Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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64 Applying Pharmacogenomics in TherapeuticsSLCO1B1 (encoding solute carrier organic anion transporter family, member 1B1).For example, three SNPs, rs1128503 (synonymous), rs2032582 (missense), andrs1045642 (synonymous) located in ABCB1, have been demonstrated to influencedirectly on statin pharmacokinetics and indirectly on statin pharmacodynamics,considering the important role of ABCB1 in transporting statins and metabolites; 108SNPs rs5883 (synonymous) and rs9930761 (intronic) in CETP gene, the proteinproduct of which shuttles cholesterol esters from high-density lipoprotein (HDL)particles to low-density lipoproteins (LDL), have been associated with HDL levels,risk for coronary artery disease, and response to statin therapy. 109 SNPs rs5908( missense) and rs12916 (3′-UTR) in HMGCR gene, which encodes an enzyme catalyzinga rate-limiting step in cholesterol biosynthesis, were found to be significantlyassociated with attenuated LDL cholesterol reduction as well as racial differences instatin therapy; 110 and SNP rs4149056 (missense) in SLCO1B1 gene, which encodesa transporter that transports certain hormones, toxins, and drugs into the liver forremoval from the body, was found to be associated with simvastatin-induced myopathyin patients, while the effect of rs4149056 on statin pharmacokinetics was shownto vary with statin type. 111 In addition, a multiple-loci interaction model that combinespolymorphisms from different candidate genes was shown to be a better predictorfor LDL cholesterol-lowering effects. 112CancersDuring the past decade, cancer research has witnessed extensive utilization of novelhigh-throughput profiling technologies. Large cancer-focused projects, such asthe Cancer Genome Atlas (TCGA) Project sponsored by the National Institutes ofHealth, have begun to significantly enhance our current knowledge of cancer pathogenesisand responses to therapeutics. Pharmacogenomic biomarker discovery foranticancer drugs has benefited from these technological advances, with novel biomarkersbeing identified for better prediction of sensitivity to cancer therapies. Weshowcase here some novel biomarkers recently proposed or developed for anticancerdrug responses, particularly using hematological malignancies as an example.For example, Ph+/Ph− status for the Philadelphia chromosome has been proposedto be a “chromosomal” biomarker that may predict survival response to TKIs, includingimatinib and nilotinib, used to treat chronic myeloid leukemia (CML). Previousstudies suggested that treatment with these TKIs significantly improves survivalcompared with survival rates in the pre-TKI era in patients with Ph+ CML. 113–115With the availability of these TKIs, a molecular biomarker, BCR-ABL gene fusion,which represents the product of Ph+ status, could enable us to measure the molecularresponse to the TKIs, thus helping determine treatment efficacy and guide furtherclinical decision. A recent study showed that assessment of BCR-ABL1 transcriptlevels at three months was the only requirement for predicting outcome for patientswith CML treated with TKIs. 116 However, this molecular biomarker has not yet beenvalidated sufficiently to be cleared by the US FDA for clinical use.Another example of recently implicated novel biomarkers for anticancer drugresponse is the mutation status of JAK2 gene (which encodes Janus kinase 2) intreating acute myeloid leukemia (AML). Previous studies showed that although
Essential Pharmacogenomic Biomarkers in Clinical Practice65JAK2 mutations (JAK2V617F) are not commonly expressed in AML, a small subsetof patients may harbor these mutations, including those with myeloproliferativeneoplasms that evolved into AML. Those patients with these JAK2 mutations werefound to respond to ruxolitinib, a JAK1/2 inhibitor. 117Psychiatric DisordersPharmacogenetic and pharmacogenomic studies have also benefited psychiatricdisorders management by identifying novel biomarkers that are associated withresponders and/or patients who may have severe side effects, such as suicidalthinking. We showcase here some examples of biomarkers based on recent studies,including GWASs on drug response. For example, SSRIs are currently themost commonly administered first-line treatment for depression and obsessive–compulsive disorder (OCD); however, more than 30% of patients do not respondto SSRIs. Therefore, novel drugs and biomarkers are needed for individualizingtreatment in patients with depression. A recent whole-genome association studyidentified novel loci associated with altered antidepressant response to SSRIs in1773 OCD cases from a family-based GWAS, 118 including SNPs rs17162912 (anintergenic variation near DISP1 gene on 1q41-q42, a microdeletion region relatedto mental retardation) and rs9957281 (located within a newly identified OCD susceptibilitygene DLGAP1, a member of the neuronal postsynaptic density complex).In addition, 13 other significant variants were also identified in 6 genes, namelyFAM225B ( encoding family with sequence similarity 225, member B, nonproteincoding), CDYL2 (encoding chromodomain protein, Y-like 2), PAFAH1B1 (encodingplatelet-activating factor acetylhydrolase 1b, regulatory subunit 1), TACC1 (encodingtransforming, acidic coiled-coil containing protein 1), CSMD1 (encoding CUBand Sushi multiple domains 1), and GAS2 (encoding growth arrest-specific 2).Therefore, these newly identified drug response loci can be tested in the developmentof personalized care of OCD patients treated with SSRIs. In addition, theseresults would also provide new targets for developing other novel drugs for treatingnonresponders.THOUGHTS FOR FURTHER CONSIDERATIONThe majority of currently known pharmacogenomic loci have not yet become pharmacogenomicbiomarkers implemented in clinical practice. Large-scale clinicaltrials in the future on these biomarkers will provide essential knowledge on theusefulness of pharmacogenetics and pharmacogenomics in alleviating severe ADRsand enhancing therapeutic efficacy in patients. Notably, given the ethnic disparitiesin drug treatments, expanding future pharmacogenomic discovery studies totarget ethnicity- or population-specific biomarkers for therapeutic phenotypes mayhelp provide better healthcare to different populations, an important component ofprecision and personalized medicine. More recently, the relationships across geneticvariants, epigenetic traits (DNA methylation, histone modifications, microRNAs)as well as gene expression phenotypes have also begun to be elucidated in humangenetics models. For example, the complex relationships across common genetic
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DedicationWe dedicate this book to
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viiiContentsChapter 10 Pharmacogeno
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EditorsXiaodong Feng, PhD, PharmD,
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ContributorsWeiguo Chen, PhDDepartm
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11 PharmacoeconogenomicsA Good Marr
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BIOMEDICAL SCIENCEApplying Pharmaco
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Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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