Heart disease risk factors: nature vs. nurture

Heart disease has several major risk factors. Some, such as smoking and lack of physical activity, can be readily controlled by lifestyle changes. Other risk factors, however, aren’t so easily controlled. Chief among these is a family history of heart disease. As the popular saying goes, you can’t choose your parents.

Genomes, Genes and GWAS

Tucked inside our cells are bundles of long, winding DNA. The complete set of DNA is known as a genome and it consists of over three billion individual DNA letters or nucleotides. The nucleotides spell out specific instructions in the form of genes. The completion of the Human Genome Project in 2003 revealed that humans have about 20,000 to 25,000 genes. Each gene carries instructions for making a specific protein or set of proteins. Genes help determine eye color and hair color, and they also can influence what diseases an individual may (or may not) get.

To better understand the role that genes can play in causing heart disease and other disorders, researchers are examining the DNA of thousands of individuals to look for variations, or misspellings, in the DNA that might be linked to a disease. DNA variations, known as single nucleotide polymorphisms (SNPs, pronounced “snips”), are very common, and occur along our DNA at a frequency of about one every 1,000 letters.

Genome-wide association studies (GWAS, pronounced “G-was”) analyze DNA across populations to pinpoint hard-to-find genetic hotspots for common diseases that are thought to have many causes, both genetic and environmental. Examples of conditions currently being studied by GWAS include asthma, Alzheimer’s disease, diabetes, hypertension, heart failure, obesity, osteoarthritis, stroke, heart disease, and many types of cancer. The results of these studies will help scientists better understand how genes interact with an individual’s lifestyle and environment (including factors such as eating behavior, cigarette smoking, physical activity level, and exposure to air pollution) to increase or decrease the likelihood of getting a disease.

What were the studies?

The research, representing scientists from 17 countries, appears in two papers in the August 5, 2010 issue of Nature. The National Heart, Lung, and Blood Institute (NHLBI) is the lead funder of the research, with additional support from several other National Institute of Health (NIH) components.

• In the initial study, researchers screened for an association among ~2.6 million common DNA misspellings (SNPs) and four lipid traits that are heritable risk factors for heart disease. The traits were: total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides.
• Researchers analyzed over 100,000 men and women of European descent from all over the world by pooling 46 lipid GWAS studies into a larger meta-analysis.
• Further analyses were performed in over 15,000 East Asians, 9,000 South Asians, and 8,000 African Americans.

What did the studies find?

• Researchers found 95 specific regions (loci) along DNA that were associated with at least one of the four heritable lipid traits. Of the 95 genetic variants or locations, 36 had previously been reported and 59 were new.
• Many of the newly discovered variants were in, or near, genes already known to play a role in lipid metabolism, including some that are the targets of lipid-lowering drugs.
• Most of the genetic variants identified in the original group of European descent were also identified in individuals of East Asian, South Asian, and African American descent, suggesting relevance across global populations.
• Many of the DNA variants found to be associated with blood lipid levels were also shown to be associated with coronary artery disease, underscoring the connection between blood lipids and heart disease.
• The effects of the individual DNA variants were additive. Individuals that had more of the ‘risk’ variants were more likely to have abnormal blood lipid levels than individuals who carried fewer variants.
• Taken together, the gene variants explained between a quarter to a third of the inherited portion of cholesterol and triglyceride measured in the blood.
• In a follow-up study published separately in the same journal and funded through the American Recovery and Reinvestment Act, researchers focused on a common DNA misspelling strongly associated with LDL-cholesterol and heart attacks in humans. The researchers painstakingly determined that the specific DNA variant altered expression of a gene in the liver, in turn affecting blood levels of LDL-cholesterol and VLDL particles.

What are the take-home messages?

Genome-wide association studies offer a valuable approach to identify DNA misspellings that may be linked to a disease or condition. GWAS only provide associations (hence the name), and do not reveal cause and effect. However, follow-up research that examines the biological significance of identified variants has led to important insights in metabolic pathways and has implications for the development of more targeted therapies to diagnose and treat heart disease.

• These types of studies raise many exciting questions regarding the future of heart disease diagnosis. In addition to routine screening of blood pressure, lipid levels, body weight, and other risk factors, clinicians may one day include genetic testing to screen for a panel of DNA variants known to contribute to an increased risk of dyslipidemias and/or heart disease.
• Both nature and nurture contribute to an individual’s risk for developing heart disease. Multiple small genetic variations can add up, and can interact with environmental and lifestyle factors to influence an individual’s risk for heart disease and other conditions.
• Some of the new variants that were identified are in genes that to date have no known function in lipid metabolism. Determining the function of these genes could shed light on new therapeutic opportunities for the prevention of heart disease.
• Health care providers can encourage their patients to keep track of their family health history. The U.S. Surgeon General offers an online tool, the Family Health Portrait, which provides individuals with the opportunity to build a drawing of their family tree and a chart of their family health history. Both the chart and the drawing can be printed and shared with family members and health care providers.

Where can I learn more?

• Biological, clinical and population relevance of 95 loci for blood lipids. Teslovich, T.M., et al., Nature, 466(7307), 707-713, August 5, 2010.
• From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Musunuru, K., et al., Nature, 466(7307), 714-719, August 5, 2010.
• Genomics: Variations in blood lipids. Shuldiner, A.R., and T.I. Pollin, Nature, 466(7307), 703-704, August 5, 2010.
• NIH genomic mapping study finds largest set of genes related to major risk factor for heart disease (NHLBI news release)
• NHLBI large-scale DNA sequencing project population studies (Backgrounder)
• Researcher Profile: Meet Deborah A. Nickerson, Ph.D., who is translating information from the Human Genome Project into ways to help people stay healthy.
• Talking glossary of genetic terms (National Human Genome Research Institute, part of the NIH)

Additional information on the study:

Research participants from NHLBI study populations contributed about half of the 100,000 genomes scanned. Among the NIH population-based studies involved in the research were the Framingham Heart Study; the Atherosclerosis Risk in Communities Study; the Cardiovascular Health Study; the SardiNIA Study; the Ages, Gene, Environment Study; the InCHIANTI Study; the Family Heart Study; the NHLBI Candidate Gene Association Resource Program; the NIH Pharmacogenetics Research Network; the deCODE MI Study; and the Women’s Genome Health Study.

October, 2010