JAMA: studies find little evidence to support genetic testing to improve CV risk assessment

Two separate studies appearing in JAMA cast doubt on the practical value of genetic testing to improve cardiovascular risk assessment.

In the first study, Nina Paynter and colleagues, led by Paul Ridker, calculated genetic risk scores based on 101 SNPs (single nucleotide polymorphisms) from 19,313 women enrolled in the Women’s Genome Health Study. They found that after adjusting only for age, patients in the lowest tertile of genetic risk had a CV risk of 3% over 10 years, compared to a risk of 3.7% for those in the highest tertile. However, once the investigators adjusted for traditional risk factors, the genetic risk score no longer provided additional information of value. By contrast, “self-reported family history remained significantly associated with cardiovascular disease in multivariable models.”

The authors conclude:

“First, genome-wide testing is increasingly available and marketed to the general public. Our study finds no clinical utility in a multilocus panel of SNPs for cardiovascular risk based on the best available literature. Second, our data confirm the utility of intermediate phenotypes such as total cholesterol, high-density lipoprotein cholesterol, and blood pressure in as much as genetic risk scores were no longer significant after adjustment for these phenotypes…. Third, our findings confirm the importance of family history of cardiovascular disease, which integrates shared genetics, shared behaviors, and environmental factors. At the same time, we believe that our data suggest areas for further biomarker research, which may improve prediction.”

In the second study, Palomaki and colleagues performed a meta-analysis to determine whether testing for 9p21 SNPs associated with heart disease can improve risk assessment and outcomes. Although they found, as expected, “a statistically significant association between 9p21 SNPs and heart disease… the magnitude of the association was small. They concluded:

In summary, showing that a genetic test has clinical validity does not necessarily lead to improved health. Clinical trials need to demonstrate that use of the test is associated with changes in physician management decisions, patient motivation and long-term behavioral changes, improved health outcomes, and/or reduced costs to the health care system.

Here is the JAMA press release:

Use of Multiple Genetic Markers Not Associated With Improved Ability to Predict Risk of Cardiovascular Disease in Women

CHICAGO – Creation of a genetic risk score comprised of multiple genetic markers associated with cardiovascular disease (CVD) was not associated with significant improvement in CVD risk prediction in a study that included more than 19,000 women, according to a study in the February 17 issue of JAMA.

“Risk prediction is a central part of cardiovascular disease prevention and refining prediction strategies remains important for targeting treatment recommendations. One area of potential improvement has been the discovery of genetic markers for cardiovascular disease as well as intermediate phenotypes [physical manifestations] such as cholesterol and blood pressure. Recent efforts using genome-wide association studies have greatly expanded the discovery of genetic markers associated with cardiovascular disease,” the authors write. “While multiple genetic markers associated with cardiovascular disease have been identified by genome-wide association studies, their aggregate effect on risk beyond traditional factors is uncertain, particularly among women.”

Nina P. Paynter, Ph.D., of Brigham and Women’s Hospital, Boston, and colleagues, constructed two genetic risk scores based on a comprehensive literature-based selection of genetic markers known to be associated with either cardiovascular disease or an intermediate phenotype and tested the scores to assess their predictive ability. The study included 19,313 initially healthy white women in the Women’s Genome Health Study, followed up over a median (midpoint) of 12.3 years. Genetic risk scores were constructed from the National Human Genome Research Institute’s catalog of genome-wide association study results published between 2005 and June 2009.

A total of 101 single nucleotide polymorphisms (SNPs) reported to be associated with cardiovascular disease or at least 1 intermediate cardiovascular disease phenotype were identified and risk alleles (an alternative form of a gene) were added to create a genetic risk score. During follow-up, 777 cardiovascular disease events occurred (199 heart attacks, 203 strokes, 63 cardiovascular deaths, 312 coronary artery revascularizations).

After analysis, the researchers found an absolute cardiovascular disease risk of 3 percent over 10 years in the lowest tertile (group) of genetic risk (73-99 risk alleles) and 3.7 percent in the highest tertile (106-125 risk alleles). However, after adjustment for traditional factors, the genetic risk score was not associated with cardiovascular disease risk. “In contrast, family history of premature [heart attack] remained an independent risk factor for incident cardiovascular disease even after adjustment,” the authors write.

“We believe these data have clinical relevance for several reasons. First, genome-wide testing is increasingly available and marketed to the general public. Our study finds no clinical utility in a multilocus panel of SNPs for cardiovascular risk based on the best available literature. Second, our data confirm the utility of intermediate phenotypes such as total cholesterol, high-density lipoprotein cholesterol, and blood pressure in as much as genetic risk scores were no longer significant after adjustment for these phenotypes,” the researchers write. “Third, our findings confirm the importance of family history of cardiovascular disease, which integrates shared genetics, shared behaviors, and environmental factors. At the same time, we believe that our data suggest areas for further biomarker research, which may improve prediction.”

“While the importance of genetic data in understanding biology and etiology is unchallenged, we did not find evidence in this study of more than 19,000 women to incorporate the current body of known genetic markers into formal clinical tools for cardiovascular risk assessment.”

(JAMA. 2010;303[7]:631-637.)

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