A paper published in the New England Journal of Medicine (NEJM) this week, entitled “Performance of Common Genetic Variants in Breast-Cancer Risk Models,” has led several media outlets to declare that common genetic variants have nothing to add when it comes to predicting breast cancer risk.  Here we’ll explain how the results of this study have been misinterpreted.

Researchers from the National Cancer Institute and other institutions looked at data from 5,590 women with breast cancer and 5,998 women without the disease.  These women, all between 50 and 79 years old, had participated in one of five studies, four in the United States and one in Poland.  Since it’s known already which women have or have had breast cancer, and which have not, the researchers were able to use their data, both genetic and non-genetic, to test the predictive power of different types of risk calculations.

The study tested five different models.  The “demographic model” considered only age, year of entry into the study and which study the woman was originally part of.  The “nongenetic model” added in several variables that are part of the so-called “Gail model,” which is the standard model used in clinical practice today to counsel women about their risk.  These variables were the number of first-degree relatives with a diagnosis of breast cancer, age at menarche, age at first live birth, and number of previous breast biopsies.  Two models used the demographic information plus genetic information for 10 SNPs (they differed in details of how the genetic risk score was calculated).  Finally, the “inclusive model” combined demographics, the Gail model and the genetic information.

The genetic models and the nongenetic model performed about the same, with genetics doing just a little bit better.  Perhaps not surprisingly, the best model was the one that used the most information.  With the inclusive model, which is based on genetic and non-genetic information, there was a net 12% improvement in risk classification over the nongenetic model for women with breast cancer.

So, SNPs did add something.  The improvement in prediction seen when SNPs are added to the nongenetic model is about the same as the improvement seen when the Gail model information is added to the simplistic demographic model.  Discounting the benefit of adding SNP information to the Gail model implicitly discounts the utility of the Gail model itself.  Peter Devilee and Matti A. Rookus made this very point in a NEJM editorial that accompanied the study.

It’s also important to remember that the study of common variations and their effect on common diseases like breast cancer is a relatively young science.  Many more variants are bound to be discovered, and these will only help further refine risk predictions.

It’s true that there is a cost associated with collecting a person’s genetic information, while collecting the information needed for the Gail model is essentially free.  (In fact, a risk calculator based on the Gail model is available at the National Cancer Institute website.) But for those people who do have their genetic information in hand, the current study shows that it can improve the estimation of their risk for breast cancer.  It should be remembered, too, that not everyone is fortunate enough to have access to their family medical history. Adoptees, for example, cannot get an accurate picture of their breast cancer risk from the Gail model.  For such women, the ability to use their own genetics to help assess their risk for breast cancer is an option that should not be dismissed.

Ultimately, it’s not about genetics vs. non-genetics — it’s about getting accurate estimates of risk to help doctors catch cancers early on, when they’re easiest to beat. Researchers should welcome any tool that can help them move closer to keeping more women healthy.  Giving up on genetics this early on in the game would be a real disservice.

Note: A similar study can be found in Nature Precedings.  The results are consistent with the NEJM study regarding the improvement in risk prediction when SNP information is added to the Gail model.  This work also shows that the improvement is larger for women at intermediate risk who are more likely to be reclassified.  Senior author David Hinds was at Perlegen Sciences when this paper was written and is currently an employee of 23andMe, Inc.

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Spring is about to, well, spring.  And for many of us, that means breaking out the Benadryl® and the tissues as pollen fills the air and our allergies kick in.

Allergies are part of the daily lives for one out of four Americans, making allergies more common than heart disease, cancer and diabetes combined.  For many people, allergies involve only symptoms that are a nuisance, like sneezing or itchy eyes.  But for some, contact with certain substances can lead to life-threatening anaphylactic shock.  To study this mysterious and growing problem, we’ve released our first allergy survey.

Allergies occur when your body reacts to a normally harmless substance, called an allergen, like it’s a dangerous invader.  Your immune system produces IgE antibodies that recognize the allergen and trigger the release of histamines.  While histamines normally help protect your body against infections, they can cause allergy symptoms when released inappropriately.  This is why many allergy medications are called “anti-histamines”.

