MM 19-20 Genetics Flashcards
Rare disease: Frequency Cause Character Percent of population Examples
Frequency less than 1/2000. Normally cause by a single gene. Generally chronic with early onset. 6-8% of population have a rare disease. Huntington's disease, Sickle-Cell anemia, Phenylketonuria.
Common disease: Frequency Cause Onset Examples
Commonly occurring
Normally polygenic or multifactorial with enviro contribution.
Onset later in life
Cancer, Heart disease, Diabetes
GWAS
Genome Wide Association Study. Uses DNA hybridization to examine the frequency of SNPs that are present for a certain disease. Helps us to understand which genes may contribute to multifactorial diseases. Looks at thousands of genes across tens of thousands of people of healthy and diseased people, using DNA hybridization chips. Rigorous statistical analysis (P-value) used to determine which SNPs occur within an isolated disease and the extent of their effect (odds ratio).
GWAS so far has not found many complex diseases with strong, predictive odds ratios. GWAS is, however, helping us to understand the biological causes of common diseases and treat disease phenotypes more specifically by prescribing drugs more specifically. We are also learning that some drugs may work for diseases for which they weren’t made (repurposed).
P-Value
Measure of statistical significance. The probability that a result occurs by chance.
Odds ratio
The odds that a disease will occur given a particular genome, compared to the odds of a disease occurring in the incense of the genome.
Schizophrenia and GWAS
Schizophrenia is a common disease. We now know it is highly polygenic. Identified 108 significant Loci but none of the individual odds ratios are great enough to make the test predictive.
HLA gene, however, indicates 10% increase in acquiring disorder.
Genes identified point to Ca signaling, immune disregulation, and glutamertergic neurotransmission.
So complex that individual risk profiling is not advised.
Multifactorial disease
A common disease resulting from polygenetic and environmental factors.
Clinical relevance of genetic variation in drug metabolizing enzymes and example:
People break down drugs differently, depending on their genetic profile. In some cases, a drug may have contraindications or toxicity build up, while in other people a drug may have lower efficacy. Certain drugs are now recommended to be coupled with genetic testing).
EX: Azathioprine reduces DNA synthesis by inhibiting Nucleotide synthesis. Used for autoimmune disorders and cancers. The target is one of several pathways. TPMT is an enzyme that sends it down another pathway, inactivating the drug. Genetic variability in TPMT effects the efficacy and toxicity of Azathioprine.
Cytochrome P450 protein family (CYPs)
CYP450 proteins are found mostly in liver and small intestine. The CYP450 family of proteins break down drugs and hormones. There are hundreds of isoenzymes that add to complexity making high variability among individuals. It is therefore a major contributor to the variance of pharmacological effects.
Clinical relevance of genetic variation in the target of drugs and example:
Pharmacogenetics efficacy differs from person to person due to genetic variation in the target gene. In such cases, different dosages are necessary.
Ex: Warafin has a narrow therapeutic index and must be closely monitored. The drug target is Vitamin K epoxide reductase (VKOR). Differences in this gene account for 25% of the drugs variability. So genetic testing is now recommended for determining Warafin dosages.
Clinical relevance in genetic variating in ‘off target’ genes and HLA.
HLA is the region that codes for Class 1, 2 and compliment immune system. It is the most diverse region of the genome. Variation within HLA contributes to various adverse immune responses to drugs.
Carbamazepine is an anti-epileptic drug that can cause Stephen Johnson Syndrome (the separation of epidermis from dermis) due to a specific HLA gene.
Clinical relevance of genetic variation in a gene that causes a specific disease and example.
A disease phenotype can be caused by different genetic defects. Treatment depends on isolating the correct defect.
Ex: Most cystic fibrosis is caused by a defect in CFTR genes. However, a defect can alter the proteins shape, its turnover rate, its synthesis, etc. Effective treatment depends on what is wrong with the protein.
Barriers to the clinical integration of pharmacogenetics tests.
Expensive
8-10 weeks for results
Limited interpretation of results
Many drugs yet to be studied
Rheumatoid Arthritis and GWAS
Autoimmune disorder affecting joints in hands and feet. 5-10/1000. Begins at age 40+. Treated with steroids and methotrexate.
GWAS identified 101 related genes.
The genes pointed to T/B cell and cytokine cell related signaling pathways.
Risk profiling not advised.
Age Related Macular Degeneration and GWAS
Neurodegeneration of retina leads to vision impairment. Onset 40+.
GWAS identified 19 distinct loci. If you have 2 of them, odds of getting disease are 2-3x higher.
