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genetics and atherosclerosis
CVM
44
Medical
Graduate
03/26/2010

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Cards

Term
what is genomics?
Definition
the use of genetics to look at something broader
Term
how much risk does each possible genetic disorder add to one individual pt?
Definition
between 1.12 -1.75 (2 is 2x the risk)
Term
is familial combined hyperlipidemia (FCH; increased VLDL & LDL) monogenic? how much risk does it pose a pt for coronary artery disease (CAD)?
Definition
FCH is not monogenic and it contributes to ~10-20% risk for CAD
Term
what is increased in the blood of someone with FCH?
Definition
APO B100 (increased VLDL and LDL)
Term
what receptor genes are chylomicrons associated with?
Definition
APO B48, CII, and E
Term
what receptor genes are VLDLs associated with?
Definition
APO B100, CII, E, and LPL
Term
what receptor genes are HDLs associated with?
Definition
APO A1, CII, E, ABCA-1, ABCG-1, CETP, PLTP
Term
what receptor genes are LDLs associated with?
Definition
LDL receptor, LP, PCSK9
Term
what genes, if increased will increase risk of CHD?
Definition
APOB-48, B-100, CIII, E (e-4), PCSK9, APO(a), PLTP
Term
what genes, if increased will decrease risk of CHD?
Definition
APO CII, E (e-2), LPL, LDL-R, HDL, CETP, PCAT, ABCA-1
Term
where are chylomicrons made? what are they derived from? what receptors do they have?
Definition
in epithelial cells, they are derived from dietary lipids. nascent chylomicrons have APOB-48
Term
where are VLDLs made? where are they derived from? what receptor genes do they have?
Definition
VLDLs are made by liver cells, they are derived from the liver's synthesis of FA (plus any FA from chylo remnants packaged as TG). nascent VLDL has APOB100
Term
what is APO B a stuctural component of?
Definition
VLDL, IDL, LDL, and Lp(a); apoB-100 is a vital ligand for the LDL receptor
Term
are there many polymorphisms in the APO B gene?
Definition
yes, 50-60% of variations in plasma apoB are genetically determined
Term
what are increased plasma levels of apoB associated with
Definition
ischemic heart disease, stroke
Term
what is mutation in the apoB gene shared by both VLDL (B-100) and chylomicrons (B-48)?
Definition
exon 1; a deletion of 9 bases (3 AAs - so not loss of function) associated with ischemic heart disease
Term
what are the 2 mutations in the apoB gene found only in VLDL (B-100)?
Definition
exon 26; C->T (homozygous T associated w/increased risk of MI/CAD - highest risk of APOB mutations) and exon 29 G->A (carriers of A associated with increased risk of MI/CAD)
Term
where is APO E found, what is its main role?
Definition
APO E resides on VLDL and its remnants as well as chylomicrons, and it is supplied by HDL. it has anti-atherogenic role as a ligand for LDL receptors and absolute ligand for LDL-receptor-related protein
Term
what are other roles of APO E?
Definition
APO E has a role in neurologic diseases, as well as inhibition of platelet aggregation, SMC & EC proliferation and promotes anti-inflammatory activity
Term
what are the 3 polymorphisms of APO E? which are good/bad?
Definition
E4,3,& 2. E2 is "good" w/a slightly higher risk of CAD and E4 is "bad" w/a slightly higher risk of CAD (both are c)
Term
what does APO C II do?
Definition
APO C II: activates lipoprotein lipase, chylomicrons/VLDL get it from HDL. this is good in terms of CAD risk, b/c it is taking TGs out of the blood stream
Term
what does APO C III do?
Definition
APO C III: inhibits TG lipoprotein lipase hydrolysis, this increases risk for CAD
Term
are the ApoE, C-I, C-II genes clustered together?
Definition
yes
Term
what does lipoprotein lipase do? are there any mutations that affect it?
Definition
hydrolyzes TG and releases apoprotein and phospholipids for HDL to use. S447X, a common variant truncates LPL, resulting in higher activity - which decreases risk of CAD
Term
do endothelial cells their own lipase?
Definition
yes, but it's relation to CAD risk is still unknown
Term
what does hepatic lipase do?
Definition
hepatic lipase extracellularly hydrolyzes lipoprotein triglycerides and phospholipids in chylomicron remnants, sdLDL, HDL, and IDL. it has both pro and anti atherogenic effects. afro-caribbean males have a mutation here that affords them les CAD risk (better lipid profile)
Term
where is LDL derived from? what is it composed of? that is the major APO protein? what does it do?
