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Genomic Medicine in Family Practice

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Genomic Medicine in Family Practice Genomic Medicine in Primary Care Christine Kessler MN, CNS, ANP-BC, BC-ADM, CDTC, FAANP B2 Genomic Medicine in Primary Care Newsinhealth.gov Christine Kessler MN, CNS, ANP-BC, BC-ADM, CDTC, FAANP Metabolic Medicine Associates Co-chair Metabolic & Endocrine Summit (MEDS) [email protected] Objectives Have you been using genetic (“-omic”) testing in your facility for the following? Have you wondered why….? Or WHY? • Do so many people receive no benefit or greater side effects from Is caffeinated coffee highly beneficial for some (like me) but deadly for prescribed medications? others? • Do some people have more severe symptoms and morbidities with COVID-19? • Do some people develop greater CV risk eating a Mediterranean diet than reduced risk? Or “therapeutic” diets don’t work for everyone? • Do some people have severe hypertension & DM but NO kidney issues? • Do some people have prolonged sequela from TBI than others with same injury? • Do some people gain weight eating the same calories than a skinnier person eats regardless of exercise? Giphy.com 1 Genomic Medicine in Primary Care Christine Kessler MN, CNS, ANP-BC, BC-ADM, CDTC, FAANP B2 Unless you Healthgrades.com nih.gov are an It is illogical to assume all people have equal RISKS to health or RESPONSE to drugs, foods or food components!! identical twin ….but are we really? Hopewellva.gov directorsblog.nih.gov Pinterest.com A case to ponder • PT: 9 y/o boy • Hx: ADHD, OCD, Tourette disorder • Rx: methylphenidate, clonidine and fluoxetine • Symptoms: vague c/o of nausea, occasional vomiting and mild HA developing slowly first weeks/months of Rx • What next: Genes-environment-biology • Reported to PCP but missed consideration of drug-source • Progressed to overt metabolic toxicity symptoms with severe GI distress, low grade fever, incoordination, disorientation and – finally generalized seizures….coma…death • Adoptive parents under investigation Which drug(s) were the problem & why? Goals of Precision Medicine 1. Incorporate patients' genetic and other molecular information as part of routine medical care. 2. Improve ability to predict which treatments will work best for specific patients. 3. Improve predicting (risk), preventing, diagnosing, and treating a wide range of diseases. 4. Help to better integrate electronic health records in patient care, and improve access medical data. 2 Genomic Medicine in Primary Care Christine Kessler MN, CNS, ANP-BC, BC-ADM, CDTC, FAANP B2 When your offer treatment to your patient do you…? A “person” refers to a human being. So “personalized” can mean anything from having monogrammed stationary or luggage to ascribing personal qualities. Soo0..National Academy of Sciences proposed using the term “precision medicine” in 2011. Wait a minute…what about Personalized medicine? Moving toward precision medicine. Lancet. 2011, 378( 9804):1677-1756, e6-e7 What about Genetics vs Genomics? First, let’s take a little dive into the gene pool each other and with the environment FYI: Genomics has a role in 9 of the 10 leading causes of death in the US http://www.cdc.gov/nchs/fastats/deaths.htm Remembering some genetic basics • 25,000-30,000 genes found in every human cells. • All humans have 99.9% identical genetic makeup • The remaining 0.1% difference may provide useful information about diseases • An extra or missing chromosome • A mutation in a single gene 3 Genomic Medicine in Primary Care Christine Kessler MN, CNS, ANP-BC, BC-ADM, CDTC, FAANP B2 Remembering some genetic basics A single variation in these 3 billion bases can cause or prevent disease.—wow! ◦ Single nucleotide polymorphisms, or “SNPs” SNPs > 470 SNPs have been identified on the vitamin D receptor gene alone ghr.nim.nih.gov Examples of SNPs – disease Relationships Copy Number Variants (CNVs) (colon cancer) (breast & ovarian Ca) (Parkinson disease) • ApoE4 (Alzheimer disease., worse TBI outcomes ...and?) (thrombosis) (HIV/AIDS resistance) (Obesity)-- https://en.wikipedia.org/wiki/Copy-number_variation Genome & Epigenetics (environment matters!) • EPIGENETICS Can activate or silence genes via: • Environment can produce immediate affects that are imprinted long term (temperature, radiation, stress, food, drug, nutrients, aging) • Effects can be temporary, a lifetime or cross generations WhatIsEpigenetics.com 4 Genomic Medicine in Primary Care Christine Kessler MN, CNS, ANP-BC, BC-ADM, CDTC, FAANP B2 Genetic risk: SNPs & SNVs Epigenetics: Environmental influences: Diet Genes Smoking Physical activity Intratrauterine factors Sleep Drugs EDC Genetic risk CNV alleles Grarup, N., Sandholt, C.H., Hansen, T. et al. Diabetologia (2014) 57: 1528. https://doi.org/10.1007/s00125-014-3270- 4 Hmmm, The path to pathology is