Physician Assistants and Personalized Medicine Francis S. Collins, M.D., Ph.D. National Human Genome Research Institute PAEA Annual Meeting October 27, 2007

Collins et al., Nature 4/24/03

A SMALL SAMPLING OF COOL THINGS ABOUT THE GENOME Humans have fewer protein-coding genes than expected – only about 20,000 Only about 1.5% of the human genome is involved in coding for protein, but there are numerous complex critical functions encoded in the rest of the DNA instruction book We are all 99.9% the same at the DNA level

Cystic fibrosisAdult onset diabetesAIDS

SNP A SNP B

Searching for genetic causes of disease in the pre-genome era

“Genome Wide Association” Approach to Common Disease: The View from 2002 Identify all 10 million common SNPs Collect 1000 cases and 1000 controls Genotype all DNAs for all SNPs That adds up to 20 billion genotypes At 50 cents a genotype, that’s $10 billion for each disease – completely out of the questionAt 50 cents a genotype, that’s $10 billion for each disease – completely out of the question

Genome Wide Association Approach to Common Disease: The View from 2007 Identify an optimum set of 300,000 tag SNPs Collect 1000 cases and 1000 controls Genotype all DNAs for all SNPs That adds up to 600 million genotypes Genotyping just dropped to $0.0012, so that’s $800,000 for each diseaseGenotyping just dropped to $0.0012, so that’s $800,000 for each disease

Searching for genetic causes of disease in the genome era

Confirmed genetic contributors to common human diseases (April 2007) CF3 GCKR FTO CDKN2A 8q24 #2 8q24 #3 8q24 #4 8q24 #5 8q24 #6 ATG16L1 IRGM 5p13 3p21 10q21 NKX2 PTPN2 IL12B CDKN2A IGF2BP2 CDKAL1 HHEX SLC30A8 Cholesterol Obesity Coronary Dz KCNJ PPAR  Type 2 Diabetes IBD5 NOD2 Crohn’s Disease CFH Age Related Macular Degeneration CFB/C2 LOC q24 IL23R TCF7L2 Prostate cancer

Cholesterol Obesity Coronary Disease QT interval Atrial Fibrillation Type 2 Diabetes Prostate cancer Breast cancer Colon cancer KCNJ PPAR  2001 IBD5 NOD CTLA PTPN22 Age Related Macular Degeneration Crohn’s Disease Type 1 Diabetes Systemic Lupus Erythematosus Asthma Restless leg syndrome Gallstone disease CD25 IRF5 PCSK9 CFH NOS1AP IFIH1 PCSK9 CFB/C2 LOC q24 IL23R TCF7L CDKN2A 8q24 #2 8q24 #3 8q24 #4 8q24 #5 8q24 #6 ATG16L1 5p13 10q21 IRGM NKX2-3 IL12B 3p21 1q24 PTPN2 TCF2 CDKN2A IGF2BP2 CDKAL1 HHEX SLC30A8 MEIS1 LBXCOR1 BTBD9 C3 8q24 ORMDL3 4q25 TCF2 GCKR FTO C12orf30 ERBB3 KIAA0350 CD226 16p13 PTPN2 SH2B3 FGFR2 TNRC9 MAP3K1 LSP1 8q24 Confirmed genetic contributors to common human diseases (August 2007)

Cholesterol Obesity Coronary Disease QT interval Atrial Fibrillation Type 2 Diabetes Prostate cancer Breast cancer Colon cancer KCNJ PPAR  2001 IBD5 NOD CTLA PTPN22 Age Related Macular Degeneration Crohn’s Disease Type 1 Diabetes Systemic Lupus Erythematosus Asthma Restless leg syndrome Gallstone disease Multiple sclerosis Rheumatoid arthritis Glaucoma CD25 IRF5 PCSK9 CFH 2007 NOS1AP IFIH1 PCSK9 CFB/C2 LOC q24 IL23R TCF7L2 CDKN2A 8q24 #2 8q24 #3 8q24 #4 8q24 #5 8q24 #6 ATG16L1 5p13 10q21 IRGM NKX2-3 IL12B 3p21 1q24 PTPN2 TCF2 CDKN2B/ A IGF2BP2 CDKAL1 HHEX SLC30A8 MEIS1 LBXCOR 1 BTBD9 C3 8q24 ORMDL3 4q25 TCF2 GCKR FTO C12orf0 ERBB3 KIAA030 CD226 16p13 PTPN2 SH2B3 FGFR2 TNRC9 MAP3K1 LSP1 8q24 LOXL1 IL7R TRAF1 STAT4 ABCG8 GALNT2 PSRC1 NCAN TBL2 TRIB1 KCTD10 ANGLPT3 GRIN3A Confirmed genetic contributors to common human diseases (Sept 2007)

We wouldn’t think of buying shoes in a single size So why should we be satisfied with one-size- fits-all medicine?

