Red Hair, Freckles, and Other Factors Bugging Nurses– or The Future of Genetics in Practice

1. Red Hair, Freckles, and Other Factors Bugging Nurses– or The Future of Genetics in Practice Lyn Callahan, CRNA, PhD, PMHNP-BC Professor Emeritus California State University, Long Beach Private Practice, Psychiatric Mental Health Associates, Klamath Falls, OR

2. No, My school was not Hogwarts!

3. Goals for today: • Take a look at the basics • Briefly discuss future aspects of genetics in clinical practice • Think about the possibilities for more personalized medicine in the future

4. Areas of Integration of genomic information in clinical practice Preconception and prenatal testing Monitoring disease burden and recurrence Newborn Screening Genomics Disease susceptibility Prognosis and therapeutic decisions Screening and Diagnosis Adapted from K.Calzone & Jenkins J. (2013) Relevance of Genomics to Healthcare and Nursing Practice. J Nurs Scholar. 45:1,1-2

5. Gregor Mendel

6. Watson and Crick deduced DNA structure from an X-ray

7. The Dark Lady of DNA Photograph 51

9. Chromosome Staining by G-banding Chromosome spread Karyotype

10. 22 of the 23 pairs of chromosomes are the same in men and women and are called autosomes A pair of homologous chromosome #2 A pair of homologous chromosome #1 One pair is special: the sex chromosomes. Men have an X and Y, Women have two X’s. Chromosomes come in pairs (homologous chromosomes). In each pair, one chromosome comes from your father, the other from your mother.

13. But the GENIE REMAINED IN THE BOTTLE UNTIL…..

14. In 2003 scientists in the Human Genome Project obtained the DNA sequence of the 3 billion base pairs making up the human genome

15. What we’ve learned from the Human Genome Project The human genome is nearly the same (99.9%) in all people Only about 2% of the human genome contains genes, which are the instructions for making proteins

17. Other Lessons from the Human Genome Project Humans have an estimated 30,000 genes; the functions many are as yet unknown Almost half of all human proteins share similarities with other organisms, underscoring the unity of life

20. Alleles: different forms of a gene at the same locus on homologous chromosomes.

21. Homozygous = Identical alleles at a given locus on a pair of homologous chromosomes

23. Phenotype: the appearance or observable nature of an individual; the visible effects of the interaction of the genotype and the environment.

24. Modes of Inheritance ☺ Autosomal dominant (a dominant gene expressed in the heterozygous state) ☺ Autosomal recessive (expressed only in homozygous individual, disease only if both alleles are abnormal) ☺ Codominant (full expression of both alleles in heterozygous state) ☺ X-linked (usually affects male offspring; the abnormal X-linked gene acts as dominant gene when paired with the Y chromosome)

25. Genetic Variation • There is about a 3 million bp difference between any two non-related individuals. • Common variant sequences (alleles) occur every 1/1000-1/1500 bp. • There are an estimated 2-3 common variants (on average). • If a variant allele occurs in less than 1% of the population it is called a rare allele or a mutation • If a variant allele occurs in greater than 1% of the population it is called a polymorphism

26. Genetics in the Past • Conditions caused by an extra or missing chromosome or part of a chromosome • Conditions caused by a mutation in a single gene or in a mitochondria

27. Type Chromosomal Single Gene Multifactorial (Emory & Rimoin, 1997) Lifetime Frequency 3.8/1000 20/1000 646/1000 Types and Frequencies of Genetic Diseases

28. Importance to Advanced Practice Nurses • Quality care requires understanding of patient pathology and patient response to drugs and other treatments. • Pathology and pharmacology are now being considered in terms of how much of the effect or response is genetic and how much is environmental • Genetics, in the future, may be able to explain variations from the normal responses observed in patients and provide information allowing the nurse to avoid negative events by having greater knowledge of the individual’s potential response to certain drugs or procedures

29. Cystic fibrosis Depression, BPD, Schizophrenia Heart Dx, DM, Cancer, etc. AIDS

30. Genetic testing for disease • Identification of risk factors • PKU, APOE4 • Identification of protective factors • ALDH2 alcohol dependence • Development of DNA-based diagnostic testing • Huntington’s Disease • Identification of novel pathological mechanisms>leading to more effective treatment • Impetus for personalized medicine development and utilization—estimate response and interaction

31. Where are we with the Mood Disorders? Complexity issues-neuronal structure, transmitter , reuptake Presence of multiple, partially overlapping susceptibility genes Role of environmental stresses on expression

