Page 109 - Hematology_ Basic Principles and Practice ( PDFDrive )

80 Part I Molecular and Cellular Basis of Hematology

TABLE A Selection of Relevant Websites
8.1
Genomic Variants Description Address
National Human Genome Research Website of the NHGRI with the aim to improve http://www.genome.gov/
Institute (NHGRI) human health by genome research
GenBank NIH genetic sequence database—an annotated http://www.ncbi.nlm.nih.gov/genbank/
collection of all publicly available DNA sequences
The 1000 Genomes Project A deep catalogue of human genetic variation http://www.1000genomes.org/
dbSNP Repository of all types of short genetic variations http://www.ncbi.nlm.nih.gov/SNP/
<50 bp in length
dbVar Archive of large-scale genomic variants (generally http://www.ncbi.nlm.nih.gov/dbvar/
>50 bp) such as insertions, deletions,
translocations and inversions
ClinVar Archive of reports of the relationships among human http://www.ncbi.nlm.nih.gov/clinvar/
variations and phenotypes
Database of genomic variants (DGV) Catalogue of human genomic structural variation http://dgv.tcag.ca/dgv/app/home
The Encyclopedia of DNA Elements Project to identify all functional elements in the http://www.genome.gov/10005107
(ENCODE) human genome sequence
Roadmap Epigenomics Project Public resource of human epigenomic data http://www.roadmapepigenomics.org/
International HapMap Project Public resource to find genes associated with human http://hapmap.ncbi.nlm.nih.gov/
disease and response to pharmaceuticals
Pediatric Cancer Genome Project Decodes the genomes of more than 600 childhood http://www.pediatriccancergenomeproject.org/
cancer patients site/
Pharmacogenomics Description Address
Pharmacogenomics Knowledge Base Most comprehensive website on pharmacogenomics http://pharmgkb.org
Clinical Pharmacogenetics Provides guidelines that enable the translation of https://www.pharmgkb.org/page/cpic
Implementation Consortium genetic laboratory test results into actionable
(CPIC) prescribing decisions for specific drugs
(see Table 8.2)
U.S. Food and Drug Administration— Contains a list of FDA-approved drugs with http://www.fda.gov/drugs/scienceresearch/
Pharmacogenomic Biomarkers pharmacogenomic information in their labeling researchareas/pharmacogenetics/
ucm083378.htm
Cytochrome P450 Homepage Comprehensive data collection on cytochrome P450 http://drnelson.uthsc.edu/CytochromeP450.html
Human CYP Allele Nomenclature Unified allele designation system, and database of http://www.cypalleles.ki.se/
Committee CYP alleles and their associated effects
The UCSF-FDA TransPortal A public drug transporter database http://dbts.ucsf.edu/fdatransportal/

region of the gene encoding a centrosomal protein 72 kD (CEP72)
was recently found to be significantly associated with vincristine- HAPLOTYPES, LINKAGE DISEQUILIBRIUM,
induced peripheral neuropathy in children with acute lymphoblastic AND HAPMAP
leukemia (ALL), and in vitro experiments have shown that the
CEP72 promoter rs924607 TT polymorphism creates a binding Combinations of SNPs are commonly inherited together in the same
site for a transcriptional repressor leading to lower expression of region of DNA, forming haplotypes. Genome-wide haplotypes can
CEP72 mRNA and increased sensitivity of neurons and ALL cells be constructed by linkage disequilibrium (LD) analysis. LD analysis
to vincristine. 5 is a statistical measure of the extent to which particular alleles or
In addition, diverse classes of small to long noncoding RNAs SNPs at two loci are associated with each other in the population,
(ncRNAs) have emerged as important regulators of gene expression and LD occurs when haplotype combinations of alleles or SNPs at
and genome stability. For example, micro-RNAs (miRNAs) are small different loci occur more frequently than would be expected from
(19- to 22-nucleotide–long), single-stranded RNA molecules that can random association. SNPs and alleles of interest are presumably
influence cellular mRNA levels or impair translation after binding to inherited together if they are physically close to each other (usually
miRNA binding sites at the target gene’s 3′-untranslated region. SNPs <50 kilobases [kb]), producing strong LD. Therefore SNPs that are
in miRNA binding sites or in the sequence encoding miRNAs have in LD with a disease phenotype or response-to-drug phenotype can
the potential to alter binding and function of miRNAs, respectively. mark the position on the chromosome where a susceptibility gene
Indeed, a so-called miRSNP, which is defined as a functional SNP is located, even though the SNP itself may not be the cause of the
that can interfere with miRNA function, had been reported to affect phenotype.
the expression of the antifolate target dihydrofolate reductase, thereby By studying millions of SNPs in hundreds of individuals from
influencing antifolate pharmacodynamics. 6 geographically diverse populations, the international HapMap con-
Collectively, these examples demonstrate that SNPs in function- sortium created genome-wide maps of haplotypes (see Table 8.1).
ally different genomic regions can influence drug disposition and The HapMap project has revealed a block-like structure of LD, as
response. well as the existence of areas of low or high recombination rate, and