Title: The Genetic Basis of Atherosclerosis: Familial Hypercholesterolaemia: Type III Hyperlipoproteinaemia
1The Genetic Basis of AtherosclerosisFamilial
HypercholesterolaemiaType III
Hyperlipoproteinaemia
2Type III Hyperlipoproteinaemia
- Hyperlipoproteinaemia is a condition closely
associated with atherosclerosis - Hyper-(abnormal elevation of)-lipoprotein-aemia
(biochemical condition of blood)
- Type III variant was the first clinical syndrome
to be recognised as hyperlipoproteinaemia. - Classified by Addison and Gull in 1851
- Low incidence 1 in 10,000
http//www.cwrl.utexas.edu9000/10089
3Type III Hyperlipoproteinaemia
- Causes an increase in both the serum cholesterol
and fasting triglyceride concentrations. - 7 12mmol/litre (270-470mg/dl) for cholesterol
- 5 20 mmol/litre (450 1800 mg/dl) for
triglycerides
- Autosomal recessive condition with variable
penetrance - causes mutation on gene for apoE
- More common in men, with a definite incidence by
early adulthood.
4Type III Hyperlipoproteinaemia
Cholesterol, phospholipids, triglycerides and
apolipoproteins (Apo) are packaged as chylomicrons
Attie, 2003 Biochemistry and Cell Biology of
Lipoprotein Assembly. http//www.biochem.wisc.edu/
attie/research/researchLDLR.html
5Type III Hyperlipoproteinaemia
From Durrington, P.N. (1995) Hyperlipidaemia
Diagnosis and Management. 2nd edition. London
Butterworth-Heinemann
6Type III Hyperlipoproteinaemia
- Chylomicron remnants require ApoE to bind to
hepatic remnant receptor
- Intermediate Density Lipoproteins (IDL) require
ApoE to lipolyze into Low Density Lipoproteins
(LDL) or to be cleared by the liver
- Dysfunctional ApoE causes accumulation of
chylomicron remnants and IDL collectively known
as ß-VLDL
From Walden Heagle (1994) Apoprotein E in
lipidemia, Annals of Internal Medicine, Vol.120,
12, 1026-1036
7Type III Hyperlipoproteinaemia
- Apo E is a protein with two independently folded
domains - the amino-terminal region contains
receptor-binding domain
- Almost all of the apoE mutations in type III
hyperlipoproteinaemia cause the lipoprotein to
have abnormal binding properties that involves
residues 136 to 146
From Walden Heagle (1994) Apoprotein E in
lipidemia, Annals of Internal Medicine, Vol.120,
12, 1026-1036
- Results in the removal of a positively charged
amino acid in the binding domain
8Type III Hyperlipoproteinaemia
The Apo E gene
- Apo E has been cloned, sequenced, and mapped to
chromosome 19
- The normal form of apoE is apoE3 (Cys112, Arg158)
- Type III hyperlipoproteinaemia most common
isoform is apo E2 - Involves a single nucleotide substitution
(Arginine to Cystein) at codon 158. - At least 90 of individuals with type III hLP are
homozygous for apoE2.
9Type III Hyperlipoproteinaemia
The Apo E gene
- The less common isoform is E4 (Cys112Arg).
Rarer apoE variants
From Walden Heagle (1994) Apoprotein E in
lipidemia, Annals of Internal Medicine, Vol.120,
12, 1026-1036
10Type III Hyperlipoproteinaemia
Other contributing factors
- In European countries, less than 5 of all
apoE2(Arg158Cys) homozygotes develop type III
hyperlipoproteinaemia
- Indicates that additional factors are required
for expression of phenotype. - Additional genetic, hormonal, and environmental
factors
- Eg. diabetes mellitus, alcoholism, obesity,
hypothyroidism, renal failure, and oestrogen.
11Type III Hyperlipoproteinaemia
What are the risks of developing atherosclerosis?
- Risk is increased more than 5 times at
cholesterol levels of - 7.8 mmol/L (300 mg/dL) than at
- 5.2 mmol/L (200 mg/dL).
- Hyperlipoproteinaemia accelerates the onset of
atherosclerosis so early detection is vital
From Klippel JH, Reynolds HY, Stein JH et al.
Internal Medicine, 5th Edition. St Louis Mosby
1998.
12Type III Hyperlipoproteinaemia
Courtesy of Professor PN Durrington
Striate palmer xanthomas yellow-orange
discolouration in creases of the skin on the
palms of hands, or seed-like lesions in the
palms, fingers and flexor surfaces of the wrist
Tuberoeruptive xanthomas raised yellow lesions
usually on the elbows and knees.
