Week 4 Prerecorded Genetics of Complex DIsease: Diabetes

Question 1

familial vs genetic

Answer 1

Genetic describes our DNA,. familial could be genetic, learned behavior, or environment

Question 2

does Type I or Type II have a stronger familial component?

Answer 2

Type II (type II also has a strong genetic component)

Question 3

Genetic risk factors: what are some rare diseases that can lead to diabetes? (4) Inheritance?

Answer 3

Cystic fibrosis, chronic pancreatitis, insulin receptor defects, pro-enzyme cleavage defects
(All autosomal recessive)

Question 4

Genetic risk factors: what are some very rare diseases associated with development of diabetes?

Answer 4

mitochondrial disorders: MELAS, MNGIE (Auto rec, or maternal transmission)

Myotonic dystrophy: auto dominant. patient cant let go of your hand after shaking it

Question 5

What is Maturity Onset Diabetes of the Young? cause? inheritance? Prevalence?

Answer 5

(MODY): Hypo-insulinism w/ gradual onset compared to type I DM. caused by LOF or dysfunciton of pancreatic B cells. Appears acutely like insulin depedent at older age. 1-2% of diagnosis of diabetes, Auto dom

Question 6

Type I diabetes cause?

Answer 6

an autoimmune disorders; caused by mutations in Human leukocyte antigen gene complex

Question 7

what is the human leukocyte antigen gene complex?

Answer 7

series of genes, some of which, are responsible for the antigens expressed by cells

Question 8

which HLA alleles are associated with type I diabetes?

Answer 8

95% of type I DM have DR3 or DR4 (not sufficient for Type I diabetes)

Question 9

DR3 allele product (antigen) is associated with? onset?

Answer 9

antibody against pancreatic Beta cells. later onset

Question 10

DR4 allele product (antigen ) associated with? onset?

Answer 10

antibody against insulin. earlier onset

Question 11

DR2 allele risk of diabetes?

Answer 11

Protective antigen, 30% decrease in risk for Type I diabetes

Question 12

MODY 2: Cause? severity?

Answer 12

Associated with Glucokinase, mild glucose intolerance that can be well controlled with diet. Initially noted as gestational diabetes.

Question 13

MODY Treatment

Answer 13

sulfonylureases are highly effective. not used to treat other non-MODY forms of diabetes

Question 14

how does sulfonylureas fxn

Answer 14

increase intracellular calcium to increase release of pro-insulin (may also increase sensitivity of B cells to glucose)

Question 15

MODY 1,3,4,5,6; presentation?

Answer 15

all present similarly as a delayed secretory response to glucose uptake that over-time (gradual) leads to hyperglycemia

Question 16

why focus on MODY if it only explains 1-2% of disease?

Answer 16

shows the importance of avoiding broad diagnosis (insulin resistance, diabetes, glucose intolerance) when underlying mechanism can be different from person to person. important implications in treatment

Question 17

what does GWA study stand for?

Answer 17

Geneome-wide association sutdy

Question 18

what is a GWA study?

Answer 18

determines if a genetic difference predisposes people to a certain disease

Question 19

what has GWA studies for diabetes shown? 2

Answer 19

• over 50 sNPs have been identified to have a risk (generally a small relative risk) of developing diabetes
• identified previously unrealized genes associated with diabetes

Question 20

what is TCF7L2?

Answer 20

A TF in the WNT pathway (supports glucagon synthesis)

Question 21

what is the risk of diabetes for individuals who are homozygous for mutant TCF7L2

Answer 21

2x more likely (equivalent to being obese BMI>30)

Question 22

what is FTO gene story? what did the FTO gene story reveal?

Answer 22

identified in GWA study as being thought to be associated with diabetes AND coronary artery disease AND obesity (independently), but with stricter criteria it was only associated with obesity (diabetes and coronary artery disease is a risk of obesity)

Question 23

what are some weaknesses of GWA studies?

Answer 23

1. gives associations, not causation (this sNP is associated with increased risk but does not cause it)
2. replication is absolute necessary
3. dependent on data collected in 1980s
4. generalizability: limited application to non-european

Question 24

why do different people respond differently to diabetes medication?

Answer 24

different pathways are effected in different people. further genetic studies may help with treatment

Question 25

what is the fxn of FTO gene?

Answer 25

modulates methylation of RNA and preferential production of fat

Question 26

what are some epigenetic changes (2) associated with lifestyle?

Answer 26

carbohydrate intake can influence histone modification, stress/exercise change methylation patterns

Question 27

complex disease: define

Answer 27

diseases are multi-factorial: biological (cant change), behavior, and environment