Research Article For reprint orders, please contact: reprints@futuremedicine.com Pharmacogenetic landscape of DPYD variants in south Asian populations by integration of genome-scale data Judith M Hariprakash ‡ ,1 , Shamsudheen K Vellarikkal ‡,,2 , Pavithran Keechilat 3 , Ankit Verma 2 , Rijith Jayarajan 2 , Vishal Dixit 2 , Rowmika Ravi 2 , Vigneshwar Senthivel 2 , Anoop Kumar 2 , Paras Sehgal 2 , Aradhana 2 , Akhilesh K Sonakar 2 , Sakshi Ambawat 2 , Anil K Giri 2 , Arun Philip 3 , Akhila Sivadas 3 , Mohammed Faruq 2 , Dwaipayan Bharadwaj 4 , Sridhar Sivasubbu *,2 & Vinod Scaria **,1 1 GN Ramachandran Knowledge Center for Genome Informatics, CSIR Institute of Genomics & Integrative Biology, Mathura Road, Delhi 110025, India 2 Genomics & Molecular Medicine, CSIR Institute of Genomics & Integrative Biology, Mathura Road, Delhi 110025, India 3 Department of Medical Oncology, Amrita Institute of Medical Sciences & Research Centre, Amrita University, Kochi-682041, India 4 School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India * Author for correspondence: sridhar@igib.in ** Author for correspondence: vinods@igib.in ‡ Authors contributed equally Aim: Adverse drug reactions to 5-Fluorouracil(5-FU) is frequent and largely attributable to genetic vari- ations in the DPYD gene, a rate limiting enzyme that clears 5-FU. The study aims at understanding the pharmacogenetic landscape of DPYD variants in south Asian populations. Materials & Methods: Systematic analysis of population scale genome wide datasets of over 3000 south Asians was performed. Indepen- dent evaluation was performed in a small cohort of patients. Results: Our analysis revealed signifcant differences in the the allelic distribution of variants in different ethnicities. Conclusions: This is the frst and largest genetic map the DPYD variants associated with adverse drug reaction to 5-FU in south Asian population. Our study highlights ethnic differences in allelic frequencies. First draft submitted: 2 June 2017; Accepted for publication: 8 November 2017; Published online: 14 December 2017 Keywords: 5- FU toxicity • allele frequency • DPYD • drug-related side effects and adverse reactions • pharmacogenomics • south Asia The 5-fluorouracil (5-FU) is an antimetabolite drug [1] widely prescribed for chemotherapy of solid tumors [2]. The antineoplastic drug [3] is used alone or in combination with other drugs and is a mainstay for gastrointestinal cancer [4–10]. It is estimated that nearly 40% of cancer patients administered with 5-FU develop toxicity-associated symptoms [11]. These symptoms could range from hand–foot syndrome, mucositis, granulocytopenia, neuropathy, to severe adverse events or even death in some individuals [12]. Within the cell, 5-FU is converted into multiple active metabolites through a series of enzymatic reactions. One of the active derivatives of 5-FU is fluorodeoxyuridine monophosphate, a competitive inhibitor of thymidylate synthase, which blocks the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate [1,12– 13], a crucial precursor of thymine. This results in an imbalance in nucleotide availability, crucial for rapidly dividing cancer cells [14], which leads to imbalanced cell growth and eventually cell death [12]. Additionally being a pyrimidine analog, 5-FU can incorporate into DNA and RNA, eliciting DNA-damage repair and triggering apoptosis machinery [4]. More than 80% of the administered 5-FU is converted to α-fluoro-β-alanine, which is the end point of the catabolic schemes of 5-FU [15]. Dihydropyrimidine dehydrogenase (DPD) is the first enzyme in this catabolic process that leads to clearance of 5-FU [2]. DPD is also the rate-limiting enzyme in the catabolism of 5-FU, which takes place in liver wherein DPD is abundantly expressed [1,16]. Hence, the bioavailability of 5-FU is mainly regulated by DPD, thus determining its half-life, efficacy and toxicity in treatment [2,13,17]. The human DPYD gene (NM 000110) Pharmacogenomics (Epub ahead of print) ISSN 1462-2416 10.2217/pgs-2017-0101 C  2018 Future Medicine Ltd