|International Effort Finds New Genetic Variants Associated with Lipid Levels, Risk for Coronary Artery Disease
Environmental and genetic factors influence a person's blood
fat, or lipid levels, important risk factors for coronary artery
disease (CAD). While there is some understanding of the environmental
contribution, the role of genetics has been less defined. Now,
in an international collaboration supported primarily by the National
Institutes of Health (NIH), scientists have discovered more than
25 genetic variants in 18 genes connected to cholesterol and lipid
levels. Seven of the 18 genes previously had not been connected to
these levels, while the 11 others confirm previous discoveries.
In the investigation, published online January 13 and in the February
print issue of Nature Genetics, the associated genes were
found through studies of more than 20,000 individuals and more
than 2 million genetic variants, spanning the entire genome. These
variants potentially open the door to strategies for the treatment
and prevention of CAD.
"Heart disease is a leading cause of illness, disability
and death in industrialized countries, particularly for older people," says
National Institute on Aging (NIA) Director Richard J. Hodes, M.D. "We
know that certain lifestyle factors like smoking, diet and physical
activity greatly affect a person's lipid profiles. This study
is an important, basic step in finding the genes that influence
lipid levels and heart disease so that we can better understand
the genetic contribution to cardiovascular risk."
Cristen Willer, Ph.D., at the University of Michigan's School
of Public Health, Ann Arbor, and Serena Sanna, Ph.D., at the C.N.R.
Institute of Neurogenetics and Neuropharmacology, Monserrato, Italy,
and other members of the SardiNIA Study of Aging, including investigators
at NIA, conducted the study, along with members of the Finland-United
States Investigation of Non-Insulin-Dependent Diabetes Mellitus
Genetics (FUSION) study, which included investigators in North
Carolina, Michigan, Finland, Los Angeles and from the National
Human Genome Research Institute (NHGRI). SardiNIA and FUSION
investigators also coordinated the efforts of other groups in France,
the United Kingdom and across the United States.
The purpose of the study was to identify comprehensively genetic
variants that influence lipid levels and to examine the relationships
between these genetic variants and risk of CAD. High levels of
low-density lipoprotein (LDL) ("bad" cholesterol) appear
to increase the risk of CAD by narrowing or blocking arteries that
carry blood to the heart. High levels of high-density lipoprotein
(HDL) ("good" cholesterol) appear to lower the risk.
High levels of triglycerides, which make up a large part of the
body's fat and are also found in the bloodstream, are also
associated with increased risk of CAD.
To identify genetic variants that play a role in lipid levels,
researchers turned to a relatively new approach, known as a genome-wide
association study (GWAS). The GWAS strategy enables researchers
to survey the entire human genetic blueprint, or genome, not just
the genetic variants in a few genes. The human genome contains
approximately 3 billion base pairs, or letters, of DNA. Small,
single-letter variations naturally occur about once in every 1,000
letters of the DNA code. Most of these genetic variants have not
yet been associated with particular traits or disease risks. However,
in some instances, people with a certain trait, such as higher
levels of LDL cholesterol, tend to have one version of the variant,
while those with lower levels are more likely to have the other
version. In such instances, researchers may infer that there is
an association between the values of the trait and the variants
in the gene.
Typically, GWAS studies have been carried out in samples where
all individuals are examined with the same gene chip, an experimental
device that allows investigators to measure more than 100,000 genetic
variants in a single experiment. But in this study, investigators
developed and employed new statistical methods that allowed them
to combine data across different gene chips and thus examine much
larger numbers of participants.
With the statistical power gained by new programs that facilitated
pooling of the large SardiNIA, FUSION and Diabetes Genetic Initiative
(DGI) datasets, researchers were able to identify variations in
18 genes that influence HDL, LDL and/or triglyceride levels. This
list of lipid-associated genes is substantially longer than what
was generated by analyses of individual datasets, which had only
pointed to one to three genes each. Of the seven newly implicated
genes, two were associated with HDL levels, one with LDL levels,
three with triglyceride levels and one with both triglycerides
and LDL levels. A summary of the data is available online at http://www.sph.umich.edu/csg/abecasis/public/lipids.
"These results are yet another example of how genome-wide
association studies are opening exciting new avenues for biomedical
research," says NHGRI Director Francis S. Collins, M.D.,
Ph.D., who is a coauthor of the study and an investigator in NHGRI's
Genome Technology Branch. "While some of the genetic variants
we identified are known to play a well-established role in lipid
metabolism, others have no obvious connection. Further studies
to identify the precise genes and biological pathways involved
could shed new light on lipid metabolism."
Scientists estimate that the genetic contribution to lipid levels
is about 30 to 40 percent; the genetic variants uncovered in the
new study are responsible for about 5 to 8 percent of that contribution,
the scientists note, which means there is more work to be done. "In
this study we carried out a comprehensive search for common variants
of large effect. The genetic factors still to be discovered might
turn out to be common variants with smaller effects or rare variants
with a large effect," says Karen L. Mohlke, Ph.D., of the
University of North Carolina, Chapel Hill, who co-directed the
study with Gonçalo R. Abecasis, Ph.D., of the University
of Michigan's School of Public Health.