32. Some Current Results • Evidence of linkage on : • 17p, 8p,15q, 12q23- BPD • 12q23-MDD • 3centr, 7p, 18q MDD (also anxiety,BPD) • 1p36,13q.31.1-13q.31.3 MDD • 13q.31.3 Panic Disorder • Candidate genes = SLC6A4-serotonin transporter gene—short versus long alleles- affects response to SSRIs

33. GWAS Huge numbers of SNPs for analysis 11 SNPs associated with PCLO gene overlap-MDD ATP6V1B2 near VMAT1 gene- BPD Many overlapping genes, each making a small contribution to development of mood disorder It will be necessary to tease out specific profiles at risk

34. Drug Interactions and Mechanisms

35. It is estimated that from 75-98% of interindividual variability in drug metabolizing enzyme activity is under genetic control

36. All patients with same diagnosis 1 Non-responders and toxic responders Treat with alternative 2 drug or dose Responders and patients not predisposed to toxicity Treat with conventional drug or dose Potential of Pharmacogenomics

37. Clinical Relevance • Can we predict who will derive an optimal response? • Can we predict who will have a toxicity?

38. Single Nucleotide Polymorphisms (SNP) • Pronounced “snip” • Single base pair difference in the DNA sequence • Over 2 million SNPs in the human genome • Other polymorphisms: • Insertion/deletion polymorphisms • Gene duplications • Gene deletions

39. Alleles = different DNA sequences at a locus Codon 389 1-AR Arg (0.75) Gly (0.25) Genotype = pair of alleles a person has at a region of the chromosome Codon 389 1-AR Arg389Arg Arg389Gly Gly389Gly Genetics Terminology

40. Drug Metabolizing Enzymes

41. Phase One Enzymes • Generally involve small modifications to chemical structure • Processes include dehydrogenation, hydrolysis, oxidation • Present in smaller quantities than Type II enzymes • Physical location increases vulnerability to physiological changes • Most commonly implicated factors in drug-drug and drug-diet interactions

42. Major Phase I Enzymes • Cytochrome p450 enzymes • Some variations in these enzymes are due to rare mutations while many are polymorphic

43. Impact of genetic Changes • Complete lack of enzyme>>increased plasma levels and duration of drug • Altered enzyme with no function>>increased plasma levels and duration of drug • Partially functional enzyme >>slower metabolism with a longer duration of drug • Gene duplications due to mutation>> increased metabolism with shorter drug metabolism

44. CYP2D6 Polymorphisms • CYP2D6 is responsible for the metabolism of a number of different drugs • Antidepressants, antipsychotics, analgesics, cardiovascular drugs • Codeine, fentanyl, hydrocodone, haldol • Over 100 polymorphisms in CYP2D6 have been identified but 5 common alleles account for 95% of the variation • Based on these polymorphisms, patients are phenotypically classified as: • Ultra rapid metabolizers (UMs) • Extensive metabolizers (EMs) • Poor metabolizers (PMs)

45. CYP2D6 and Codeine • Codeine requires activation by CYP2D6 in order to exert its analgesic effect • Due to genetic polymorphisms, 2-10% of the population cannot metabolize codeine and are resistant to the analgesic effects • Interindividual variability exists in the adequacy of pain relief when uniform doses of codeine are given

46. CYP2C19 • 3-5% Caucasians • 18-23% Japanese • 15-17% Chinese Poor Metabolizers • 13% Koreans • 4-18.5% African Americans • 38-79% Polynesian,Micronesian

47. CYP2C19 and Proton Pump Inhibitors • Proton pump inhibitors are used to treat acid reflux and stomach ulcers • Ulcer cure rates using omeprazole and amoxicillin by CYP2C19 phenotype: Cure Rate • Rapid metabolizers 28.6% • Intermediate metabolizers 60% • Poor metabolizers 100% Furuta, T. et. al. Ann Intern Med 1998;129:1027-1030

48. CYP2C19 • Also metabolizes • Phenobarbital • Propranolol • Dilantin • Benzodiazepine • Diazepam • Warfarin

49. Valium and CYP2C19 • Homozygous wild type – 30 hour ½ life • Heterozygous (wild type + Variant allele) – ~45 hour ½ life Homozygous (Variant allele + variant allele) – ~ 100 hour ½ life

50. Why is this important? • Interesting indicators but when will we be able to make this more clinically relevant in making drug choices and avoiding negative interactions?