A new study by Dwyer et al. [1] just published in the New England Journal of Medicine found an
association between a variation of a gene called 5-lipoxygenase (5-LO) and an increased risk for
atherosclerosis, or thickening of the arteries. 5-lipoxygenase is an enzyme which converts omega-6
fatty acid arachidonic acid to inflammation mediators such as leukotrienes etc. (a similar
inflammatory enzyme is COX-2 (cyclooxygenase-2) which converts arachidonic acid to prostaglandin E2
(PGE2), which is also a mediator of inflammation). Some earlier studies have linked inflammation and
5-lipoxygenase to atherosclerosis and coronary heart disease.
Below the abstract of the study:
"BACKGROUND: Leukotrienes are inflammatory mediators generated from arachidonic acid
(polyunsaturated n-6 fatty acid) by the enzyme 5-lipoxygenase. Since atherosclerosis involves
arterial inflammation, we hypothesized that a polymorphism in the 5-lipoxygenase gene promoter
could relate to atherosclerosis in humans and that this effect could interact with the dietary
intake of competing 5- lipoxygenase substrates. METHODS: We determined 5- lipoxygenase
genotypes, carotid-artery intima-media thickness, and markers of inflammation in a randomly
sampled cohort of 470 healthy, middle-aged women and men from the Los Angeles Atherosclerosis
Study. Dietary arachidonic acid and marine n-3 fatty acids (including a competing 5-lipoxygenase
substrate that reduces the production of inflammatory leukotrienes) were measured with the use
of six 24-hour recalls of food intake. RESULTS: Variant 5-lipoxygenase genotypes (lacking the
common allele) were found in 6.0 percent of the cohort. Mean (+/-
and racial or ethnic group was increased by 80+/-19 microm (95 percent confidence interval, 43
to 116; P<0.001) among carriers of two variant alleles, as compared with carriers of the common
(wild-type) allele. In multivariate analysis, the increase in intima-media thickness among
carriers of two variant alleles (62 microm, P<0.001) was similar in this cohort to that
associated with diabetes (64 microm, P= .01), the strongest common cardiovascular risk factor.
Increased dietary arachidonic acid significantly enhanced the apparent atherogenic effect of
genotype, whereas increased dietary intake of n-3 fatty acids blunted the effect. Finally, the
plasma level of C-reactive protein, a marker of inflammation, was increased by a factor of 2
among carriers of two variant alleles as compared with that among carriers of the common allele.
CONCLUSIONS: Variant 5-lipoxygenase genotypes identify a subpopulation with increased
atherosclerosis. The observed diet-gene interactions further suggest that dietary n-6
polyunsaturated fatty acids promote, whereas marine n-3 fatty acids inhibit, leukotriene-
mediated inflammation that leads to atherosclerosis in this subpopulation."
The study has been commented in the science news article
Gene Worsens Artery Disease <URL:http://www.sciencedaily.com/releases/2003/12/031231084356.htm>
"UCLA/USC researchers have linked a variation of a gene called 5-lipoxygenase (5-LO) to an
increased risk for atherosclerosis, or thickening of the arteries. Published Jan. 1, 2004 in the
New England Journal of Medicine, the discovery may soon enable physicians to test for modified
5-LO as a marker for cardiovascular disease.
"We discovered that the arteries of a 40-year-old with modified 5-LO look like those of a 50-year-
old with the normal version of the gene," explained Hooman Allayee, Ph.D., co-principal
investigator and human genetics researcher at the David Geffen School of Medicine at UCLA. "Our
findings suggest that this form of 5-LO speeds the development of atherosclerosis in 5 percent
of the population, intensifying a person's risk for heart attack and stroke."
Because earlier research links 5-LO to asthma, cardiologists may now be able to prescribe
current asthma medications to prevent and control atherosclerosis in persons who are at greater
risk for heart disease.
"This opens up a new market for existing asthma drugs that already target 5-LO," noted Allayee.
"Our conclusions suggest that modified 5-LO could be used as a genetic marker for heart disease
and lead to improved diagnosis, prevention, and treatment for atherosclerosis."
The findings also indicate that diet may play a key role in controlling heart disease risk.
"We found that 5-LO's adverse effect is increased by the consumption of certain polyunsaturated
fats contained in meat, yet blocked by the intake of some polyunsaturated fats found in oily
fish, such as salmon," said James Dwyer, Ph.D., co-principal investigator and professor of
preventive medicine at the USC Keck School of Medicine.
"The function of 5-LO is to convert fatty acids into molecules involved in inflammation,"
added Dwyer. "Since atherosclerosis is an inflammation of the arteries, our findings suggest
that persons with this 5-LO variation could reduce their risk of heart disease by modifying
their diet."
The team's research was driven by a mouse model developed by Margarete Mehrabian, Ph.D., senior
author and assistant professor of human genetics at the David Geffen School of Medicine at UCLA.
She was the first to show that eliminating 5-LO from the mouse genome helps protect against
atherosclerosis, even when the animal ate a fatty diet.
Mehrabian fed a high-fat diet to mice engineered without the 5-LO gene. After four months, she
compared the knockout mice's cardiac arteries to those of normal mice on the same diet.
"Though both mice ate the same diet, the normal mice's arteries were full of fatty deposits,
while the knockout mice's arteries contained none," said Mehrabian. "This confirmed our
suspicion that 5-LO could make a significant difference in cardiovascular health."
