Chapter 18: Application of Genomics to Medicine and Personalized Health Care Flashcards

Study of differences between individuals in how they respond to drugs due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity

the body absorbs, transports, metabolizes, or excretes or their metabolites

differences in the way the body responds to a drug

CYP450 has 56 functional enzymes, different alleles of genes → in absent, decreased, or increased enzyme activity → normal, poor, or ultrafast metabolism

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

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

Yes; at leat 60% (as of 2008)

Poor

Normal (Extensive)

Ultrafast

accumulates drug to toxic levels; overdosing of medication

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

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

Urinary Metabolic Ratio

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

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.

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

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

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

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

• 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: 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)

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

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

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

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

• 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

calculates association between disease and genotype

not rlly necessary to know

for cross-sectional or cohort study

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

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