Genetics: Week 9

Front 1

What is pharmacogenomics?

Back 1

how genes affect a person's response to drugs

Front 2

What is the difference between pharmacogenetics and phramacogenomics?

Back 2

Genomics = the testing has already been done.
Genetics = Testing is guessed at somewhat

Front 3

What is the goal of pharmacogenetics?

Back 3

to develop safe, effective medications tailored to a person's genetic make-up... to understand the role that a person's genes play in how well a medication works

Front 4

What is pharmacogenetics?

Back 4

The role of inheritance in individual variation in drug metabolism.

Front 5

Most drugs are altered by _____ during ___

Back 5

enzymes during metabolism in body

Front 6

The challenge of pharmacy is to make sure ___

Back 6

the active form stays active long enough and not too long

Front 7

Genetic variation can account for 95% of ___

Back 7

variability in drug effects

Front 8

Several classes of ____ are involved in medication metabolism

Back 8

liver enzymes

Front 9

The classes of liver enzymes are what?

Back 9

Cytochrome P450 family, n-acetyltransferase, thiopurine methyltransferase, and UDP=glucoronosyltransferase

Front 10

The CYP family consists of ____ enzymes that metabolize ____ classes of drugs.

Back 10

~50 enzymes that metabolize ~30 classes of drugs

Front 11

Based on genetic variation, patients could be ___, __, or ___ metabolizers of CYP family.

Back 11

poor, normal, or ultra-rapid

Front 12

Poor metabolizers (CYP) metabolize ____ resulting in ___

Back 12

metabolize slowly, resutling in higher levels of drug in the patient system.

Front 13

N-acetyltransferase, if metabolized slowly, may result in ___, fast matabolizers ____

Back 13

slow= toxicity
fast = no response to drug

Front 14

40-70% of Caucasians and African Americans are slow metabolizers when it comes to ___

Back 14

N-acetyltransferase

Front 15

What is the function of TPMT enzymes?

Back 15

Metabolizes immune suppressant drugs from a number of disorders

Front 16

What are the three groups of patients with regards to TPMT metabolism?

Back 16

deficient, intermediate, and normal

Front 17

Patients deficient in TPMT metabolizing will suffer ____

Back 17

toxicity at normal levels

Front 18

UDP-glucoronosyltransferase is a ___ drug and depending on the metabolism, patient's dosing can be ____

Back 18

chemotherapy

adjusted to minimize slow metabolism by-products and decrease side effects

Front 19

What does warfarin do?

Back 19

Prevents blood clots (while increasing bleeding risk)

Front 20

What factors may affect warfarin metabolism?

Back 20

Age, Sex, drug interactions, diet, AND genetics

Front 21

What two genes affect Warfarin function?

Back 21

Cytochrome CYP2C9 and VKORCI

Front 22

What is the most extensively studied polymorphic drug metabolizing liver enzyme?

Back 22

Cytochrome P502D6

Front 23

Polymorphisms of Cytochrome P50 2D6 can cause ___

Back 23

exaggerated or diminished drug effects

Front 24

Cytochrome P502D6 is responsible for metabolis of what?

Back 24

Analgesics, sedatives, anti-emetics, etc.

Front 25

A slower rate of enzyme metabolism will result in _____ effects.

Back 25

Exaggerated

Front 26

Results of pharmacogenomic testing allows for ___

Back 26

predictions of: specific gene variants, associated diseases, adverse drug reactions, and patient outcomes

Front 27

Pharmacogenomic tests are ____ but dont take into account ___

Back 27

fairly accurate, but don't take into account other factors in the patient's life.

Front 28

What is considered hypercholesterolemia?

Back 28

Fasting blood cholesterol level over 240 mg/dL

Front 29

Hypercholesterolemia is found in many adults as an _____

Back 29

acquired disorder

Front 30

Familial hypercholesterolemia affects ____ in ___ people and is typically noted at what age?

Back 30

1 in 500, usually young childhood even just a few weeks after birth

Front 31

Familial hypercholesterolemia is considered to have what characteristics?

Back 31

increased total serum cholesterol with increased LDL, tendinous xanthomata, and premature coronary disease

Front 32

What type of genotypic pattern does familial hypercholesterolemia have?

Back 32

May be autosomal dominant or recessive

Front 33

Familial hypercholesterolemia is an example of _____.

Back 33

Founder effect - common among specific populations where the initial founder of that population had the genetic defect.

Front 34

The phenotype of familial hypercholesterolemia is associated wtih _____

Back 34

premature death.

