Genetic factors and CVD

Question 1

What can be said of LDL-c (% change) after 2.5g EPA + DHA/d supplement for 6 weeks?

Answer 1

• High variations in individual response to the same dietary intervention
o Fish oil supplements produce wide range of concs of LDL-c
• Mean increase of 4.1%
• Range from -40% to +113%
• Factors: age, gender, baseline LDL, disease state

Question 2

What is 3g EPA/DHA per day response dependent on?

Answer 2

Response to supplementation according to apoE genotype

Question 3

What does apoE encode?

Answer 3

34-kDa glycoprotein
o most prevalent in liver + brain
o transport and clearance of cholesterol, TG and other lipids

Question 4

What does E4 lead to?

Answer 4

40-50% higher risk for CVD
o Typically higher cholesterol + TG level
o Associated with ox stress and inflammation

Question 5

What does differing affinity for binding to LDL receptor influence?

Answer 5

lipid metabolism
o	Conformational change
o	Different base in one or 2 places:
	E2 = Cys, Cys
	E3 = Cys, Arg
	E4 = Arg, Arg

Question 6

What is the most common apoE?

Answer 6

apoE3

Question 7

What can be said of E2 carriers?

Answer 7

have 20% lower risk of CHD

o E2/E2 have ~31% lower mean LDL-c compared to E4/E4

Question 8

What do E4 carriers have?

Answer 8

higher risk (higher TC + LDL-c) and inflammation
o	So is more proatherogenic

Question 9

Does every E4 allele carrier develop CVD?

Answer 9

No
o Involvement of other genetic/environmental factors?
o Additional promoter SNP increases LDL-c levels

Question 10

What happens in the influence of E3 and E4 on lipolysis cascade involved in catabolism of VLDL particles?

Answer 10

• Affinity of them to VLDL differs

- TG in VLDL is hydrolysed by LPL (with apoc-II cofactor) –> IDL + progressively smaller particles

Question 11

What does ApoE bound to these particles do?

Answer 11

alters their interaction with LDLR + clearance from plasma

Question 12

AS VLDL/IDL remnants shrink (due to removal of core TG) what happens?

Answer 12

surface components are released to HDL pool –> increased HDL level

Question 13

What does E3 cause?

Answer 13

optimal lipolysis, clearance of VLDL remntants and HDL formation

Question 14

What does E4 bind more of?

Answer 14

VLDL (due to higher affinity)  inhibition of lipolysis (prob from apoC-II displacement)

Question 15

This means, at same apoE expression…?

Answer 15

progression of lipolysis of VLDL is limited for E4

Question 16

What does higher affinity of E4 to VLDL do?

Answer 16

limits lipolysis so remain in circulation for longer

Question 17

What does apoE locus interact with?

Answer 17

dietary fat
o modifying plasma lipid levels
o modifying CVD risk
o appears to be more evident in apoE4 carriers

Question 18

Where is there a stronger adverse effect of fish oils on LDL-c levels?

Answer 18

in apoE4 carriers

Question 19

FTO gene and CVD

Answer 19

• Encodes for mRNA demethylase
• Fat mass + obesity association (higher BMI + risk of obesity in Europeans)
• BMI/obesity independent association with T2DM
• Identified through genome wide association study
• Recent meta analysis confirmed significant interaction of a particular variant in the FTO gene with CVD risk, independent of BMI and other conventional risk factors