ABSTRACT
BACKGROUND: Pharmacogenetics is involved in customizing therapy according to the genetic makeup of an individual, and is applicable for chemotherapy, radiotherapy as well as targeted therapy. Drug metabolizing enzymes (DMEs) involving both phase I, and phase II reactions are widely studied. Our study was involved in whole exome sequencing (WES) of cancer patients, followed by analysis for identifying key variations in DMEs, and associated transporters that have a potential impact on treatment outcome. METHODOLOGY: A total of 181 solid tumor patients at stage >/= III were subjected to WES by the SureSelectXT Human All Exon V6 + UTR library preparation kit, and sequencing in the Illumina NextSeq 550 system. Bioinformatics analysis involved use of GATK pipeline, and the variants were further assessed for population frequency, functional impact with annovar insilico algorithms. Further variant information from significant DMEs, and transporters were extracted and analyzed with PharmGKB to assess level of evidence and infer their impact on the pathways involved in drug response. RESULTS: The total study cohort of 181 solid tumor patients included 60 males, and 121 females respectively. Among DMEs, deleterious mutation in dihydropyrimidine dehydrogenase (DPYD; rs67376798), solute carrier organic anion transporter family member 1B1 (SLCO1B1*5), and cytochrome P450 2D6 (CYP2D6*10) associated with metabolism of anticancer drugs was detected to be in high frequency of 26%, 21% and 25% respectively. CONCLUSION: Our analysis detected variations in both phase I and phase II DMEs, as well as associated transporter genes which has been documented to reduce drug efficacy, as well as cause grade 3 and 4 toxicity. Our study reiterates the significance of pharmacogenomics in stratifying patients for appropriate therapy regimen focused at better treatment outcome and quality of life.
ABSTRACT
BACKGROUND: Hepatitis C virus (HCV) is a major health problem, particularly in high-risk groups such as kidney transplant recipients, where it can adversely affect graft survival and increase the relative risk for mortality. Recently, the role of genetic variation among HCV patients in determining the outcome of infections has been under investigation. OBJECTIVE: To investigate the association of single-nucleotide polymorphisms (SNPs) rs12979860 (located within the interleukin-28B locus), rs2228145 (interleukin-6 receptor) and rs1800795 (interleukin-6 promoter) with HCV viremia in renal transplant patients. MATERIALS AND METHODS: In this analytical cross-sectional study, 149 kidney transplant recipients, 82 males (median age: 41 years) and 67 females (median age: 45 years), were screened for HCV RNA in blood using real-time polymerase chain reaction and genotyped by sequencing (rs12979860) and restriction fragment length polymorphism (rs2228145 and rs1800795). RESULTS: HCV RNA was detected in 17 (11.41%) of the 149 patients. There was no statistically significant association between the studied SNPs and HCV viremia. However, a combination of the CT/AC/GG genotype was significantly associated with HCV viremia (odds ratio: 5.4). The genotype AA of rs2228145 in the IL-6 receptor was associated with viremia levels of >105 copies/ml (odds ratio: 5.96). CONCLUSION: To the best of the authors' knowledge, this is the first study that has shown that the CT/AC/GG genotype has an impact on HCV viremia in kidney transplant patients. Therefore, such SNP genotypes may potentially be used to identify transplant patients at risk of HCV infection.
