509 chromosome 6p linked to high hdl
- 1. Editorial Slides VP Watch, March 12, 2003, Volume 3, Issue 10 Chromosome 6p linked to high HDL A New Step Towards Understanding Resistance to Atherosclerosis
- 2. –Increased levels of HDL cholesterol are associated with late onset of atherosclerosis. –It is estimated that up to 70% of the variation in HDL-C is genetically determined1
- 3. • Mechanisms by which HDL-C is protective are incompletely understood but include: –reverse cholesterol transport from the peripheral tissues to the liver, –inhibition of LDL oxidation, –activation of endothelial NOS, –inhibition of expression of adhesion molecules by endothelial cells, and –myocardial protection.
- 4. –Familial hypercholesterolemia (FH) is associated with high LDL-C and early onset of atherosclerosis. Approximately 1/500 individuals are heterozygotes for this condition. –FH is genetically heterogeneous; mutations in different genes in at least 3 chromosomes have been described
- 5. • Mehrabian et al reported genetic locus on chromosome 6 in mice that blocks development of atherosclerosis despite extreme hyperlipidemia. They suggested PPAR-gamma gene may be responsible for this protective effect. Ref PMID: 11463718
- 6. –As featured in VPWatch of this week, Canizales-Quinteros, Tusie-Luna and colleagues2 studied an extended Mexican kindred with FH linked to chromosome 1p32 associated to elevated HDL-C linked to chromosome 6 that has an autosomal mode of inheritance. The association afforded protection against atherosclerosis.
- 7. • This kindred is unique because the elevated HDL-C (HA) was associated with familial hypercholesterolemia and displayed an independent trait. • Finding concurrent FH and HA is highly unusual because elevated LDL-C is generally inversely correlated with HDL-C.
- 8. MethodsMethods A number of candidates genes were anlyzed includingA number of candidates genes were anlyzed including LDLR andLDLR and apoB for HF andapoB for HF and apoA-I, apoA-II/apoC-III/apoA-IV cluster,apoA-I, apoA-II/apoC-III/apoA-IV cluster, apoC-II, apoE, ATP-binding cassette A type 1,apoC-II, apoE, ATP-binding cassette A type 1, peroxisome proliferator-activated receptor-peroxisome proliferator-activated receptor-γγ,, scavenger receptor class B type I,scavenger receptor class B type I, hepatocyte nuclear factor-4hepatocyte nuclear factor-4αα,, cholesteryl ester transfer protein,cholesteryl ester transfer protein, lecithin-cholesterol acyltransferase,lecithin-cholesterol acyltransferase, luteinizing hormone, lipoprotein lipase, andluteinizing hormone, lipoprotein lipase, and paraoxonase for HA.paraoxonase for HA. Linkage analysis using an autosomal dominant pattern ofLinkage analysis using an autosomal dominant pattern of inheritance was employed.inheritance was employed.
- 9. • Both LDLR and apoB genes were ruled out in this kindred. • A genomic wide scan from chromosomes 1 to 22 found a 6.75-cM long region with positive LOD scores in chromosome 1p32, in all 12 affected individuals. • Five asymptomatic individuals also shared the haplotype indicating incomplete penetrance. Results: FH locus
- 10. • All suspected genes failed to show any significant linkage. • A genomic wide scan from chromosomes 1 to 22 found a 7.32-cM long region with positive LOD scores in chromosome 6p, in all 10 individuals of the kindred with HA. • There are no known or obvious candidate genes that directly regulate HDL metabolism in this region Results: HA locus
- 11. 1) HDL-C elevation explained the antiatherogenic effect in patients with FH that had no clinical atherosclerosis. 2) The FH trait was mapped to a region in chromosome 1p32, zone that was also previously linked to FH3 . This locus showed incomplete penetrance. 3) The HA trait was mapped to a region in chromosome 6p, zone that was not previously linked to FH. In this kindred the penetrance was 90%. Conclusion:
- 12. • Although the 6p12.3-q13 locus has already been associated with the modulation of cholesterol, TG, and TG/HDL levels, it has not been previously linked to high HDL levels or to an antiatherogenic effect in humans. Conclusion:
- 13. Antiatherogenic effect conferred by this locus exceeds its effect on cholesterol level, and may also provide protection against atherogenesis-promoting conditions (risk factors such as hypertension, smoking etc) other than FH. Conclusion:
- 14. Questions: 1- Do you anticipate discovery of a gene locus on one chromosome that could explain more than 50% of atherosclerosis in general population? – Yes – No – Yes, possibly as a modifier gene
- 15. Questions: 2- Knowing that a large group of population with various risk factors including high cholesterol levels and smoking do not develop clinical atherosclerosis, which one of the following may explain such a paradox? 2-1- These subjects might have protective factors that strongly protect them against development of atherosclerosis.
- 16. 2-2- These people might have limited or extensive benign atherosclerosis but it does not link to vulnerability and clinical events (thrombosis and hemodynamic insufficiency). 2-3- They will develop atherosclerosis but perhaps at later stages of their life.