Definition
LDL is derived from VLDL and IDL, it is composed mainly of cholesterol and cholesterol ester, APO B100 is the major apoprotein, and LDL carries cholesterol to peripheral tissues w/specific LDL receptors (that recognize apoB100), LDL receptors transport LDL into peripheral tissue via endocytosis
Term
if you are missing the LDL receptor, what will you have?
Definition
familial hypercholesterolemia (the effect of which is similiar to if you are missing apoB100)
Term
is variablity in LDL-R common?
Definition
yes, causing variability
Term
what is PCSK9?
Definition
an enzyme that is either an inhibitor of LDL-R via degradation which increases risk of CAD by pushing the pt further towards famililal hypercholesteremia OR degrades LDL-C which decreases risk of famililal hypercholesteremia-like symptoms *depending on the mutation
Term
what is ACAT?
Definition
an intracellular enzyme that converts fatty acyl CoA to cholesterol ester, some of which can accumulate in macrophage foam cells in atherosclerosis
Term
are there different kinds of ACAT?
Definition
yes ACAT 1 & 2, of which 1 is in most cells and 2 is in the intestine/liver.
Term
what is lipoprotein (a) or LP(a)? how does it relate to atherogenic risk? what causes this?
Definition
LP(a) is LDL+hydrophilic glycoprotein apolipoprotein that increases risk of atherosclerosis, and is worse the more kringles it has (these are circular gene sequences) - this risk is totally genetic, *independent risk factor*
Term
are there different forms of lipoprotein (a) that may incur a higher risk of atherosclerosis?
Definition
small isoforms and high concentrations are more athero-thrombogenic. small, b/c it has to get out of the bloodstream and into the ECM to find its target
Term
why is LP(a) considered atherogenic?
Definition
it goes into the formation of plaque, it competes with and inhibits plasminogen (which also has kringles) and induces inflammation
Term
what does HDL do?
Definition
HDL mediates reverse cholesterol transport, it has antioxidant activity, and anti-inflammatory effects in vasculature (inhibits oxidized LDL upregulation of cell adhesion molecules), inhibits platelet activation, enhances endothelial vasodilation, and upregulates NOS which mediates anti-apoptosis
Term
what is the progression of HDL formation?
Definition
ABCA1 helps apoA1 form, which PCAT helps become HDL3, which PCAT helps become HDL2
Term
for every decrease of 1mg/dL of HDL-C in a pts bloodstream, how muh does their risk increase for CHD?
Definition
2-3%
Term
how much of the variation in HDL is genetically determined? what genes are involved
Definition
50% APO A-1, PCAT, ABCA-1, CETP and hepatic lipase are all involved in its formation
Term
what is the most important thing you can measure in a pt's blood in terms of lipoproteins that will reflect their risk for atherosclerosis?
Definition
apoA1/apoB ratio (B=Bad)
Term
what is PCAT and are there different kinds of it? what happens w/a deficiency?
Definition
PCAT puts LCFAs on cholesterols, making the cholesterol esters for HDL. alpha PCAT is on HDL and beta PCAT is on APO B. if you are missing alpha PCAT, you will get classic fish eye disease (opaque eye, still have beta). if you are missing alpha and beta PCAT, that is called familial PCAT deficiency. higher levels of PCAT increases HDL cholesterol levels, which protects against atherosclerosis
Term
what is ABCA? what is the correlation between low ABCA levels and low HDL levels? what is tangier disease?
Definition
the enzyme, ABCA1 is essential for initial lipidation of apoA1 to HDL (transfers cholesterol/phospholipids from peripheral tissue to HDL). 10-25% of people with low HDL have low ABCA1 too (tangier disease is an example of this as it is a mutation in ABCA1, also presents with orange tonsils).
Term
what is CETP?
Definition
CETP transfers cholesterol esters from HDL to apoB particles (VLDL, LDL) in exchange for TG. this lowers HDL and increases VLDL/LDL, however blocking it is not useful
Term
what is PLTP? where does it come from?
Definition
this remodels HDL, by taking excess phospholipid from chylomicrons and transferring it to VLDL/HDL (making them bigger). it is pro-atherogenic in mice models. PLTP is secreted by macrophages and is present in atherosclerotic lesions.
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