13Type III Hyperlipoproteinaemia
Tuberoeruptive Xanthomas
http//www.nlm.nih.gov/medlineplus/ency/imagepages
/2490.htm
14Type III Hyperlipoproteinaemia
Laboratory-based diagnostics
- lipoprotein electrophoresis to distinguish
between types of hyperlipoproteinaemia
- DNA testing for homozygousity
- Ultracentrifugation to identify cholesterol-rich
ß-VLDL
15Type III Hyperlipoproteinaemia
Treatment
- Lipid lowering medication such as
3-hydroxy-3-methylglutaryl-coemzyme A (HMG-CoA)
reductase inhibitors. - Generic names cervistatin, fluvastatin,
lovastatin, pravastatin, and simvastatin. - Reduces LDL cholesterol concentrations by 30-40
- Cholesterol-binding resins.
- Eg. cholesyramine, colestipol
- Stimulates formation of hepatic LDL receptors
that clear cholesterol - Reduces cholesterol by 8-15
- LDL apheresis LDLs are filtered out of blood
16Type III Hyperlipoproteinaemia
Summary
- Several causes of atherosclerosis.
- Type III is rare and includes several variant
apoE alleles.
- Cholesterol and IDL levels are raised above
normal.
- Multi-factorial. Both genetics and environmental
factors contribute
- Atherosclerosis is avoidable! Early diagnosis and
treatment is vital
17Type III Hyperlipoproteinaemia
References
Attie, A. (2003) Biochemistry and Cell Biology of
Lipoprotein Assembly. http//www.biochem.wisc.edu/
attie/research/researchLDLR.html site accessed
01.03.05
Durrington, P.N. (1995) Hyperlipidaemia
Diagnosis and Management. 2nd edition. London
Butterworth-Heinemann
Feussner G, Wagner A, Kohl B, Ziegler R. (1993)
Clinical features of type III hyperlipoproteinemia
analysis of 64 patients, Clin Investig. 1993
May71(5)362-6.
Germann, W.J. Stanfield, C.L. (2004) Principles
of Human Physiology, 2nd Ed, Benjamin Cummings
(2004), London San Fancisco, California.
Kimball Genetics Inc (2004) The Apo E Genotype
Test for Type III Hyperlipoproteinemia, http//www
.kimballgenetics.com/index.html site accessed
01.03.05
Klippel, J.H., Reynolds, HY, Stein JH et
al.(1998) Internal Medicine, 5th Edition. St
Louis Mosby
Kumar, P., Clark, M.(2002) Clinical Medicine, 5th
Edition. W.B.Saunders
Mahley, R.W, Huang, Y., Rall Jr, S. (1999)
Pathogenesis of type III hyperlipoproteinaemia
(dysbetalipoproteinaemia) Questions, quandaries
and paradoxes, Lipid Res. 1999.401933-1949
Mahley, R. W., Innerarity, T. L., Rall Jr, S. C.,
and Weisgraber, K. H. (1985) Lipoproteins of
special significance in atherosclerosis. Insights
provided by studies of type III
hyperlipoproteinemia, Annals of the New York
Academy of Sciences, Vol 454, Issue 1 209-221,
New York Academy of Sciences
18Type III Hyperlipoproteinaemia
References
Smith, JF. (2005) Hyperlipoproteinaemia, Dr.
Joseph F. Smith Medical Library
http//www.chclibrary.org/ site accessed
01.03.05
Villiers, WJS, Westhuyzen, DR, Coetzee, GA,
Henderson, HE (1997) The Apolipoprotein
E2(Arg145Cys) Mutation Causes Autosomal Dominant
Type III Hyperlipoproteinemia With Incomplete
Penetrance, Arteriosclerosis, Thrombosis, and
Vascular Biology. 199717865-872
Walden, C.C, Heagle, R.A. (1994) Apoprotein E
in lipidemia, Annals of Internal Medicine,
Vol.120, 12, 1026-1036
Warrel, DA, Cox, TM, Firth, JD, Benz Jr, E (2003)
Oxford Textbook of Medicine Volume 2, 4th
Edition. Oxford University Press, Oxford
ACKNOWLEDGEMENTS Thiha Aung would like to thank
Professor Steve Humphreys, Director of Centre for
Cardiovascular Genetics, UCL, for his time in
answering questions related to Atherosclerosis
and type III hyperlipoproteinaemia.