1) A Mexican family with familial hypercholesterolemia (FH) linked to chromosome 1p32 was found to also have elevated HDL-C (high-density lipoprotein cholesterol) linked to chromosome 6p, which protected against atherosclerosis despite FH. 2) The FH trait mapped to chromosome 1p32, a region previously linked to FH, while the elevated HDL-C trait mapped to chromosome 6p, a region not previously linked to FH. 3) This family provides evidence that a locus on chromosome 6p confers an anti-atherogenic effect exceeding its effect on cholesterol levels, and may protect against risk factors beyond FH like hypertension and smoking.

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.