Genetics Help Predict Heart Disease Risk, Statin Benefits

Coronary heart disease is the leading cause of death in the United States. It’s caused by a waxy substance called plaque that builds up inside the blood vessels of the heart. Risk factors include unhealthy blood cholesterol levels, high blood pressure, smoking, diabetes, lack of physical activity, unhealthy diet, and excess weight. Making lifestyle changes, such as quitting smoking, following a healthy diet, and being physically active, often can help prevent or treat heart disease. Medicines such as statins, which lower LDL cholesterol, may be prescribed if lifestyle changes aren't enough.

Genetics may one day help doctors know with precision which patients would most benefit from medication. Image credit: wildpixel/iStock/Thinkstock.

Genetics also plays a role in heart disease risk. Numerous genetic variations known as single-nucleotide polymorphisms (SNPs) are associated with disease risk. A group of researchers from Brigham and Women’s Hospital, Washington University School of Medicine in St. Louis, and Massachusetts General Hospital asked whether a composite of these SNPs could predict people who are at risk for heart disease complications and who might benefit the most from statin therapy.

The team analyzed data from 5 studies representing more than 48,000 people who had experienced almost 3,500 coronary heart disease-related events such as heart attack and death. The researchers calculated a genetic risk score for each participant based on 27 heart disease-associated SNPs and divided them into low, intermediate, and high genetic risk categories. The work was funded in part by NIH’s National Heart, Lung, and Blood Institute . Results appeared online on March 4, 2015, in The Lancet.

The scientists found that people with a high genetic risk score had an increased risk of coronary heart disease, even after adjusting for traditional risk factors such as age, cholesterol levels, and smoking history. Participants in the high genetic risk category had an approximately 70% greater risk of heart attack compared with those at lowest genetic risk.

The genetic risk score also predicted the ability of statin therapy to reduce the risk of a coronary heart disease-related event, such as a heart attack. Statin therapy resulted in 13%, 29%, and 48% relative risk reductions in the low, intermediate, and high genetic risk groups, respectively. This suggests that people with the highest genetic risk could have the largest clinical benefit from statin therapy.

“There is ongoing debate over which individuals should be allocated statin therapy to prevent a first heart attack,” says co-first author Dr. Nathan O. Stitziel of Washington University. “Genetics appears to be one way to identify high-risk patients.”

“These findings could play an important role in helping physicians understand which patients will benefit the most from statin therapy,” adds co-first author Dr. Jessica L. Mega of Brigham and Women’s Hospital.

The researchers note that genetic risk scores could also be used to help select participants for clinical trials, as they could identify people who might benefit most from a specific therapy, such as statins.

—by Carol Torgan, Ph.D.

Breast Cancer in Young Women

Most breast cancers are found in women who are 50 years old or older, but breast cancer also affects younger women. About 11% of all new cases of breast cancer in the United States are found in women younger than 45 years of age.

Some young women are at a higher risk for getting breast cancer at an early age compared with other women their age. If you are a woman under age 45, you may have a higher risk if—

• You have close relatives (parents, siblings, or children) who were diagnosed with breast or ovarian cancer when they were younger than 45, especially if more than one relative was diagnosed or if a male relative had breast cancer.
• You have changes in certain breast cancer genes (BRCA1 and BRCA2), or have close relatives with these changes.
• You have an Ashkenazi Jewish heritage.
• You were treated with radiation therapy to the breast or chest during childhood or early adulthood.
• You have had breast cancer or certain other breast health problems such as lobular carcinoma in situ (LCIS), ductal carcinoma in situ (DCIS), atypical ductal hyperplasia, or atypical lobular hyperplasia.
• You have been told that you have dense breasts on a mammogram.

What can I do to reduce my risk?

Breast cancer in a woman under the age of 45 is relatively rare compared to older women, but some women have higher risk for this disease. If you're a woman in this age group, it is important that you—

• Know how your breasts normally look and feel. If you notice a change in the size or shape of your breast, you feel pain in your breast, or you have nipple discharge other than breast milk (including blood), talk to a doctor right away.
• Talk to your doctor if you have a higher risk. If you have a family history of breast or ovarian cancer or other risk factors, you should talk to your doctor about ways to manage your risk. If your risk is high, your doctor may suggest that you get genetic counseling and be tested for changes, called mutations, in your BRCA1 and BRCA2 genes. Your doctor may also talk to you about getting mammograms earlier and more often than other women, whether other screening tests might be right for you, and medicines or surgeries that can lower your risk.

