Erik Haley Chronic Diseases 4/1/13 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

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

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

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:

Family History Data

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

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

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

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

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

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

Gene Therapy

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

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

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

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

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

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

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

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

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

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: 1. Integrate evidence based genomic applications into public health 2. Evaluate genomic tests to identify opportunities to improve health/transform healthcare 3. Develop and provide communications about public health genomics to various audiences

Sources CDC Genomics: Targeting DNA: /clinicalintervention.pdf /clinicalintervention.pdf Epigenetics: whatisepigenetics.pdf whatisepigenetics.pdf Genome Sequencing Failures: /practicalgenetics.pdf /practicalgenetics.pdf