Diagnostics Preventive Medicine Disease with Genetic Component Time Accelerated by Human Genome Project and HapMap Identify Genetic Defect(s)

Coincidence or heredity? Uterine Cancer 48 Uterine Cancer 48 Colon Cancer 56 Colon Cancer 56 Colon Cancer 51 Colon Cancer 51

Uterine Cancer 48 Uterine Cancer 48 Colon Cancer 56 Colon Cancer 56 Colon Cancer 51 Colon Cancer 51 Genetic testing reveals that those with cancer carry a mutation in MLH1

Genetic testing reveals that two other family members are at high risk Uterine Cancer 48 Uterine Cancer 48 Colon Cancer 56 Colon Cancer 56 Colon Cancer 51 Colon Cancer 51

Taking a good family history will be supplemented, not supplanted, by genetic testing

% confidence interval curves R ecurrence score for individual patients Source: Paik, et al., N Engl J Med, December 2004 Genomics Is Not Just About Heredity: Using Gene Expression To Predict Cancer Recurrence Multigene assay predicts recurrence of tamoxifen-treated, node-negative breast cancer Gene expression analysis was combined with an algorithm for calculating risk for distant recurrence

Diagnostics Preventive Medicine Disease with Genetic Component Time Accelerated by Human Genome Project and HapMap Identify Genetic Defect(s) Pharmacogenomics

Analysis of VKORC1 and CYP2C9 reveal variable warfarin dose response Needs low-dose Needs high-dose Slow P450 metabolizers Variants at these two genes account for ~60% of variability in therapeutic dose Prospective trials now underway FDA has added information about genetics to label Rieder, M. et al. NEJM 352: , 2005

Diagnostics Therapeutic Developments Gene Therapy Drug Therapy Preventive Medicine Disease with Genetic Component Time Accelerated by Human Genome Project and HapMap Identify Genetic Defect(s) Pharmacogenomics

Imatinib (Gleevec™) – Specifically Targets An Abnormal Protein, Blocking Its Ability To Cause Chronic Myeloid Leukemia Chromosome 9;22 translocation CML Bcr-Abl fusion protein Gleevec™ Bcr-Abl fusion protein Normal

Ethical, Legal, and Social Implications An integral component of the Human Genome Project

Will effective policy solutions to genetic discrimination be found?

S th H.R th S.358 H.R.493 “GINA”

Will appropriate oversight of new genetic tests be instituted?

Prediction: Physician Assistants Will Play a Lead Role in the Personalized Medicine Revolution And lots of resources are being developed to assist you…

“81% of programs expressed the need to enhance the quality and extent of genetic and molecular medicine in their curricula…”

Top 10 Topics For PA Education In Genetics/Genomics 1.“Genetics 101” – basic concepts in genetic and genomic science 2.The family history 3.Preconception and prenatal genetics 4.Newborn screening and pediatric genetics 5.Adult genetics 6.Cancer genetics 7.The genetics of common disease 8.Pharmacogenetics 9.Ethical, legal, and social aspects of genetics 10.Genetic counseling and genetic referrals

Personalized Medicine: A future dream

Betty’s story in 2015 Betty completes the Surgeon General’s family history tool at age 25, learns of uncles with early heart disease. She consults her PA, who works in a practice that has made an effort to stay informed about genomic medicine. She suggests complete genome sequencing for $1000. Betty inquires about the risk of genetic discrimination, but effective legislation has outlawed this. She is found to have three gene variants that have been shown conclusively in well validated studies to increase her risk of early heart attack 4-fold. She and her PA design a program of prevention based on diet, exercise, and medication precisely targeted to her genetic situation.

Betty’s story continues Betty does well until age 75. She develops left arm pain that she assumes is due to gardening, but her care providers know her higher risk and diagnose an acute MI. Referring to her genome sequence, the PA and MD choose the drugs that will work best to treat her. She survives and is alive and well in the 22 nd century.

Personalized Medicine: Could the dream become a nightmare?

Betty’s story gone wrong Betty never learns about her family history, educational efforts for the public and health care providers were defunded, community efforts never got off the ground, and Betty’s PA and MD thought genetics was irrelevant to practice. Betty hears about genome sequencing, but after seeing her brother lose his health insurance from this information, she decides not to. Betty eats an unhealthy diet, gains weight, and develops high blood pressure. While tests to predict which drug would be most effective for Betty have been proposed, they have never been validated, and are not reimbursed.

Betty’s story gone wrong, continued Betty’s hypertension is treated with a drug that causes a hypersensitivity reaction, so she stops treatment. After 10 years of uncontrolled hypertension, Betty develops left arm pain at age 50. Unaware of her high risk, her PA assumes this is musculoskeletal and prescribes rest. Betty returns to the ER a few hours later in cardiogenic shock. The absence of her genome sequence information prevents immediate optimum choice of therapy. Betty dies in the ER.

Charge to all of us: SAVE BETTY!!!

Personalized Medicine: The dream needs YOU!

Challenge of Rising U.S. Health Expenditures Biomedical Research Must Deliver 8% 10% 12% 14% 16% 18% 20% National Health Expenditures as a Percent of GDP 1980 Actual Projected Source: Percent of U.S. GDP $4.1 trillion

Translating Genomics… Genomic discoveries relevant to common disease diagnosis and management are coming at an increasing rate. Basic discoveries are leading to the development of clinical applications. Ergo, improved healthcare is around the corner!

Translating Genomics… Genomic discoveries relevant to common disease diagnosis and management are coming at an increasing rate. Basic discoveries are leading to the development of clinical applications. Mind the gap! Ergo, improved healthcare is around the corner!

The Future Paradigm: The 4 P’s Transform Medicine from Curative to Preemptive Preemptive PersonalizedPredictive Participatory Era of Precision Medicine

Progress in Genotyping Technology Nb of SNPs Cost per genotype (Cents, USD) ABI TaqMan ABI SNPlex Illumina Golden Gate Illumina Infinium/Sentrix Affymetrix 100K/500K Perlegen Affymetrix MegAllele Affymetrix 10K Courtesy S. Chanock, NCI