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Use of pyrosequencing to detect clinically relevant polymorphisms in dihydropyrimidine dehydrogenase.

Common human diseases, such as cancer, have been associated with multiple types of variation in the genome, including sequence repeats and deletions and single-nucleotide polymorphisms (SNPs) (1). Of these, SNPs are the most abundant in the human genome (2)(3). As a result of the efforts of many groups (4), an estimated 5 million SNPs are now deposited in public databases (5), providing a resource for determining how genomic variation affects human biology. Building on this work, many groups have shown that drug response is also influenced by genomic variation (6). Multiple SNPs have been identified that have a major impact on response to chemotherapy (7)(8)(9)(10)(11); it is therefore necessary to have rapid and efficient SNP evaluation techniques to analyze genes that influence chemotherapy response.

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the three-step degradation of uracil to β-alanine (12). This is the only endogenous pathway for production of the neurotransmitter β-alanine (13). DPD also degrades >80% of the anticancer agent 5-fluorouracil (5-FU), a pyrimidine analog used to treat colorectal cancer, and limits the oral absorption of the drug (13). DPD activity is found to be highest in liver and mononuclear cells, but it is also present in most other human tissues (14).

Variation in DPD activity can lead to nonbeneficial physiologic conditions. A complete absence of DPD has been associated with the hereditary metabolic disorder thymine-uraciluria (9). This is characterized by mental retardation and is sometimes accompanied by other neurologic disorders, such as microcephaly, motor retardation, and autism (9). In addition, decreased DPD activity leads to severe toxicity from 5-FU even when typical doses are administered. This is often accompanied by severe diarrhea, neutropenia, and sometimes, neurotoxicity (9).

The DPYD gene located on chromosome 1p20 …