Front 35

In a patient with familial hypercholesterolemia, the _____ are defective or absent with unregulated synthesis of ____

Back 35

1. LDLR proteins absent
2. unregulated synthesis of LDL-C

Front 36

How many allelic variants are there of the LDLR gene?

Back 36

1000

Front 37

Patients homozygous for familial hypercholesterolemia will have ___

Back 37

atherosclerosis early in childhood with 8X normal cholesterol levels

Front 38

Heterozygous familial hypercholesterolemia will have ___

Back 38

2X LDL-C levels with atherosclerosis in 20's and 30's

Front 39

What screening tools exist for familial hypercholesterolemia?

Back 39

- family hx of early heart disease
- pedigrees
- fasting lipid profile

Front 40

When is mutation testing done for diagnosis of familial hypercholesterolemia?

Back 40

Only in families with history of early coronary heart disease

Front 41

____ causes bilateral renal cysts, renal disease, intracranial anuerysms, aortic dissection, cysts in other organs

Back 41

PKD polycystic Kidney disease

Front 42

PKD is caused by defects in ___ and ___ genes

Back 42

PKD1 and PKD 2 genes

Front 43

The PKD1 and PKD2 genes code for ___

Back 43

polycystin 1 and polycystin-2

Front 44

The most common form of PKD is ____

Back 44

ADPKD - autosomal dominant

Front 45

What is the most common potentially lethal single-gene disorder in the U.S?

Back 45

Polycystic Kidney Disease

Front 46

ARPKD is commonly observed in ____

Back 46

children

Front 47

Patients with PKDI mutation swill have ____ than patients with PKD2 mutation.

Back 47

larger kidneys with more cysts

Front 48

In ____ scarring and cysts replace functional parenchyma.

Back 48

PKD

Front 49

____% of people with PKD will have renal failure by 60 yrs

Back 49

50

Front 50

Patients with PKD are very susceptable to _____ cancer and _____ problems

Back 50

1. aggressive renal cancer
2. extra-renal manifestations

Front 51

PKD causes disruption of the normal function resulting in ___

Back 51

lack of solute filtering
lack of water balance
renal stones
HTN

Front 52

Extra renal manifestations of PKD include:

Back 52

inferior vena cava problems, abdominal and intracranial aneurysms, liver cysts, and cysts elsewhere in body.

Front 53

PKD is most commonly autosomal ____

Back 53

dominant

Front 54

Polycystin-1 and -2 are integral to _____.

Back 54

specific membrane structures

Front 55

About 5% of mutations resulting in PKD are ____ mutations

Back 55

de novo (new)

Front 56

In PKD, mutation proteins produce ______ that may normally be found in many different organs.

Back 56

ineffective protein complexes

Front 57

85% of PKD patients have a mutation in _____

Back 57

PKD1

Front 58

PKD 1 patients present _____ and more ____ than PKD2

Back 58

younger and more severely

Front 59

Evidence indicates that the _____ can lead to variability in gene expression of PKD.

Back 59

position of mutation in the affected gene

Front 60

A patient with homozygous Autosomal Dominant PKD, it will result in

Back 60

Spontaneous abortion (not compatible with life)

Front 61

PKD is a ______ disease, meaning nearly all adults with the mutation have some level of disease.

Back 61

Highly penetrant

Front 62

The penetrance level of PKD-1 is ____ than PKD-2

Back 62

higher

Front 63

Offspring expresses PKD at ______ level as parents.

Back 63

SAME

Front 64

What does triplet repeat expansion refer to? (PKD)

Back 64

the patient with more triplet repeats will be more mutated (worse PKD) than just one triplet repeat.

Front 65

How is PKD diagnosed?

Back 65

Cysts are diagnosed through imaging, etiology confirmed by genetic testing

Front 66

Testing for PKD is done in ______ or _____

Back 66

asymptomatic patients with family Hx, or a symptomatic

Front 67

Children with ____ should be screened for ADPKD?

Back 67

Large echogenic kidneys without distinct macroscopic cysts

Front 68

Siblings of affected patients with PKD have _____

Back 68

50% likelihood of being affected

Front 69

When is genetic counseling indicated for PKD?

Back 69

For those affected or at high risk of having PKD

Front 70

If familial mutation of PKD has been identified, ____ can be performed, even prenatally.

Back 70

Testing

Front 71

Treatment for pKD is dependent on ___

Back 71

Stage at diagnosis

Front 72

What are some components of PKD treatment?

Back 72

lifestyle modifications for associated HTN, Renal protective medications to increase renal blood flow, decrease protein consumption, avoid nephrotoxic drugs

Front 73

Where does familial malignant melanoma originate?

