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1

Autosomal Dominant Disorders (know 3)

- Familial Hypercholesterolemia
- Hereditary nonpolyposis colon cancer
- Adult polycystic kidney disease
- Polyposis of the colon
- BRCA1 and BRCA2 breast cancer
- Marfan syndrome

2

Autosomal Recessive Disorders (know 3)

- Deafness
- Hemochromatosis
- Sickle cell anemia
- Beta Thalassemia
- Cystic Fibrosis
- Hereditary Emphysema (PI ZZ)
- Phenylketonuria

3

X-Linked (Know 3)

- Hemophilia A
- G6PD Deficiency
- Duchenne/Becker Muscular Dystrophy
- Color Blindness

4

Somatic Cell Disorders

- Caused by DNA mutations in specific somatic cells (as opposed to DNA changes in all cells).
- E.g. Cancer

5

Mitochondrial Disorders

- Caused by mutations in cytoplasmic mitochondrial DNA
- Mostly rare with maternal inheritance
- E.g. Leber hereditary optic neuropathy, myopathy

6

Multifactorial or Common Disorders

- Caused by multiple genes and their interaction withenvironmental factors, some genes may have major effects but most of them have relatively minor but additive effects
- E.g. common congenital defects, including cleft lip, cleft palate and congenital heart disease (25-50% of pediatric hospital admissions), common adult diseases, including coronary heart disease, diabetes, hypertension, neurodegenerative diseases.
- Diseases aggregate in families but do not show clear segregation. Significantly higher risk to family members of affected individuals than the general population.

7

What is the Spectrum of Human diseases?

Single gene diseases to multifactorial diseases to infectious diseases

8

What are the common adult diseases with the highest burden in the U.S.?

1) Cardiovascular disease
2) Arthritis
3) Diabetes
4) Cancer (all types)
5) Alzheimer's Disease
6) Schizophrenia
7) Parkinson's Disease

9

What are the approaches to identify genetic components in common diseases?

- Family Studies
- Twin Studies
- Adoption Studies

10

What is the principle of multifactorial diseases?

- The threshold for first degree relatives is higher than the general population and second and third degree relatives (Goes down from there)

11

What affects an individual's recurrence risk?

- The relationship of an unaffected person to the affected relatives - the risk declines sharply as the degree of relatedness decreases
- The number of affected relatives - the risk increases with the number of affected relatives
- The severity of expression of the disease in affected relative - the risk increases with the severity of the disease
- The sex of the affected relatives - the risk increases for children of the less frequently affected sex.

12

What is the application of genetics in medicine (genomic medicine)?

- Presymptomatic diagnosis
- Preventative intervention
- Pharmacotheraphy: can we use genetic info to decide whether we want to the this drug or other drug.. potentially most useful

13

What are the categories of Drug-Metabolizing Enzymes?

- Esterases
- Transferases
- Reductases
- Oxidases
- Cytochromes P

14

What is the point of studying pharmacogenomics GWAS on drug response?

- People show different responses based on genotype

15

What are the strategies for genetic studies of complex diseases?

- Linkage studies = need families
- Association Studies: need unrelated cases and controls
- Positional Candidate Genes: know approximately where it is, don't know exactly which gene
- Biological Candidate Genes
- Genome-wide association diseases (GWAS)
- Sequencing
- Targeted sequency
- Whole-Genome Sequencing
- Exome Sequencing

16

Explain Odds Ratios

Odds ratio (OR) in genetic association studies; when we try to find effect of a variant.
OR = 1; means no effect (baseline)
OR = 1.5; odds are 1.5 higher than individual without the variant
OR = below 1; means it is a protective variant

17

What are the models of Missing Heritability?

- Infinitesimal Model
- Rare Variant Model
- Broad-Sense Heritability

18

Infinitesimal Model

- Many common variants of small effects

19

Rare Variant Model

- Many rare alleles of large effects

20

Broad-Sense Heritability Model

(Basically Multifactorial)
- Genotype-by-genotype interactions (epistasis)
- Genotype-by-Environment Interactions
- Epigenetic effects (impact of chromatin modification on the effect of genotype through DNA methylation and histone modification)

21

What are the functions of blood vessels?

- Blood vessels form a closed system of tubes that carries blood away from the heat (in arteries), transports it through the tissues of the body (in arterioles, capillaries, and venules), and then returns it to the heat (in veins).
- Exchange of substances between the blood and body tissue cells through the capillaries.
- Nutrients and oxygen diffuse from the blood through interstitial fluid into tissue cells. Waste products, including carbon dioxide, diffuse from tissue cells through interstitial fluid into the blood.

22

What are sinusoids?

Capillaries in the liver

23

What are hepatocytes?

Liver cells

24

Space of Disse

Space between the hepatocytes and the sinusoids

25

Deaths due to Cardiovascular disease - List by percentages (high to low)

- Coronary Heart Disease - 49%
- Stroke - 16.4%
- Other - 16.2%
- High Blood Pressure - 7.8%
- Heart Failure - 7.2%
- Diseases of the arteries - 3.4%

26

Who has higher prevalence of cardiovascular disease in the age ranges of 20-39, 40-59, 60-79, and 80+? (Males or Females)

20-39: Males
40-59: Males
60-79: Basically the same, but females
80+: Females

27

What is the genetic evidence for CHD?

- Family history of CHD is an independent risk factor for CHD
- Heritability for myocardial infarction (MI) ranges from 25% to 60%
- Family history of premature CHD is associated with subclinical atheroschlerosis, including carotid intima-media thickness (IMT) and coronary artery calcification (CAC)
- Heritabilities for IMT and CAC range from 35% to 60%.

28

What is the heritability for risk factors for CHD?

- Total cholesterol (40-60%)
- HDL-cholesterol (45-75%)
- Triglycerides (40-80%)
- Lp(a) (90%)
- Body mass index (25-60%)
- Homocysteine (45%)
- Fibrinogen (20-50%)
- Systolic blood pressure (50-70%)
- Diastolic blood pressure (50-65%)
- Type-2 Diabetes (40-80%)

29

Describe Inflammation

- When white blood cells invade and become active in a tissue

30

Atherosclerosis and Heart Attack - stepwise process

1. LDL circulates through the intima-media space
2. LDL becomes oxidized and is trapped in the media
3. Oxidized LDL signals to endothelial cells to release adhesion molecules and chemokines
4. Adhesion molecules bind circulating monocytes and chemokines lure the monocyte/adhesion molecules into the intima-media space
5. Monocytes mature into macrophages within the intima-media space and consume the oxidized LDL particles
6. Macrophages filled with oxidized LDL become "foam cells"
7. Muscle in the media grows around and over the foam cells to form a fibrous cap - this is a plaque
8. As plaques accumulate, they form fatty streaks, one of the first visible signs of atherosclerosis
9. When too many of the fatty foam cell plaques accumulate the artery wall weakens and bursts
10. Clotting factors in the released fatty cells cause a blood clot to form in the lumen
11. Clot leads to halted blood flow and heart attack