To determine if the genetic variants associated with lipid levels
also influence risk of heart disease, the researchers compared
their results with results from the Wellcome Trust Case Control
Consortium's recent genome-wide association study of CAD
involving 15,000 British individuals. They found that all gene
variants associated with increased LDL levels also were more prevalent
among people with CAD. People with the gene variant for high triglyceride
levels also had an increased risk for CAD, although the relationship
was not as strong. No relationship was found between HDL and CAD.
"It was surprising that while it was clear that genetic
variants that increase your ‘bad' cholesterol are also
associated with increased risk of heart disease, we did not find
that variants influencing your ‘good' cholesterol were
associated with decreased risk of coronary artery disease. Perhaps
that result will lead us to re-examine the roles of good and bad
cholesterol in susceptibility to heart disease," remarks
Identifying a correlation among genes influencing lipid levels
and risk for coronary heart disease is a first step in a long path
to potentially important clinical implications. "What we're
looking for, ultimately, are novel therapeutics and/or life-style
modifications that can be recommended to individuals to help manage
blood lipid levels and reduce risk of heart disease," says
David Schlessinger, Ph.D., chief of the NIA's Laboratory
of Genetics and NIA Project Officer for SardiNIA.
This study also demonstrates the power of international collaboration
in genetic analyses. None of the studies that cooperated to make
this work possible were large enough to find all of these important
associations alone. By working together, previously unsuspected
genetic influences on lipid levels and heart disease were revealed.
SardiNIA is funded by NIA and FUSION receives support from the
National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) and NHGRI. Additional genetic data were provided by DGI,
which involves Finnish and Swedish individuals and is a collaboration
of the Broad Institute of Harvard and MIT, Cambridge, Mass.; Lund
University, Malmo, Sweden; and Novartis, Basel, Switzerland.
In addition to the NIA; NHGRI; University of Michigan, Ann Arbor;
University of North Carolina, Chapel Hill; Department of Health
and Functional Capacity, National Public Health Institute, Helsinki,
Finland; Keck School of Medicine, University of Southern California,
Los Angeles; and the C.N.R Institute of Neurogenetics and Neuropharmacology,
other institutions with researchers taking part in the study were:
Geriatrics Operating Unit, Institute for the Endocrine and Metabolic
Pathology, Rome; Clinical Trials Services Unit, University of Oxford,
England; National Center of Genotypage, Genomic Institute, Commissionership
of Atomic Energy, Evry, France; Department of Social Medicine,
University of Bristol, England; University of Maryland School of
Medicine, Baltimore; Departments of Public Health and of Medical
Data Processing, School of Medicine, Paris; Research Unit of Nutritional
Epidemiology, Bobigny, France; London School of Hygiene and Tropical
Medicine, University of London; and Department of Public Health,
University of Helsinki, Finland.
Data used in this analysis were generated by studies supported
by NIA, NHGRI, NIDDK and the National Heart, Lung and Blood Institute
(NHLBI), all part of NIH; the Wellcome Trust; the American Diabetes
Association; the Department of Veteran Affairs; the British Heart
Foundation; the United Kingdom's Medical Research Council;
and the French Ministry of Higher Education and Research. The genome-wide
scans of the FUSION participants' DNA were performed at the
Center for Inherited Disease, using funding from NIH and Johns
Hopkins University, Baltimore.
Also today, another NIH-supported genome-wide association study
involving the SardiNIA, FUSION and DGI groups was released in the
advance online publication of Nature Genetics. In this
study, an international team, including many researchers from the
lipid investigation, found evidence that common genetic variants
recently linked to osteoarthritis may also play a minor role in
For consumer information on heart disease, visit the NHLBI website
The NIA leads the federal government effort conducting and supporting
research on the biomedical and social and behavioral aspects of
aging and the problems of older people. For more information on
aging-related research and the NIA, please visit the NIA website
The National Institute of Diabetes and Digestive and Kidney Diseases,
a component of the NIH, conducts and supports research in diabetes
and other endocrine and metabolic diseases; digestive diseases,
nutrition, and obesity; and kidney, urologic, and hematologic diseases.
Spanning the full spectrum of medicine and afflicting people of
all ages and ethnic groups, these diseases encompass some of the
most common, severe, and disabling conditions affecting Americans.
For more information about NIDDK and its programs, see www.niddk.nih.gov.
NHGRI's Division of Intramural Research develops and implements
technology to understand, diagnose and treat genomic and genetic
diseases. Additional information about NHGRI can be found at www.genome.gov. For
more information about genome-wide association studies, go to www.genome.gov/20019523.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.