Flashcards in Week 4 Prerecorded Genetics of Complex DIsease: Diabetes Deck (27):
familial vs genetic
Genetic describes our DNA,. familial could be genetic, learned behavior, or environment
does Type I or Type II have a stronger familial component?
Type II (type II also has a strong genetic component)
Genetic risk factors: what are some rare diseases that can lead to diabetes? (4) Inheritance?
Cystic fibrosis, chronic pancreatitis, insulin receptor defects, pro-enzyme cleavage defects
(All autosomal recessive)
Genetic risk factors: what are some very rare diseases associated with development of diabetes?
mitochondrial disorders: MELAS, MNGIE (Auto rec, or maternal transmission)
Myotonic dystrophy: auto dominant. patient cant let go of your hand after shaking it
What is Maturity Onset Diabetes of the Young? cause? inheritance? Prevalence?
(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
Type I diabetes cause?
an autoimmune disorders; caused by mutations in Human leukocyte antigen gene complex
what is the human leukocyte antigen gene complex?
series of genes, some of which, are responsible for the antigens expressed by cells
which HLA alleles are associated with type I diabetes?
95% of type I DM have DR3 or DR4 (not sufficient for Type I diabetes)
DR3 allele product (antigen) is associated with? onset?
antibody against pancreatic Beta cells. later onset
DR4 allele product (antigen ) associated with? onset?
antibody against insulin. earlier onset
DR2 allele risk of diabetes?
Protective antigen, 30% decrease in risk for Type I diabetes
MODY 2: Cause? severity?
Associated with Glucokinase, mild glucose intolerance that can be well controlled with diet. Initially noted as gestational diabetes.
sulfonylureases are highly effective. not used to treat other non-MODY forms of diabetes
how does sulfonylureas fxn
increase intracellular calcium to increase release of pro-insulin (may also increase sensitivity of B cells to glucose)
MODY 1,3,4,5,6; presentation?
all present similarly as a delayed secretory response to glucose uptake that over-time (gradual) leads to hyperglycemia
why focus on MODY if it only explains 1-2% of disease?
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
what does GWA study stand for?
Geneome-wide association sutdy
what is a GWA study?
determines if a genetic difference predisposes people to a certain disease
what has GWA studies for diabetes shown? 2
-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
what is TCF7L2?
A TF in the WNT pathway (supports glucagon synthesis)
what is the risk of diabetes for individuals who are homozygous for mutant TCF7L2
2x more likely (equivalent to being obese BMI>30)
what is FTO gene story? what did the FTO gene story reveal?
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)
what are some weaknesses of GWA studies?
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
why do different people respond differently to diabetes medication?
different pathways are effected in different people. further genetic studies may help with treatment
what is the fxn of FTO gene?
modulates methylation of RNA and preferential production of fat
what are some epigenetic changes (2) associated with lifestyle?
carbohydrate intake can influence histone modification, stress/exercise change methylation patterns