Genetic Marker for Stroke and Cardiovascular Disease Discovered.

Scientists studying the genomes of nearly 5,000 people have pinpointed a genetic variant tied to an increased risk for stroke, and have also uncovered new details about an important metabolic pathway that plays a major role in several common diseases. Together, their findings may provide new clues to underlying genetic and biochemical influences in the development of stroke and cardiovascular disease, and may also help lead to new treatment strategies.

“Our findings have the potential to identify new targets in the prevention and treatment of stroke, cardiovascular disease and many other common diseases,” said Stephen R. Williams, Ph.D., a postdoctoral fellow at the University of Virginia Cardiovascular Research Center and the University of Virginia Center for Public Health Genomics, Charlottesville.

Stroke is the fourth leading cause of death and a major cause of adult disability in this country, yet its underlying genetics have been difficult to understand. Numerous genetic and environmental factors can contribute to a person having a stroke. “Our goals were to break down the risk factors for stroke,” Dr. Williams said.

The researchers focused on one particular biochemical pathway called the folate one-carbon metabolism (FOCM) pathway. They knew that abnormally high blood levels of the amino acid homocysteine are associated with an increased risk of common diseases such as stroke, cardiovascular disease and dementia. Homocysteine is a breakdown product of methionine, which is part of the FOCM pathway. The same pathway can affect many important cellular processes, including the methylation of proteins, DNA and RNA. DNA methylation is a mechanism that cells use to control which genes are turned on and off, and when.

But clinical trials of homocysteine-lowering therapies have not prevented disease, and the genetics underlying high homocysteine levels – and methionine metabolism gone awry – are not well defined.

Dr. Williams and his colleagues conducted genome-wide association studies of participants from two large long-term projects: the Vitamin Intervention for Stroke Prevention (VISP), a trial looking at ways to prevent a second ischemic stroke, and the Framingham Heart Study (FHS), which has followed the cardiovascular health and disease in a general population for decades. They also measured methionine metabolism – the ability to convert methionine to homocysteine – in both groups. In all, they studied 2,100 VISP participants and 2,710 FHS subjects.

In a genome-wide association study, researchers scan the genome to identify specific genomic variants associated with a disease. In this case, the scientists were trying to identify variants associated with a trait – the ability to metabolize methionine into homocysteine.

Investigators identified variants in five genes in the FOCM pathway that were associated with differences in a person’s ability to convert methionine to homocysteine. They found that among the five genes, one – the ALDH1L1 gene – was also strongly associated with stroke in the Framingham study. When the gene is not working properly, it has been associated with a breakdown in a normal cellular process called programmed cell death, and cancer cell survival.

They also made important discoveries about the methionine-homocysteine process. “GNMT produces a protein that converts methionine to homocysteine. Of the five genes that we identified, it was the one most significantly associated with this process,” Dr. Williams said. “The analyses suggest that differences in GNMT are the major drivers behind the differences in methionine metabolism in humans.”

“It’s striking that the genes are in the same pathway, so we know that the genomic variants affecting that pathway contribute to the variability in disease and risk that we’re seeing,” he said. “We may have found how genetic information controls the regulation of GNMT.”

The group determined that the five genes accounted for 6 percent of the difference in individuals’ ability to process methionine into homocysteine among those in the VISP trial. The genes also accounted for 13 percent of the difference in those participants in the FHS, a remarkable result given the complex nature of methionine metabolism and its impact on cerebrovascular risk. In many complex diseases, genomic variants often account for less than 5 percent of such differences.

“This is a great example of the kinds of successful research efforts coming out of the GARNET program,” said program director Ebony Madden, Ph.D. “GARNET scientists aim to identify variants that affect treatment response by doing association studies in randomized trials. These results show that variants in genes are associated with the differences in homocysteine levels in individuals.”

The association of the ALDH1L1 gene variant with stroke is just one example of how the findings may potentially lead to new prevention efforts, and help develop new targets for treating stroke and heart disease, Dr. Williams said.

“As genome sequencing becomes more widespread, clinicians may be able to determine if a person’s risk for abnormally high levels of homocysteine is elevated,” he said. “Changes could be made to an individual’s diet because of a greater risk for stroke and cardiovascular disease.”

The investigators plan to study the other four genes in the pathway to try to better understand their potential roles in stroke and cardiovascular disease risk.