Back 73

melanocytes in basal layers of epidermis

Front 74

What is the rarest but deadliest form of skin cancer?

Back 74

Familial Malignant Melanoma

Front 75

Familial Malignant Melanoma is _____ in men and ____

Back 75

higher incidence in men wiht increasing death rate

Front 76

_____ occurs spontaneously 80-90% of the time, 10-20% are familial.

Back 76

Melanoma

Front 77

What are singificant problems with melanoma?

Back 77

early metastasis, poo treatment of response.

Front 78

What is FAMMM?

Back 78

Familial Atypical Multiple Mole and Melanoma Syndrome

Front 79

What are the two types of FAMMM?

Back 79

DNS - dysplastic nevus syndrome
AMS - (visual) atypical mole syndrome.

Front 80

Appearance of a large number of dysplastic nevi at an early age is suggestive of ___

Back 80

Familial malignant melanoma

Front 81

WHat environmental factors are significant in familial malignant melanoma

Back 81

Exposure to new radiaton, sunburn, childhood exposure, intesnisty of UV light, (UV alters gene penetrance of FAMMM)

Front 82

What genetic chromosomal region has been implicated in familial malignant melanoma?

Back 82

9p21

Front 83

FAMMM involves interplay of ____ with ____

Back 83

environmental factors with genetic predisposition

Front 84

Phenotypic expresion of FAMMM will vary dependent on ____

Back 84

ancestry

Front 85

CDKN2A, CDK4, p14ARF, and MCIR are gene setes that appear to be involved in ___

Back 85

nevi & melanoma

Front 86

What are some familial risk factors for FAMMM?

Back 86

melanoma in relatives, pancreatic adenocarcinoma, breast CA, CNS cancers, non-melanoma skin cancer

Front 87

What are personal risks for FAMMM?

Back 87

malignant melanoma, dysplastic nevi, freckles in childhood, UV light exposure, multiple sunburns, pancreatic CA, xeroderma pigmentosa, Retinoblastoma

Front 88

Routine testing for germline malignant melanoma is ____

Back 88

unneccesary

Front 89

Clinical testing for mutations of malignant melanoma are for ___

Back 89

patients with personal or family hx of malignant melanoma

Front 90

What factors affect prognosis of malignant melanoma?

Back 90

- stage of disease
- level of invasion of primary lesion
- location and size of primary lesion
- general health of pt

Front 91

Management of malignant melanoma includes ____ and treatment depends on ____.

Back 91

1. increased surveillance,
2. treatment depends on staging

Front 92

Treatment of stage 1 malignant melanoma involves ___.

Back 92

surgery to remove lesion and unaffected margin

Front 93

WHat environmental factors are significant in familial malignant melanoma

Back 93

Exposure to new radiaton, sunburn, childhood exposure, intesnisty of UV light, (UV alters gene penetrance of FAMMM)

Front 94

What genetic chromosomal region has been implicated in familial malignant melanoma?

Back 94

9p21

Front 95

FAMMM involves interplay of ____ with ____

Back 95

environmental factors with genetic predisposition

Front 96

Phenotypic expresion of FAMMM will vary dependent on ____

Back 96

ancestry

Front 97

CDKN2A, CDK4, p14ARF, and MCIR are gene setes that appear to be involved in ___

Back 97

nevi & melanoma

Front 98

What are some familial risk factors for FAMMM?

Back 98

melanoma in relatives, pancreatic adenocarcinoma, breast CA, CNS cancers, non-melanoma skin cancer

Front 99

What are personal risks for FAMMM?

Back 99

malignant melanoma, dysplastic nevi, freckles in childhood, UV light exposure, multiple sunburns, pancreatic CA, xeroderma pigmentosa, Retinoblastoma

Front 100

Routine testing for germline malignant melanoma is ____

Back 100

unneccesary

Front 101

Clinical testing for mutations of malignant melanoma are for ___

Back 101

patients with personal or family hx of malignant melanoma

Front 102

What factors affect prognosis of malignant melanoma?

Back 102

- stage of disease
- level of invasion of primary lesion
- location and size of primary lesion
- general health of pt

Front 103

Treatment of stage II malignant melanoma involves ___

Back 103

wide skin excision and optional sentinel lymph node biopsy

Front 104

Treatment of stage III malignant melanoma involves ____.

Back 104

Wide skin excision and lymph node biopsy with a- interferon

Front 105

Treatment of stage IV malignant melanoma involves ___.

Back 105

poor prognosis due to metastasis. Surgery to remove tumors and relieve symptoms, possibly radiation and chemotherapy

Front 106

More than 50% of patients with malignant melanoma will have a ____

Back 106

recurrence