The biological process of how symptoms occur after the release of histamines is relatively well-understood, but the question of why the immune systems of people with allergies react to otherwise inoffensive substances like pollen or peanuts remains.  There is a growing body of evidence that supports the “hygiene hypothesis.”  This theory says that our immune systems need early exposure to parasites like roundworms and tapeworms to mature properly.  Without such exposure the risk of developing allergies is increased.  This fits with the observation that allergies are more common and generally on the rise in industrialized countries where parasite infections are far less common than in the developing world.

It is also clear, however, that genetics play a large role in whether you develop allergies.  Having a family history of allergy puts you at much higher risk for also having an allergy, although it may not be the same type. For example, a family history of asthma, which is a type of allergic disease in most cases, puts you at higher risk for a food allergy. While a few genes have been shown to be associated with allergy, the genetic picture is far from complete.  If by learning more about the genetics of allergy we could help predict which children may be more likely to develop a dangerous food allergy for example, precautionary measures could be taken.  In addition, we may discover better ways to treat different allergies.

At best, allergies are annoying.  At worst, they’re deadly.  You can help us take the first steps to understanding the genetics of allergy by completing our new allergy survey.  In the meantime, I’ll be investing in Kleenex!

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Today the National Institutes of Health (NIH) announced its plans to create a public database in which genetic test providers will voluntarily deposit information about their services that can then be searched by researchers, consumers, health care providers, and others. The aim of this Genetic Testing Registry, which is expected to be launched in early 2011, is to enhance access to information about the availability, validity, and usefulness of genetic tests.

“The need for this database reflects how far we have come in the last 10 years,” said NIH Director Francis S. Collins, M.D., Ph.D., in a press release. “The registry will help consumers and health care providers determine the best options for genetic testing, which is becoming more and more common and accessible.”

“We welcome the news of the Genetic Testing Registry,” said 23andMe co-founder Anne Wojcicki in response to the announcement.  “23andMe has always been committed to providing individuals with the information they need to make the most of their own genetic information.  We look forward to working with the NIH on this project.”

More information about the Genetic Testing Registry is available from the National Center for Biotechnology Information here.  Comments and questions can be submitted from this page.  There is also a list of background reading materials.

Francis Collins has done several interviews in the past few weeks where he has discussed the role of genetics in health care, now and in the future. A quick video interview with the Washington Post can be seen here.  An hour long interview he did on the Diane Rehm show is available here.

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The U.S. Food and Drug Administration (FDA) has updated the label information for the commonly used anti-clotting medication Plavix® (clopidogrel) to stress to physicians that patients carrying certain genetic variations may not receive the full benefit from the drug.

Plavix reduces the chance a harmful clot will develop by preventing blood cells called platelets from sticking together. Usually prescribed in combination with aspirin, Plavix has been shown to help reduce the risk of subsequent heart attacks or strokes in people who have already suffered from a cardiovascular event. Plavix also reduces the risk of heart attack and stroke in people diagnosed with peripheral artery disease.  The drug is also is used to lower the risk of blood clots in people with unstable angina (chest pain) caused by partially blocked arteries and in those who have had a stent implanted to help keep their arteries open.

Once inside the body, Plavix is absorbed in the intestines and then converted into its active form by enzymes in the liver. But some people have genetic variations that reduce the activity of one of the most critical enzymes — CYP2C19. This, in turn, reduces the amount of active drug in the bloodstream and its effectiveness in preventing clots.

The FDA first added information about poor metabolizers of Plavix to the drug label in May 2009. Additional data has prompted them to add the boxed warning to further caution physicians that some of their patients may be at risk, inform them that testing for CYP2C19 variations is available (although no test is FDA-approved specifically for determining Plavix efficacy), and recommend that other medications or increased dosages of Plavix be used in patients identified as poor metabolizers.

“We want to highlight this warning to make sure health care professionals use the best information possible to treat their patients,” said Mary Ross Southworth, Pharm.D., a clinical analyst in the Division of Cardiovascular and Renal Products in the FDA’s Center for Drug Evaluation and Research, in a press release.

