Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes

Vincristine is an effective chemotherapeutic drug for various cancers, including acute lymphoblastic leukemia (ALL). Unfortunately, clinical utility is restricted by dose-limiting vincristine-induced peripheral neuropathies (VIPN). We sought to determine the association of VIPN with a recently identified risk variant, CEP72 rs924607, and drug absorption, distribution, metabolism, and excretion (ADME) gene variants in pediatric ALL. This was followed by a meta-analysis of pharmacogenomic data from over 500 patients. CEP72 rs924607 was significantly associated with VIPN (P = 0.02; odds ratio (OR) = 3.4). ADME analyses identified associations between VIPN and ABCC1 rs3784867 (P = 5.34 × 10 −5 ; OR = 4.9), and SLC5A7 rs1013940 (P = 9.00 × 10 −4 ; OR= 8.6); genes involved in vincristine transport and inherited neuropathies, respectively. Meta-analysis identified an association with a variant related to TTPA (rs10504361: P = 6.85 × 10 −4 ; OR = 2.0), a heritable neuropathy-related gene. This study provides essential corroboratory evidence for CEP72 rs924607 and highlights the importance of drug transporter and inherited neuropathy genes in VIPN

Genealogical relationship among members of selection and production populatoins of yellow-cedar (Callitropsis nootkatensis) in the absense of parental information

The recurrent selection scheme of tree improvement programs follows three main steps; namely, phenotypic selection of candidate tree from natural stands or plantations, followed by breeding and testing, and finally the cycle is completed by the identification of elite genotypes for production population(s) establishment and/or starting a new round of selection. An innovative approach to reduce both efforts and the length of the breeding cycle was attempted for yellowcedar (Chamaecyparis nootkatensis) through capitalizing on natural matings in the forest, application of high intensity phenotypic selection at very early age (1 -year-old seedlings), followed by vegetative propagation and intense clonal testing over multiple sites and years to identify superior genotypes for inclusion into production populations. This approach has proven to be successful and significant gain was captured through this short-cut; however, the genetic relationship among early age selections as well as superior genotypes is unknown. DNA fingerprinting (SSRs), pairwise relative kinship estimates, pedigree reconstruction as well as the STRUCTURE program were used to determine the genetic relationship among 3, 1-year-old greenhouse selections from reforestation seedling crops and highlighted the presence of co-ancestry among members of the selection and production populations. Results from the pairwise relative kinship estimates (Mzuuc: Ritland 1996) indicated the presence of full- and half-sib family structure and the family structure was verified using Wang’s (2004) pedigree reconstruction COLONY program and individuals within each seedlot were grouped into multiple full-sib families of various sizes (1-10) nested within several half-sib families (17-21). The STRUCTURE program (Pritchard 2000) provided pictorial classification of the seedlots and grouped their individuals in multiple cohorts (9-10). In spite of violating the STRUCTURE program assumptions, good correspondence was observed between the COLONY and STRUCTURE analyses, indicating that the selected seedlings originated from a limited number of seed donors. The species’ social status and reproductive biology, methods of natural stand seed collection and commercial seedling production, and the high selection intensity applied at the greenhouse stage, all point to limiting the selection to fewer trees in spite of the large number of seed donors constituting these seedlots. Build up of co-ancestry in selection and production populations will cause an incorrect estimation of genetic gain and unintentional reduction in genetic diversity in reforestation material.Forestry, Faculty ofGraduat

Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes

10.1002/cpt.1179CLINICAL PHARMACOLOGY & THERAPEUTICS1052402-41