not straight So….does diet cause disease? Metabolic Microbiome differences Genetic Disease Disease Diet Diet factors Which increases or decreases risk Body size Stress Food components Cooking & Physical activity storing method There are even more causes for genetic variation Your genes (DNA) is not destiny… it’s a set of possibilities Environment can alter your genetic risks…for better or worse • Microbiomics Cell 2014 157241-253DOI: (10.1016/j.cell.2014.02.012) 5 Genomic Medicine in Primary Care Christine Kessler MN, CNS, ANP-BC, BC-ADM, CDTC, FAANP B2 Types of Genetic Testing Medical Genetic Testing • Scientific Research • Between species: phylogenetics • Within human species • Medical • Diagnostic, predictive, carrier, prenatal, newborn • Identification: DNA Fingerprinting • Military/large scale disasters http://www.ornl.gov/sci/techresources/Human_Genome/medicine/g • Identification of remains enetest.shtml • Paternity • Forensic • Criminal investigations • DNA Databases: UK; USA • Exoneration of wrongfully convicted (Innocence project) 3 Categories of Genetic Disorders Monogenic (Single Gene) Disorders Cardiac channelopathies (and SCD) • Hereditary hemochromatosis small variations of genes with huge environmental impact Polygenic Disorders Types of Medical Genetic Testing - Results from a combination of genetic and environmental factors (“polygenic risk scores”) - Multifactorial disorders can be identified in multiple family generations: • Genome-wide association study (GWAS) • Obesity • Hypertension • Exome sequencing – sequencing the protein-coding regions of our DNA (of greatest interest now) • Hypercholesterolemia • Coronary artery disease • Stroke • Genome sequencing – sequencing the coding and regulatory • Autoimmune disorders elements of our DNA • Alzheimer’s disease The exome makes up only 1.5% of the whole human genome, however • Parkinson’s disease ALL protein coding genes are found in the exome. • Schizophrenia & bipolar affective disorder • Alcoholism • Cancer www.raregenomics.org/ (accessed April 12, 2021) 6 Genomic Medicine in Primary Care Christine Kessler MN, CNS, ANP-BC, BC-ADM, CDTC, FAANP B2 García-Gutiérrez MS, et al .Biomarkers in Psychiatry: Concept, Definition, Types and Relevance to the Clinical Reality. Front. Psychiatry, 2020; 11:432 PTT, viral load (HCV) Pain relief Selected Examples of Biomarkers CRP, IL-6 UACR Ventilator use • Biofluid markers • Physical Markers A1C, lipids BP Drug levels: digoxin, tacrolimus, ECG vancomycin Troponin Psoriatic plaque BRCA 1&2 APOE-4 gene BMI Types of Biomarker Use Example of Potential Predictive Biomarkers for Biomarkers associated with more serious COVID-19 Outcome in Traumatic Brain Injury morbidities & mortality These laboratory biomarkers might help in prognostic risk stratification of patients with COVID-19 Inflammatory genes/SNP Findings Also high risk associated Obesity , Metabolic syndrome, Diabetes, & Neurodegenerative diseases New focus on necrosis and inflammation biomarkers Kermali M, et al. The role of biomarkers in diagnosis of COVID-19 - A systematic review. Life Sci. 2020;254:117788 7 Genomic Medicine in Primary Care Christine Kessler MN, CNS, ANP-BC, BC-ADM, CDTC, FAANP B2 FYI: Leading causes of Death in US (2015) Pharmacogenetics--- Good news! • Drug-induced causes: 55,403 Murphy SL, et al. Deaths: Final Data for 2015. National Vital Statistics Reports. 2017; 66(6):1-73. https://ce.mayo.edu/genomics/content/clinical-pharmacogenomics-case-based-approach-your-practice-2019 ! Can get genetic test panels for over 200 medications https://www.acc.org/latest-in-cardiology/articles/2017/02/20/09/27/pharmacogenomics-in-cardio-oncology Schork 2015 So what are varied drug effects? Pharmacogenomics • Improve dosing • Enhance effectiveness Drew, L. Pharmacogenetics: The right drug for you. Nature 537, S60–S62 (2016) 8 Genomic Medicine in Primary Care Christine Kessler MN, CNS, ANP-BC, BC-ADM, CDTC, FAANP B2 Nomenclature for CYP450 Fast facts on CYP450 Non-CYP-related genetic influence • Found mainly in liver • but also in intestine (reducing bio-availability), lungs, placenta & kidney • Non-CYP-related genetic implications include: • CYP 1A2, 2C9, 2C19, 2D6, 3A4, 3A5 – metabolize 90% of drugs • catechol-O-methyltransferase (COMT) for ADHD drugs • Genetic SNPS in these enzymes influence patients response to drugs • Transporter protein SLCO1B1 for statins • CYP2D6 a major player in drug metabolism: antidepressants (25% of SSRIs), antihypertensive (beta-blocker), chemotherapy, tramadol, codeine • CYP2C19*2 affects PPI metabolism • CYP2C9 *2,*3 affects warfarin and phenytoin metabolism • CYP3A4, CYP3A5 affects fentanyl, midazolam, tarcolimus Time to consider the number 1 drug in The Coffee (Heart & Cancer) Gene Conundrum the world-- COFFEE FAST vs SLOW metabolizers SLOW = increased MI/ tachy Are you crazy?
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