Pharmacogenomics/Pharmacogenetics October 12 Lecture

advantages in using animal models in pharmacogenetic/biomed research

-can mimic almost any human trait/condition -can perform studies not possible in humans drug does, toxicity studies, studies that require harvesting tissue. -rodents often model system of choice. -mice offer many adv.: demonstrate genetic variation (inbred strains differ, selective breeding) -which genes mediate differences -Create pop. that segregate susceptibility, resistance alleles. -Test/examine mice for trait of interest.

allele?

allele: almost all genes have polymorphisms (mutations) alternate form of a gene. (single or multiple mutations). -some genes/loci have many alleles -two alleles at every locus (exon, entire xsome, arbitrarily, we say its a gene) homosygous, hetero -some have no functional consequences other are dramatic

heritability

drug responses or variation in drug responses. h2= proportion of variation in a trait accounted for by genetics. TRAITS NOT INHERITED. GENES ARE! calculated? h2=Vg/Vp Vg= genetic Vp=phenotypic

Pharmacogenetics

examines INDIVIDUAL DIFFERENCES (genetic variation) in drug response. just because someone doesnt respond doesnt mean genetics dont play a role is the study of inherited genetic differences in drug metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects.

Pharmacogenomics

is the study of how GENES affect a person's response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person's genetic makeup

Haplotype

series of alleles found at linked locus on a xsome. -collection of specific mutations within a given segment of DNA gene. -sets of SNPs on xsome that are statistically associated (linked) :depiction of defined segment of DNA(gene for example) and a persons's unique mutations in that gene.

methodologies to demonstrate genetic variation

show that it runs in family! relative risk ratio: estimate of degree of familial clustering of a trait.prob that one has the altered response vs one doesn't segregation analysis: uses statistical models to estimate mode of inheritance of trait (pedigree) -mode of inheritance, dominant, recessive, etc. twin studies: MZ twins 100% genetically identical DZ 50% genetically identical -if MZ twins more similar on a trait than DZ twins, evidence that genes play role -environmental role -can estimate heritability of trait.

therapeutic effects

some drugs have no therapeutic effect in certain individuals.

Genome-wide mapping don't need to know anything about drug response or metabolism, etc.

still fish for genetic variation thru genome and correlate that to altered drug response. may not find any variation but when you do, follow up on those areas Select population with people that do and dont respond. THEN you marker thru to genotype them( can be dinucleotide repeats) look for everyone who has A doesnt respond andT for no response

monogenic traits

trait/phenotype (anything you can measure) due to ONE gene. disorder due to mutation(s) in single gene

polygenic traits

trait/phenotype due to many genes. disorder duet o mutations in many genes. -most alterations in drug response is due to polygenic. makes it hard if you have lots of mutations in 10 diff genes. how do you get a good drug!

candidate studies in humans REQ'S a prior knowledge of disease state, drug path, drug metabolism, drug response. If know Metabolism (phase 1 phase 2 enzymes) , can look at enzymes for synthesis, transporter,

way to find what gene is responsible for phenotypic variation. -reason to believe gene may play a role, and can go right to that gene. often though you know there's variation. so you want to fish at all areas correlated with alter drug response. have specific gene, sequenced, know polymorph, mutations, look to see if correlated. have 2 sets of people. subject has the disease (dont respond to drug) and control that doesnt have the disease (respond to drug) everybody who does respond=has one particular mutation. and vice versa. (ex everyone that has the A,vs T base pair)