rs67376798 — DPYD D949V

DPYD D949V — Reduced Fluoropyrimidine Metabolism

The DPYD gene encodes dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme responsible for metabolizing 80-90% of fluoropyrimidine chemotherapy drugs¹¹ 80-90% of fluoropyrimidine chemotherapy drugs
These include 5-fluorouracil (5-FU), capecitabine, and tegafur, among the most widely used cancer treatments worldwide. DPD breaks down these drugs into inactive metabolites, preventing toxic accumulation.

The D949V variant (c.2846A>T) is one of four decreased-function DPYD variants recommended for mandatory pre-treatment screening by the European Medicines Agency²² mandatory pre-treatment screening by the European Medicines Agency
The EMA mandates testing for DPD deficiency before fluoropyrimidine treatment in all cancer patients across Europe. and included in Clinical Pharmacogenetics Implementation Consortium (CPIC) Level 1A guidelines³³ Clinical Pharmacogenetics Implementation Consortium (CPIC) Level 1A guidelines
Level 1A is the highest evidence tier, indicating variant-specific prescribing guidance in clinical guidelines with strong supporting evidence.

The Mechanism

The D949V variant replaces aspartic acid with valine at codon 949 in the 4Fe-4S ferredoxin-type iron-sulfur binding domain⁴⁴ 4Fe-4S ferredoxin-type iron-sulfur binding domain
This domain is critical for the enzyme's catalytic activity. The aspartic acid residue is highly conserved across 100 vertebrate species. This is a non-conservative substitution — aspartic acid is a charged, polar amino acid while valine is hydrophobic and uncharged, creating substantial physicochemical disruption to protein structure⁵⁵ substantial physicochemical disruption to protein structure.

In vitro studies show the variant reduces DPD enzyme activity to 39-59% of wild-type when expressed in cell lines⁶⁶ In vitro studies show the variant reduces DPD enzyme activity to 39-59% of wild-type when expressed in cell lines
Studies by Offer et al. 2014 and van Kuilenburg et al. 2016 demonstrated this consistent reduction. In heterozygous carriers (one copy of the variant), DPD activity measured in peripheral blood mononuclear cells is reduced by approximately 30%⁷⁷ DPD activity measured in peripheral blood mononuclear cells is reduced by approximately 30%
This translates to a 40-80% reduction in 5-fluorouracil clearance.

The Evidence

A 2013 meta-analysis of 7,365 patients across eight cohort studies⁸⁸ A 2013 meta-analysis of 7,365 patients across eight cohort studies
Meulendijks et al. demonstrated carriers of c.2846A>T have a 3.0-fold increased risk (95% CI 2.2-4.1) of severe fluoropyrimidine toxicity. Severe toxicity includes life-threatening diarrhea, mucositis, bone marrow suppression, and hand-foot syndrome.

The prospective Alpe-DPD study (Henricks et al. 2018)⁹⁹ prospective Alpe-DPD study (Henricks et al. 2018)
This landmark Dutch multicenter study genotyped 1,181 patients before fluoropyrimidine treatment and adjusted doses based on genotype. demonstrated that pre-emptive genotyping with 50% dose reduction in heterozygous D949V carriers reduced severe toxicity rates to levels comparable to non-carriers. Initially, CPIC recommended 25-50% dose reduction for decreased-function variants like D949V, but updated this to a firm 50% reduction in November 2018¹⁰¹⁰ updated this to a firm 50% reduction in November 2018
The update was based on evidence that 25% reduction was insufficient to prevent toxicity in many carriers. following the Henricks study results.

Recent case reports of homozygous D949V carriers¹¹¹¹ Recent case reports of homozygous D949V carriers
Individuals with two copies of the variant have even more severely reduced DPD activity. indicate that >50% dose reduction may be necessary in this rare genotype, or alternative non-fluoropyrimidine chemotherapy should be considered.

The 2023 PhotoDPYD study of 8,054 Spanish cancer patients¹²¹² 2023 PhotoDPYD study of 8,054 Spanish cancer patients
This is the largest European assessment of DPYD variant frequencies to date. found c.2846A>T in 1.3% of patients (105 heterozygous carriers, 3 homozygous), making it the second most common clinically relevant DPYD variant after HapB3. The variant is found at similar frequencies (~0.6% allele frequency) across European populations¹³¹³ found at similar frequencies (~0.6% allele frequency) across European populations
gnomAD v4 reports 7,583 heterozygous and 29 homozygous carriers among 1,179,644 European alleles.

Practical Implications

If you have one copy of the D949V variant and require fluoropyrimidine chemotherapy, your oncologist should reduce the starting dose by 50% and carefully titrate upward based on tolerance. This approach maintains treatment efficacy while dramatically reducing the risk of severe toxicity. Pre-emptive DPYD screening has been shown to be cost-effective¹⁴¹⁴ Pre-emptive DPYD screening has been shown to be cost-effective
The cost of screening is offset by reduced hospitalizations for severe toxicity, which can exceed $180,000 per incident. and is now standard of care across much of Europe.

The four-variant DPYD panel (including D949V, DPYD*2A, DPYD*13, and HapB3) captures approximately 20-30% of patients who will experience severe fluoropyrimidine toxicity¹⁵¹⁵ approximately 20-30% of patients who will experience severe fluoropyrimidine toxicity
The remaining 70-80% of toxicity cases are due to other factors including rare DPYD variants, drug interactions, and non-genetic factors. This means that even with a normal result on this panel, careful monitoring during fluoropyrimidine treatment remains essential.

Interactions

The D949V variant is one of four clinically actionable DPYD variants that together define DPD metabolizer status. Compound heterozygosity — carrying D949V along with another decreased or no-function DPYD variant (rs3918290/DPYD*2A, rs55886062/DPYD*13, or rs75017182/HapB3) — results in poor metabolizer status with activity score of 1.0¹⁶¹⁶ poor metabolizer status with activity score of 1.0
The DPYD activity score system assigns 0.5 points per decreased-function allele and 0 points per no-function allele, with normal being 2.0. requiring even more aggressive dose reductions (typically ≥50% reduction with very gradual titration) or selection of alternative chemotherapy. Three compound heterozygous cases were documented in the PhotoDPYD study¹⁷¹⁷ Three compound heterozygous cases were documented in the PhotoDPYD study
Two carried DPYD*2A + c.2846A>T and two carried HapB3 + c.2846A>T. Such combinations dramatically increase toxicity risk and require specialized pharmacogenomic guidance.