Allayee applied Mehrabian's findings to blood samples that Dwyer had collected from 470 healthy
middle-aged women and men in USC's Los Angeles Atherosclerosis Study. The researchers had
recorded each participant's diet and used ultrasound to measure the thickness of each subject's
carotid arteries - a primary target for atherosclerosis.
"Doctors often use an ultrasound of the carotid artery as a surrogate marker for heart disease,"
said Dwyer. "There is a strong link between artery thickness and heart attack risk."
Allayee analyzed the DNA in the blood samples and discovered six different versions of 5-LO. The
modified versions had missing or extra DNA sequences.
Dwyer grouped the DNA samples by 5-LO type and compared the carotid artery thickness of people
with the modified gene to those with the normal version. The team discovered that people
possessing the 5-LO variation showed more advanced atherosclerosis. In fact, their carotid
arteries measured up to 120 microns more than the average size of 650 microns. (A micron equals
one millionth of a meter.)
"Even after we adjusted for all the variables that could affect carotid artery thickness, such
as smoking, age, high cholesterol and blood pressure, the arteries of persons with the 5-LO
variation were still 50 microns thicker," said Allayee. "This equals a disease progression of
five to 10 years. We realized that modified 5-LO could be used as a marker for heart disease."
The researchers' next step will be to replicate their findings in other populations. If the team
learns that 5-LO is also implicated in the rupture of hardened fatty deposits in the artery --
the leading cause of heart attacks -- the findings could lead to early detection of individuals
at high risk for coronary heart disease. ..."
The study has also been commented in the articles
First Link Found In Humans Between Common Gene And Artery-clogging Disease
<URL:http://www.sciencedaily.com/releases/2004/01/040101090622.htm>
and
Carriers of Variant 5-Lipoxygenase Alleles Have Increased Carotid Intima-Media Thickness Affected by
Dietary Intake of Specific Fatty Acids
12/31/2003 By Joene Hendry
<URL:http://www.docguide.com/news/content.nsf/news/2D8E08B38589D61085256E0C004AF21B>
See also this, somewhat related web page:
The 5-Lipoxygenase Pathway Forms Circuits of Inflammation During Human Atherogenesis <acrc-gu.de00000806Open ↗
en.php>
"Oxidation products of low-density lipoproteins have been suggested to promote inflammation
during atherogenesis and reticulocyte-type 15-lipoxygenase has been implicated to mediate this
oxidation. In addition, the 5-lipoxygenase cascade leads to formation of leukotrienes, which
exibit strong pro-inflammatory activities in cardiovascular tissues. Here, we studied both
lipoxygenase pathways in human atherosclerosis. The 5-lipoxygenase pathway was abundantly
expressed in arterial walls of patients afflicted with various lesion stages of atherosclerosis
of the aorta and of coronary and carotid arteries. 5- lipoxygenase localized to macrophages,
dendritic cells, foam cells, and mast cells, and the number of 5- lipoxygenase expressing cells
markedly increased in advanced lesions. By contrast, reticulocyte-type 15- lipoxygenase was
expressed at levels that were several orders of magnitude lower than 5-lipoxygenase in both
normal and diseased arteries. Cultured endothelial, smooth muscle cells, and blood leukocytes
differentially expressed cysteinyl leukotriene and leukotriene B4 receptors, respectively. In
endothelial cells, leukotrienes C4 and D4 triggered a short-lived rise in intracellular free
Ca++ ions followed by oscillating Ca++ spikes that persisted > 60 minutes and, unlike the
thrombin response, preferentially occurred in the nucleus. Ca++ responses in endothelial cells
but not those in leukocytes were resistant towards the cysteinyl leukotriene 1 receptor
antagonist, montelukast, indicating distinct roles of leukotriene receptors in different cell
lineages that constitute atherosclerotic lesions. Our data support a new model of human
atherogenesis in which 5-lipoxygenase cascade-dependent inflammatory circuits consisting of
different leukocyte lineages and arterial wall cells evolve within the blood vessel wall during
critical stages of lesion development. They raise the possibility that anti leukotriene drugs
may be effective treatment regimen in late stage disease. Future studies will focus attention on
genetically defined mouse models of cardiovascular disease to obtain evidence for functional
impacts of the 5- lipoxygenase and other genes on atherogenesis and on other forms of arterial
wall injury responses."
References:
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<URL:http://content.nejm.org/cgi/content/short/350/1/29> (abstract) <URL:http://www.ncbi.nlm.ni-
h.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14702425&dopt=Abstract>
"... Conclusions Variant 5-lipoxygenase genotypes identify a subpopulation with increased
atherosclerosis. The observed diet–gene interactions further suggest that dietary n–6
polyunsaturated fatty acids promote, whereas marine n–3 fatty acids inhibit, leukotriene-
mediated inflammation that leads to atherosclerosis in this subpopulation."
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"Inflammation is believed to have a key role in atherosclerosis. Leukotrienes are important
inflammatory mediators generated from arachidonic acid by the enzyme 5- lipoxygenase. This study
found that variant genotypes of the 5-lipoxygenase gene, which lacked the common allele, were
associated with an increase in intima– media thickness of the carotid artery. A diet high in
arachidonic acid further increased the effect of the gene on this measurement.
This study has found a gene–diet interaction that appears to be involved in the pathogenesis of
atherosclerosis."
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Matti Narkia