A recently approved drug, Effient® (prasugrel), may be an alternative for some patients identified as poor metabolizers. Like Plavix, Effient prevents platelets from forming blood clots. The advantage is that the conversion of Effient to its active form can take place in the presence of the genetic variations that affect Plavix. Studies have shown that Effient is effective at preventing heart attacks, strokes and stent-blocking clots.  The risk of dangerous bleeding, however, is higher with this drug.

23andMe Health Edition and Complete Edition customers can view their data for genetic variations in CYP2C19 in the Clopidogrel (Plavix) Efficacy Drug Response Report.

A downloadable PDF version of the Clopidogrel (Plavix) Efficacy report is available to help customers share their results with their doctors.

Only a physician can determine whether Plavix is the right medication for a particular patient and at what dosage it should be given.  The information contained in 23andMe Drug Response reports should not be used to independently establish a drug regimen or abolish or adjust an existing course of treatment.  If you are concerned about Plavix, talk to a health professional.

• Read more about the Plavix label update here and here.
• Just last month the FDA updated the label on another anti-clotting medication, warfarin, to include more information on the effects of genetic variations.  Read more here in the Spittoon.

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Colorectal cancer is the third most common cancer (excluding skin cancers) and the second leading cause of cancer-related deaths in the United States. Each year about 150,000 people are diagnosed with the disease.

Risk factors for colorectal cancer include age (most cases occur in people over 50), ethnicity (African Americans and Ashkenazi Jews have particularly high rates of the disease), a personal history of colon polyps or colorectal cancer, and the presence of inflammatory bowel disease (Crohn’s disease or ulcerative colitis).  Obesity, physical inactivity, smoking and heavy drinking have also all been associated with increased risk for colorectal cancer.

Genetics contribute to a person’s colorectal cancer risk, although non-genetic factors seem to play a larger role.  About 5% of people with colorectal cancer, however, develop the disease as a result of either familial adenomatous polyposis (FAP) or Lynch syndrome, two cancer syndromes caused by serious genetic mutations.

Anyone with a family history of colorectal cancer should talk to their health care professional about what screening procedures, and possibly what genetic tests, are right for them.

Research to find common genetic variants associated with colorectal cancer risk has yielded several good associations, but together they explain only a small part of the genetic contribution to the disease. There are probably many more variants with small effects left to be found, as well as rare variants with larger effects.  23andMe customers can see their results for three replicated SNP associations in the Colorectal Cancer Research Report.  Spittoon posts addressing colorectal cancer can be found here, here, here and here.

Learn More About Your Risk

Several online tools are available to help you get a better idea of your risk for colorectal cancer.

• National Cancer Institute
• Washington University School of Medicine Siteman Cancer Center
• My Family Health Portrait – a free online tool provided by the Surgeon General that can help you assemble your family’s health history

Get Involved

You can contact the following organizations to learn more about colorectal cancer and find out how to get involved in Colorectal Cancer Awareness Month.

• Colon Cancer Alliance
• American Cancer Society

And for those who want an up-close lesson about colorectal cancer, click here to see if the Prevent Cancer Super Colon™ is coming to a town near you.

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Faces of America is a four-part series in which Harvard scholar Henry Louis Gates, Jr. uses genealogy and genetics to explore the family histories of 12 renowned Americans in an effort to understand what made the United States the place it is today.

The final episode, “Know Thyself” airs this Wednesday (March 3) on PBS.  In this segment, DNA is used when the genealogical paper trails ends to give the participants an even deeper understanding of who they are and where they came from.

All of the participants who chose to learn about their genetics were analyzed using the 23andMe Ancestry Edition.  Our scientists Joanna Mountain and Brenna Henn (who make some cameo appearances!) helped with the analysis of the participants’ mitochondrial and Y chromosome haplogroups, global origins and ancestry paintings.

In addition to learning about their ancestors, Faces of America guests who choose to participate in our new Relative Finder feature will join the thousands of other people who now have the ability to find living relatives based on their DNA.

