ADRs

adverse drug reactions; one of the top 5 leading causes of death/illness. results in over 100k deaths

Pharmacogenetics

the study of genetic influences on an individual’s response to drugs

Are ADRs (Adverse Drug Reactions) preventable?

Yes; at leat 60% (as of 2008)

Three types of metabolizers

Poor

Normal (Extensive)

Ultrafast

Poor metabolizer

accumulates drug to toxic levels; overdosing of medication

Normal (extensive) metabolizer

reaches steady-state levels within the therapeutic range (no change)

Ultrafast metabolizer

fails to maintain serum levels within the therapeutic range; underdosing of medication

What test can identify the extensive and poor metabolizer phenotype?

Urinary Metabolic Ratio

What is a urinary metabolic ratio?

a simple test that, after the administration of a probe drug, can identify the extensive metabolizer and the poor metabolizer phenotype

How can genetic alterations impact drug metabolism?

mutations, deletions, or insertions → loss or gain of function in the biochemical systems that metabolize the drug

EX)

Gene deletion → decrease in enzyme activity → higher concentration doses and/or during a greater length of time (top) → side effects.

Gene duplications and gain-of-function polymorphisms → increase the enzymatic activity → lower active drug concentration ➔ no effect.

Metabolizer Abbreviations: PM, IM, EM, UM

Poor Metabolizer, Intermediate Metabolizer (normal), Extensive Metabolizer (normal), Ultrarapid Metabolizer

CYP2D6

Acts on 25% of all prescription drugs;

• 7-14% of people with a slow-acting form
• 7% are a super-fact acting form
• 35% are carriers of a non-functional
  allele

Goals of Pharmacogenetics

• Maximize drug efficacy
• Enhance drug safety
• Reduce drug toxicity
• Provide hope to develop more efficient treatment strategies
• Personalized Therapy

Overall Advantage of Pharmacogenetics and Genetics Approach

Personal genomics is as the means to move from one-size-fits-all to a more individualized approach (precision medicine) to healthcare

Advantages of Pharmacogenetics and Genetics Approach

• DNA samples for genotyping or sequencing can be obtained from not only blood samples, but also saliva
• A patient's genotype or sequence needs only to be measured once per lifetime
• Rapidly decreasing costs of assays

Gaps between Knowledge and Clinical Applications

Gaps: limitations on genetic test use, implementation of new testing programs, appropriately interpreting genomic information, educating health care providers

Introduction of personal genomics into clinical practice
has been slow

Clinicians: lack of knowledge and self-confidence to make recommendations based on genomics and pharmacogenetic test results (McCullough et al., 2011)

Solutions

Education: at least a 4-8 hr pharmacogenomics course as part of the education curriculum for medical students,
pharmacists (Daly 2014); We should provide continuing education on genomic medicine for healthcare providers and offer decision support to our personal genomics

Translational research: the more clinical validity, the more evidence to provide a test with a clear clinical purpose, therefore improve clinical care

Genetic Epidemiology

how genotypes and environmental factors interact to increase or decrease susceptibility to disease

Relative Risk Ratio (RRR)

[a/ (a + b)] / [c/(c + d)] = RRR

[(affected + present) / total] / [(affected + absent) / total] = RRR

Mapping Human Disease Genes by
Association (Population Based)

• Does not depend upon Mendelian
  inheritance pattern
• An allele at a locus at increased or decreased frequency in affected compared with controls known as a disease association

Odds Ratio (OR)

calculates association between disease and genotype

Odds Ratio Equation

not rlly necessary to know

Relative Ratio (RR)

for cross-sectional or cohort study

the further RR or OR diverges from 1...

the greater is the effect of the genetic variant on the association

OR vs RR

OR is for a case-control study; RR is for a cross-section or cohort study