Reading your family history

(This article was first printed in the August 2003 issue of the Harvard Health Letter. For more information or to order, please go to http://health.harvard.edu/health.)

Don’t jump to conclusions when you see a disease ‘running in the family.’ Inherited genes are just one of many explanations.

When we see similarities among family members, one of the first thoughts is “it must be in the genes.” And often enough, shared traits — including many health conditions — are a genetic inheritance. That’s one reason family history is a standard part of the medical chart.

But it’s easy to be misled. Just because something seems to run in a family doesn’t mean genes are responsible. It takes an expert to properly assemble and then interpret a medical pedigree. But here are a few suggestions for how to begin thinking about family patterns of disease.

Families pass on other things besides genes. “Portion sizes also run in families,” says Dr. Susan Pauker, a member of the Health Letter’s editorial board and a geneticist. “It may contribute to familial obesity along with inherited genetic changes.” Pauker’s point is that family influences, traditions, and circumstances must also be factored into any family history — not simply the vagaries of DNA. For example, a family may carry genetic changes for cleft palate, but if the family usually eats foods high in folic acid, the chance that a child might be born with a cleft palate is reduced. This is called multifactorial or polygenic (many genes) inheritance.

No family tree is an island. The generation of Americans that fought and won World War II has been dubbed the Greatest Generation. But for a host of reasons — free cigarettes for GIs, tobacco company marketing, introduction of the filtered cigarette, a laggard response from the medical community — it may also go down in history as the smokiest. As a result, heart disease and lung cancer rates soared in the decades following the war.

Americans in the 21st century will be subject to a different set of health-affecting influences: smaller families, lengthening life expectancy, and health as part of the consumer mind-set. When it comes to a clear-cut case like smoking and lung cancer, it’s easy to keep historical contingencies in mind when scanning the family tree. It doesn’t take a geneticist to figure out that your Uncle Joe probably died of lung cancer in 1970 because he smoked two packs a day since his teens. But if the causes of a disease are less certain — take breast cancer, for example — then there may be no easy way to take these historical influences into account. Interpretations of a family medical history get trickier than ever.

From what we know now, diseases caused by a single genetic change are relatively rare. Diseases that we know are caused by a single genetic mutation (or change) that is passed down from generation to generation include Huntington’s disease (4–7 cases per 100,000); hemophilia A (1 in 8,500 male births) passed by mothers to their sons; Duchenne muscular dystrophy (1 in 3,500 male births), also linked to the mother’s X chromosome; and sickle-cell anemia (1 in 400 African Americans), a recessive disorder for which both parents need to have inherited the genetic change in order for their child to be affected by the disease. Many people are affected by these conditions, but they’re needles in the haystack compared with disorders caused by a combination of many genetic changes plus environmental factors, such as heart disease, cancer, and depression. Diseases due to single genetic changes just aren’t that common.

Keep in mind that when doctors and others talk about “a gene” causing such and such a disease, what they’re really saying is that certain changes in the DNA within that gene cause the disease. (The gene is really just an address on the chromosome.) Different changes have different effects. For example, it’s changes in one particular gene that cause Huntington’s disease. But some will lead to mild disease, whereas others lead to more severe cases.

Early onset is more suggestive of a strong genetic influence. Many of the known inherited disease genes make their presence felt relatively early. For example, breast cancer is more likely to have an inherited genetic cause if it occurs before menopause. In Alzheimer’s disease, it’s a similar story: Onset before age 55 is more suggestive of an inherited genetic mutation than onset after age 80. Why? It may be that scientists have just had more success so far identifying genes that cause disease in younger people. But it is also likely that many diseases are caused by a genetic vulnerability to specific environmental — which is to say, nongenetic — exposures. The longer you live, the greater the chance you’ll encounter — or accumulate to some kind of tipping point — the exposure that results in disease.

Will genetic tests uproot the family tree? Scientists have collected a wealth of genetic information. Yet for the most part, genetic tests aren’t now part of our routine medical care. Why? Because something as low tech (and low cost!) as a blood pressure measurement or stepping on a scale still provides a lot more useful information about disease risk and management than some genetic tests. So far, genetic tests have taken hold in areas where no conventional alternative exists. Prenatal testing is probably the clearest example. Recurrence risks of family diseases and predictions of disease severity are others. Depending on age, disease, and family history, some cancer patients are tested for the handful of known inherited cancer genetic abnormalities, such as mutations in the BRCA genes for breast cancer.

But it’s not out of the realm of possibility that these exceptions will become the rule, and doctors will order a battery of genetic tests in the same way they now order blood work. Why depend on medicine’s equivalent of circumstantial evidence when you’ve got the DNA right in hand?

But genetic tests will not replace the family history — and may even make it more important than ever. Doctors will need to know your family history before deciding which of many tests to order. The expense of testing everyone for every known disease-causing gene is likely to be too high. Moreover, once the genes are identified, the family history will help the doctor assess how those genes might behave and therefore determine future screening and treatment. What’s past is prologue.

Genes are the map, not the journey. Genetic changes help predict whether you are at risk for a disease, but there are very few that we know about now that predict perfectly. More will be identified. Presumably, computers will help us find telling combinations. But the predictive powers will never be 100%. Dr. Pauker compares our genetic code to a road map, how it is expressed to driving:

“No matter how clear the map, you get stuck in traffic jams, encounter construction, find that a bridge is out, or find a high-speed bypass. Environmental realities influence when and even if we reach our goals in life, along with our genetic inheritance.”