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

4 Applying Pharmacogenomics in Therapeutics
There are different types of polymorphisms such as single nucleotide polymorphisms
(SNPs), variable number tandem repeats (VNTRs), gene insertion (ins)
and deletion (del), copy-number variants (CNVs), and premature stop codons.
A SNP is the result of a single base substitution, and novel SNPs continue to be
discovered. Some SNPs lie outside the protein-coding regions of the gene and
may alter the expression level of a gene, and others lie within the protein-coding
regions of the gene. These SNPs may or may not alter protein synthesis and are
called nonsynonymous and synonymous polymorphisms, respectively. Enzymes,
drug transporters, and/or receptors are examples of proteins that are genetically
polymorphic, whose functional levels can be categorized as increased, decreased,
or no change in protein activity. Examples exist where a polymorphism is present
at a higher frequency in a certain ethnic group. 4 When determining clinical relevance,
relationships between the polymorphism, the drug, and the disease should
be examined for an individual. Drug dosing, efficacy, toxicity, PK, and/or PD may
be affected by the polymorphism. A polymorphism may also influence disease
prognosis, susceptibility, or be used as a screening test for certain diseases. 5
EFFICACY: OMEPRAZOLE
Clinical Case
DS is a 47-year-old Chinese American male who complains of a “burning stomach
pain” with “bloating and heartburn.” The pain occurs between meals, awakens him
at night, and is not relieved with antacid use. He is an otherwise healthy male with
no significant past medical history. He denies smoking, alcohol intake, and illicit
drug use. Current medications and supplement use include a daily multivitamin.
Vital signs are within normal limits with pertinent laboratory values of hemoglobin
13.0 g/dL and hematocrit 43%. He has no signs of bleeding (no bruising, no nose
bleeds, and guaiac test negative). The physician is planning to start DS on a twoweek
triple therapy consisting of omeprazole, amoxicillin, and clarithromycin.
Background
Omeprazole is indicated for the treatment of various gastric acid–related disorders
(e.g., duodenal ulcer, gastric ulcer, gastroesophageal reflux disease [GERD], and
Zollinger–Ellison syndrome). Most patients with GERD and/or Helicobacter pylori–
related peptic ulcer present with abdominal pain often described as “burning.”
Omeprazole is used in combination with one or two antibiotics for H. pylori
eradication. 6–8 It is an irreversible inhibitor of the proton pump (or H + /K + -ATPase),
thus decreasing acid secretion in the stomach. Omeprazole is primarily metabolized
by CYP2C19 and to some extent by CYP3A. 9
Gene/Allele of Interest and Functional Effect
The CYP2C19 gene is localized at chromosome 10q24.1–q24.3. 10,11 The normal
(wild-type) allele is CYP2C19*1. At least 34 CYP2C19 variant alleles have been