Genomics

1. Genomics Erik Haley Chronic Diseases 4/1/13

2. Genomics • Public Health Genomics focuses on the application of genomic research to health benefits. • Genomics plays a role in 9 of the 10 leading causes of death in the US- most in cancer or heart disease • One of the main risks for heart disease is familial hypercholesterolemia – a family condition that results in high levels of bad cholesterol

3. Genetics of Humans • Humans have approximately 29,000 genes but this only amounts to about 2% of the genome • The remaining DNA is either non-coding introns, transposable elements, regulatory sequences or a variety of other elements • Of the known proteins in the human body, only half have a well known function

4. Epigenetics • Epigenetics involves looking at environmental or developmental factors that influence gene expression • Methods of modifying DNA expression include histone modification, methylation, non-coding RNA interference – all of which help reprogram the genome during embryogenesis • This reprogramming is essential for cell differentiation – understanding how it occurs can allow deprogramming

5. Family History • People who have a family member with a chronic health condition have an increased risk of developing the disease • A good record of family history would contain three generations of family members, ages and causes of death and age of diagnosis for any chronic diseases • Family Health Portrait Website: https://familyhistory.hhs.gov/fhh-web/home.action

6. Family History Data

7. Genetic Testing • Currently, there are over 2000 genetic tests available at clinical settings. Most diagnose rare genetic disorders such as duchenne muscular dystrophy. • Research is trying to develop tests that will measure an individual’s risk factors for chronic diseases or response to medicine

8. Genetic Testing- Drawbacks • Most genetic testing available now has limited use due to the genetic components for many chronic diseases being unknown. • Effective testing mostly for uncommon ailments • Many genetic tests are misused due to premature marketing • Evaluation of Genomic Applications in Practice & Prevention • Some genetic tests for hereditary cancers not effectively implemented into practice

9. Genetic Testing • One of the main fears of genetic testing is the possibility of genetic discrimination • In 2008, the Genetic Information Nondisclosure Act was put into practice to prevent discrimination in both employment and insurance on the basis of genetics • The Affordable Care Act also prohibits variation of insurance premiums based on disease or genetics

10. Perinatal Genomics • Pre-conception genetic screening is currently available that can identify inheritable conditions before a child is conceived as well as pre-implantation genetic screening • Pre-implanatation screening can lead to parents selecting which embryo to implant via in vitro fertilization • Newborn screening involves a genetic screen for several conditions upon birth – amount varies by state

11. Autoimmune Diseases • Most autoimmune diseases, including Diabetes Type 1 and Rheumatoid Arthritis, have a genetic component • Over 200 genetic loci have been linked to autoimmune disorders- no causal information has been currently identified • Most genetic factors carry moderate risk but are involved with other environmental factors- cannot use genomics alone

12. Gene Therapy • Gene therapy involves replacing a harmful mutant gene with an accurate copy using a viral vector • Currently, no gene therapy programs have FDA approval, yet over 2000 clinical trials were performed within the last 5 years • Additional use for gene therapy is to treat cancer by having an oncolytic virus insert a sequence that leads to cell death

13. Gene Therapy

14. Gene Therapy Techniques • One method of gene therapy is to insert proper alleles to replace mutant forms – nonsense mutants (early stop codon) can also be repaired by inserting a random amino acid into the mutation site • Alternative methods include using miRNA to silence certain genes by preventing transcription or changing splice sites of the pre-messenger RNA

15. Gene Therapy- Drawbacks • One of the drawbacks of using viral vectors is non-specific insertion into a cell – one 2002 case had 25% insert before a proto-oncogene leading to leukemia • Many cancer cells contain an over-expression of surface proteins found on normal cells – normal cells can uptake oncolytic viruses leading to tissue death

16. Regeneration • Genetic analysis of newts and zebrafish determined that they are able to re-grow limbs by using highly proliferative muscle, cartilage, neural cells • In humans, Rb protein and ARF prevent muscle cells from continuing mitosis- RNAi was shown to relieve this blockade • Risks for such a procedure involve an higher risk for cancer in cells with mitotic controls inhibited

17. Gene Mapping • The 1000 Genomes Project published a map of the variation in the human genome to show differences in disease risk and physical attributes • The project results showed that common mutations were global while rarer ones are often limited to ethnic groups/nations • Limited use – no phenotype data and population size

18. Health Equity • One of the hopes of genomics is that it will help reduce the inequality of health care between racial and ethnic groups • However, genomic data has shown that there is little difference between groups compared to within groups; many variants have low risk factors • Genomic information may be helpful by providing better information about who should receive specific treatments and the size of the expected benefit

19. State Participation • Currently, only four states have health departments that have integrated genomic knowledge into chronic disease prevention problems (MI, MN, OR, UT) • Many more states have programs to analyze newborn infants and education/awareness programs

20. Human Genome Epidemiology Network • OPGH established the HuGE network to help translate genetic research findings into opportunities for preventative medicine • HuGE is currently a network containing scientific research data as well as synthesis of new research projects and translation of results to humans • http://hugenavigator.net/HuGENavigator/home.do

21. Value • The current benefit from genetic testing remains small – genetics only plays a small role in many chronic diseases and few therapies exist to treat disease • Whole genome sequencing fails to predict risk of most common diseases • Ideally, genomics can reveal areas for possible interventions to take place – ie. B and T cell inhibitors for patients who show autoimmune disorders • Unfortunately, most genetic information about chronic diseases is very limited

22. Cost • Pharmaceutical companies have used genomic strategies for drug development but this has normally not led to late- stage development • Cost of therapeutic development has tripled since 1990 while the number of FDA approved drugs per year remains constant – many drug failures after investment • Drug companies often work with academia or government to increase effectiveness of produced drugs

23. Future Plans • One of the largest gaps in genetic research is why individuals respond differently to drugs and treatment • CDC’s Office of Public Health Genetics has the following goals for 2013: • Integrate evidence based genomic applications into public health • Evaluate genomic tests to identify opportunities to improve health/transform healthcare • Develop and provide communications about public health genomics to various audiences

24. Sources • CDC Genomics: http://www.cdc.gov/genomics/about/AAG/index.htm • Targeting DNA: http://www.commed.vcu.edu/Chronic_Disease/genetics/2013/clinicalintervention.pdf • Epigenetics: http://www.commed.vcu.edu/Chronic_Disease/genetics/whatisepigenetics.pdf • Genome Sequencing Failures: http://www.commed.vcu.edu/Chronic_Disease/genetics/2013/practicalgenetics.pdf