A step towards personalized prevention

Image by Nadav Kupiec, Broad Institute

The past few years have seen a dramatic increase in the number of genome-wide association studies, in which the genomes of many people are scanned to locate genetic variations that contribute to disease. The hope is that the knowledge will improve human health by revealing the basic mechanisms of disease, pinpointing new targets for drug development, or identifying patients most likely to benefit from existing treatments.

Insights from these whole genome studies have now been applied to heart disease, one of the leading causes of death in the developed world. In a new study, a team of researchers including several from the Broad Institute of MIT and Harvard designed a panel of genetic variants that may help identify patients at high risk of cardiovascular events like heart attack. Published in the March 20 issue of New England Journal of Medicine, the work represents a significant first step towards a personalized approach that may help prevent the damaging effects of high cholesterol before heart disease develops.

One aim of personalized medicine is to help predict disease risk. That knowledge can help guide treatments, which when available may slow or prevent progress of disease. In the realm of cardiology, genetics could help identify young patients at high risk of later developing heart disease; the patients could then be treated with medication like cholesterol-lowering statins to prevent cholesterol build-up and the damage it inflicts on blood vessels.

Work published last year by Broad researchers and others in the Diabetes Genetics Initiative identified several genetic changes that influence a person’s level of cholesterol — a known risk factor for heart disease. Nine of those single-letter differences, or SNPs, have now been combined into a cardiovascular predictive score by a team of scientists from Lund University in Sweden and the Broad Institute, led by first author Sekar Kathiresan, director of preventive cardiology at Massachusetts General Hospital and a genetics researcher in the Program in Medical and Population Genetics at the Broad Institute. From the DNA of study participants, the number of unfavorable SNPs — those contributing to higher LDL cholesterol or lower HDL cholesterol levels — were tallied, producing a genotype score that ranged from zero to 18.

The researchers hypothesized that the score would be linked not only to cholesterol levels, but also to cardiovascular disease itself. To assess disease risk and incidence over a period of time, the team tested the DNA of over 5,000 people enrolled in a Swedish cardiovascular study over a decade ago. Participants were initially assessed for standard risk factors, such as family history of heart attack, blood pressure, and levels of cholesterol in the blood, after which they were followed for roughly ten years to observe who would develop heart disease and who remained healthy. Blood samples taken during the initial assessment were stored for future DNA analysis, providing the team with samples to probe for genetic differences.

After comparing genotype scores with lipid levels in the blood, the team confirmed that the selected SNPs relate to HDL and LDL cholesterol. In addition, the score was useful in classifying patients along a range of lipid levels. Patients with a score of 6 or lower had average HDL and LDL levels of 60 and 152 mg/dL, compared to 51 and 171 mg/dL for those with a score of 13 or higher.

Importantly, the results also showed that genotype is an independent risk factor for heart attack, stroke, or death from heart disease. The score did not, however, improve risk prediction when considered along with more traditional factors, but it did help reclassify patients at intermediate risk levels as having more or less risk. “This is perhaps the most interesting thing to come out of this study — that the panel of SNPs is related to risk of heart attack in patients, even after accounting for the risk due to LDL and HDL levels,” said Kathiresan.

Two possibilities could explain this observation. Cholesterol levels are taken at one point in time and may be affected by a variety of factors ranging from diet to time of day. “Compared to a single measurement of cholesterol in the blood, gene variants are something you’re born with, so they may be a better indicator of your true cholesterol burden over a lifetime,” said Kathiresan. In addition, although the SNPs are associated with cholesterol, they may directly influence heart attack and atherosclerosis through another means, independent of cholesterol. “This suggests that a panel of SNPs could give us insights into cardiovascular disease, beyond what we can achieve by studying traditional risk factors.”

Before the genotype score can be used in the clinic, the team will need to improve their model. More whole genome studies must be performed to discover all the genetic variants that influence cardiovascular risk. The researchers estimate that future scores could incorporate up to 100 SNPs, including the six new variants recently identified in an association study by Kathiresan and colleagues at the Broad.

Another key issue is to prove that their model has real value in the clinic. “There’s an assumption that predicting risk automatically means health will improve,” said Kathiresan. But even with a score that accurately predicts risk, scientists and physicians must still prove through the rigor of clinical trials that such knowledge will help improve or even prevent heart disease.