It's All in the Family (History)

When talking with salespersons, you expect each one to push his or her own product. Sometimes it's just hype. But often the opinions seem to reflect a sincere belief in the value of a product or service.

So it's reasonable that geneticists would extol genomic testing as the best way to understand personal health risks and susceptibilities, right? Odd as it may seem, many genetics experts are convinced that, given our current understanding, family health history, not genetic testing, provides the best insight into personal disease risk and possibly even disease prevention.

A Brief History of Family History

The emphasis on family health history is not a new idea. In 2004 the US Surgeon General established National Family History Day to coincide with Thanksgiving Day each year. The idea was for families to talk about their family health history during the holiday gathering.

Yet a lot has changed since 2004. Genome-wide association studies (GWAS) have demonstrated genetic associations in a wide variety of diseases and disorders, including Crohn's disease, many cancers, Alzheimer's disease, type 2 diabetes, obesity, and heart disease, as well as genetic influences on response to medications.

Early in 2006, the National Heart, Lung, and Blood Institute launched the Framingham Genetic Research Study to investigate the genes influencing cardiovascular and other chronic diseases. This study tied into the Framingham Heart Study, which was started in 1948 and which continues to study cardiovascular and other risk factors in nearly 15,000 participants over 3 generations.

In November 2010, using data from this Framingham substudy, investigators showed that the presence of atrial fibrillation in a first-degree relative increases the risk for the disorder in previously unaffected individuals by 39% (hazard ratio = 1.39; P = .003). Yet adjusting for 4 genetic variants known to be associated with atrial fibrillation in GWAS made little difference.^[1]

Family Health History Trumps Genomic Screening...Until It Doesn't

The Framingham study is not an isolated event. A paper presented at the 2010 meeting of the American Society of Human Genetics (ASHG) also showed that family history can trump genetic assessments of disease risk.^[2]

The study directly compared accuracy of family history risk assessment vs personal genomic screening in determining the risk for breast cancer (women only), prostate cancer (men only), or colon cancer (both men and women) in 22 men and 22 women.

Each participant's risk was categorized as general population, moderate, or high for the respective cancers. Overall, however, agreement of the 2 risk assessments was low.

For example, personal genomic screening predicted moderate or high risk for prostate cancer for 8 individuals whose family history indicated only general population risk. Genomic screening also indicated moderate risk for colon cancer in 12 participants whose family history indicated only general population risk.

At the same time, of the 3 men with high hereditary risk for prostate cancer, none was classified as high risk by their genomic assessment; among 10 women with high hereditary risk of breast cancer, only 1 was identified as high risk by genomic screening.

The authors expressed concern about patients who might chose personal genomic screening instead of evaluation of family history. "Family history...is still the proven gold standard, and this should be used to clinically evaluate an individual's risk of developing cancer until further research is done to prove that personal genomic screening can predict an individual's risk or can be integrated with family history risk assessment to increase sensitivity," they concluded.

Another (unrelated) ASHG presentation further illustrated the challenges in assessing disease risk based on both family history and genetic screening. Analysis of data from a Toronto-based healthcare clinic that offers family health history as well as genetic analysis showed that higher risk for disorders as determined by family history correlates about 50% of the time with genetic analysis indicating higher risk. However, there is less agreement in the opposite direction; for most cases in which genomic assessments indicated a higher risk, there was a negative family history of the health problem.^[3]

The Best of Both Worlds

How can a patient or a healthcare provider choose between family history and genomic screening? Which is more dependable? Which yields more valuable information?

Judging by the reports and studies above, a family history of disease risk is supported by genomic results roughly half the time, suggesting the involvement of other genes and/or single-nucleotide polymorphisms (SNPs) yet undetected, or perhaps of environmental effects.

Conversely, the somewhat puzzling lack of disease in many patients whose genomic scan indicates high risk may simply represent our ignorance of genetic interactions. For example, a risk gene might be present, but so are other genes that afford protection or that inhibit expression of the potentially harmful variant. Because these protective genes were also inherited, the absence of disease in their family history is understandable.

In cases in which family history indicates high risk and the effects of genetic mutations are well characterized (eg, in families carrying BRCA1/2 or mutations associated with age-related macular degeneration),^[4,5] personal genomic screening would certainly be of value. But given the frequent lack of correlation between genomic screening and an individual's health profile, the fact that many geneticists consider family health history as the gold standard for disease risk assessment is perhaps not so surprising after all.

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