genotyping is essential before starting therapy. These drugs are backbone treatments for colorectal, breast, gastric, pancreatic, and head-and-neck cancers. The standard approach is straightforward:

For heterozygous (*2A) carriers (AG genotype): Start at 50% of the standard dose, then titrate upward based on tolerability and therapeutic drug monitoring. Your oncologist should measure 5-FU plasma levels to ensure you're achieving therapeutic concentrations without toxicity. Most carriers can eventually increase to 65-80% of standard doses.

For homozygous carriers (AA genotype) or compound heterozygotes: Fluoropyrimidines are ¹⁵¹⁵ FDA label states no dose of fluorouracil has been proven safe in individuals with absent DPD activity contraindicated — no dose has been proven safe. Your oncologist must choose an alternative chemotherapy regimen. There is an ¹⁶¹⁶ FDA-approved antidote uridine triacetate for emergency rescue from 5-FU overdose FDA-approved antidote (uridine triacetate) for emergency overdose situations, but prevention through genotyping is far preferable.

Testing is now routine in Europe but remains inconsistent in North America. If your oncologist hasn't ordered DPYD testing, request it explicitly. Most genetic testing companies offer targeted DPYD panels covering *2A plus the other three clinically actionable variants (c.1679T>G, c.2846A>T, c.1236G>A/HapB3). Turnaround time is typically 2-5 days. The test is cost-effective: preventing even one case of severe toxicity saves $155,000-180,000¹⁷¹⁷ $155,000-180,000
Cost of managing severe fluoropyrimidine toxicity including hospitalization and rescue therapy in healthcare costs compared to ~$160-250 for genotyping.

Interactions

DPYD*2A is one of four "high-priority" DPYD variants routinely tested before fluoropyrimidine therapy. The other three are rs55886062 (DPYD*13, c.1679T>G), rs67376798 (c.2846A>T), and rs75017182 (HapB3 haplotype). Each contributes additively to DPD deficiency. Approximately 0.07% of patients are compound heterozygotes, carrying two different DPYD risk variants simultaneously. In compound heterozygous states (e.g., *2A plus c.2846A>T), the combined enzyme deficiency may approach homozygous levels, requiring fluoropyrimidine avoidance rather than dose reduction. If testing reveals multiple DPYD variants, discuss with your oncology team immediately — this dramatically changes dosing strategy.

Some cancer centers also test for rare variants like c.557A>G (more common in individuals of African ancestry) or perform DPYD sequencing to capture novel loss-of-function mutations. While *2A, *13, c.2846A>T, and HapB3 account for the majority of predicted DPD deficiency, additional variants continue to be discovered.