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Studies Indicate Family History, Traditional Risk Factors Remain Key to Much of Disease Risk Prediction

NEW YORK (GenomeWeb News) – Several new studies are underscoring the importance of family history and traditional risk factors for assessing disease risk.
In a pair of studies appearing in today’s issue of the New England Journal of Medicine, two teams of researchers investigated the type 2 diabetes risk prediction provided by common genetic variants in several large cohorts. The first study suggests genotyping provides little additional predictive power over traditional clinical risk factors and family history, while the second indicates that DNA variants added a small amount of predictive value to family history and clinical factors, becoming more informative over increased follow-up time.
“Despite the intuitive appeal of a genetic risk score, it remains an untested hypothesis that genetic information allows better prediction of the risk of diabetes than knowledge of common risk factors alone,” Massachusetts General Hospital researcher James Meigs, lead author on one of the NEJM papers, and his colleagues wrote.
Meanwhile a study presented at the American Association for Cancer Research’s International Conference on Frontiers in Cancer Prevention Research this week in Washington, DC, suggests that a family history of breast cancer is linked to significantly increased breast cancer risk — even in women who test negative for BRCA1 and BRCA2 mutations.
In the first of the type 2 diabetes studies, Meigs and his team genotyped 2,776 individuals of European descent enrolled in the Framingham Heart Study for 18 diabetes-associated variants using Sequenom’s iPLEX. Based on this data, the team assigned each participant with a genotype score between one and 36, depending on the number of risk alleles they carried.
Of the nearly 2,800 individuals genotyped, phenotypic and follow-up data — such as medical history, physical exams, fasting blood samples, and a family history questionnaire — was available for 2,377 people.
During 28 years of follow-up, the researchers found that 255 of the participants developed type 2 diabetes.
When they looked at genotype information on its own, the researchers found that those with the highest genotype scores were at increased risk of type 2 diabetes over those with the lowest scores. Even so, when they looked at genotype in combination with other factors, the team found that this genotype information added very little predictive power to models based on family history and various traditional risk factors.
“The results suggest that ‘personalized medicine’ that is made possible by the expanded understanding of genetics is not yet as useful for the prediction of the risk of diabetes in adults as it is for other potential applications,” the authors wrote.
Based on their results, Meigs and his colleagues proposed that family history may encompass not just genetic predisposition to the disease, but also non-genetic factors such as family behavior and environment. They also noted that the SNPs tested probably represent just a small part of diabetes heritability and do not take into account rare genetic polymorphisms, structural variants, or yet to be identified common risk alleles.
“With the current state of knowledge, the genotype score doesn’t help us sort out who is at elevated risk any better than measures like weight,” Meigs said in a statement. “We may eventually find out that those individuals without known risk factors who still develop type 2 diabetes have more diabetes-risk genes, once we know what more of those genes are.”
As such, Meigs emphasized that “genetic risk evaluation for diabetes is still in its infancy. As additional risk genes are discovered, the value of genetic screening is likely to improve,” he said. “But with current knowledge, the measurements your physician makes in a standard checkup tell what you need to know about your type 2 diabetes risk, and genetics doesn’t tell you much more.”
In a second NEJM study, an international team of researchers genotyped 16 SNPs and looked at their association with various clinical factors, including insulin secretion and action, over a median follow-up time of 23.5 years in more than 16,000 Swedish individuals and nearly 2,800 Finnish individuals.
Overall, the team found several type 2 diabetes risk predictors, including a family history of the disease, body-mass index, liver-enzyme levels, current smoking status, blood pressure, serum triglyceride levels, and measurements of insulin secretion and action.
The team found significant associations between type 2 diabetes and 11 of the common variants tested in the Swedish Malmö Preventive Project cohort that were independent of clinical risk factors. They also pinpointed several associations between specific variants and certain clinical factors. For instance, the team linked impaired beta cell function with eight of the genetic variants and found four variants that could predict the transition from impaired fasting glucose levels or impaired glucose tolerance to type 2 diabetes.
But when they combined genetic and clinical information, the researchers found that genotype data only improved diabetes risk prediction slightly.
“[T]he addition of data from genotyping of the known DNA variants to clinical risk factors (including a family history of diabetes) had a minimal, albeit statistically significant effect on the prediction of future type 2 diabetes,” senior author Leif Groop, a diabetes and endocrinology researcher at Sweden’s Lund University, and his colleagues wrote. “[T]he inclusion of common genetic variants that are associated with type 2 diabetes very slightly improved the prediction of future type 2 diabetes, as compared with the inclusion of clinical risk factors alone.”
The predictive power of genetic risk factors did increase with longer follow-up, as the predictive power of clinical risk factors decreased.
“[T]he inclusion of common genetic variants that are associated with type 2 diabetes very slightly improved the prediction of future type 2 diabetes, as compared with the inclusion of clinical risk factors alone,” the authors concluded. “Although this effect might be too small to allow for individual risk prediction, it could be useful in reducing the number of subjects who would need to be included in intervention studies aimed at the prevention of type 2 diabetes.”
In a third study, led by University of Toronto cancer researcher Steven Narod, investigators followed 1,492 BRCA1- and BRCA2-negative women over at least five years. The women came from 365 families with a history of breast cancer, defined as two or more breast cancer cases in close relatives under 50 years old or three or more cases in relatives of any age.
The researchers found that a family history of breast cancer increased breast cancer risk 4.3-fold above that of average women based on local breast cancer registries. For women under 40, the risk increased by almost 15 times. The absolute risk for women between the ages of 50 and 70 years old was about one percent annually, while it was about 0.4 percent per year for women between the ages of 30 and 50 years old.
“In clinical practice we often see families with a significant history of breast cancer and negative BRCA1 and BRCA2 tests, and it is often difficult to counsel them about their risk without this information,” Narod said in a statement. “It is clear that genes are involved, but it is hard to be more specific.”
He suggested the data may help physicians counsel patients and improve early detection and prevention efforts. “It is clear to me that the risk is high enough that we need to discuss options such as breast MRI for screening and chemoprevention with tamoxifen or raloxifene,” he said. “Our hope is to be able to prevent or pick up on breast cancer early enough to stop patients from dying. We will see what patients decide to do with this advice.”

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