If you haven’t been watching this series, there’s still time to catch up on what well-known Americans Elizabeth Alexander, Mario Batali, Stephen Colbert, Louise Erdrich, Malcolm Gladwell, Eva Longoria, Yo-Yo Ma, Mike Nichols, Her Majesty Queen Noor, Dr. Mehmet Oz, Meryl Streep and Kristi Yamaguchi have learned about their family histories.  The first three episodes are all available online:

Episode 1: Our American Stories

Episode 2: Becoming American

Episode 3: Making America

Check your local listings for Faces of America here.

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The journal Current Biology has a special review issue on the global genetic history of Homo sapiens.  The articles are written for a fairly technical audience, but if it’s a topic you’re interested in, you might want to check it out.  All of the articles are available online for free.

• Archaeogenetics — Towards a ‘New Synthesis’?
• The Evolution of Human Genetic and Phenotypic Variation in Africa
• The Archaeogenetics of Europe
• The Human Genetic History of South Asia
• The Human Genetic History of East Asia: Weaving a Complex Tapestry
• The Human Genetic History of Oceania: Near and Remote Views of Dispersal
• The Human Genetic History of the Americas: The Final Frontier
• The Genetics of Human Adaptation: Hard Sweeps, Soft Sweeps, and Polygenic Adaptation

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Researchers from Penn State University, the University of New South Wales in Australia, and the Baylor College of Medicine have sequenced the genomes of four individuals from different groups of the click-speaking San of southern Africa, as well as of Bishop Desmond Tutu of South Africa.  Their results, published online yesterday in the journal Nature, are providing striking new insights into human genetic diversity.

Joanna Mountain, 23andMe’s Senior Director of Research, has been studying the genetics of click-speaking peoples of Africa for over ten years.  Dr. Mountain said the new study “has demonstrated that any two San individuals are as genetically different from one another as a European and a Chinese individual. Clearly the linguistic diversity of the San is matched or even exceeded by their genetic diversity. Furthermore, even though the San Bushmen are often described, even by this study’s authors, as the ‘oldest known lineage of modern humans,’ the new genetic data reveal that the San have evolved genetically as much as any group, partly through the random mutations that occur over time, but also through changes that enabled them to handle their often challenging, exceedingly dry environment.”

Read more about this study:

• New York Times
• Technology Review
• Not Exactly Rocket Science

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Tufts of hair rescued from the permafrost in Greenland and then tucked away in a basement in Denmark for more than 20 years have given scientists their first glimpse into the genetics of an ancient human.

Eske Willerslev and Morten Rasmussen of the Centre for GeoGenetics at the Natural History Museum of Denmark and the University of Copenhagen, along with an international team of collaborators, have sequenced 80% of the genome of a man from the Saqqaq Culture who walked the earth about 4,000 years ago.  By comparing this ancient DNA sequence to what is known about the genetics of modern humans, the researchers were able to piece together a picture of what the man they call Inuk (“human” or “man” in Greenlandic) likely looked like, where his people came from, and how he’s related to modern populations.  The results were published online today in the journal Nature.

Inuk’s DNA revealed that he had type A+ blood.  He likely had brown eyes and thick, dark hair.  His skin was probably not the light color found in modern day Europeans.  Inuk’s earwax was dry and he had shovel-graded front teeth, both characteristics common in Asian and Native American populations.  Several of the genetic variants he carried suggest that he had a metabolism and body mass well-suited to cold climates. The researchers even found that Inuk’s genetics are indicative of an increased risk of baldness.

“Because we found quite a lot of hair from this guy, we presume he died quite young,” Willerslev said in a press briefing.

(Although as Harvard professor and Luxuriant Flowing Hair Club for Scientists member Steven Pinker found when analysis of his DNA also suggested a propensity for baldness, DNA is not always destiny.)

Analysis of Inuk’s Y chromosome revealed that his paternal haplogroup is Q1a, which is commonly found among Siberian and Native American populations. Previous analysis by the same research group had revealed that Inuk’s maternal haplogroup, determined by his mitochondrial DNA, is D2a1.  This same lineage is commonly found in modern-day Aleuts of the Commander Islands in the Bering Sea and the Siberian Sireniki Yuits (Asian Eskimos).

Since discovery of the remains of the Saqqaq Culture in the 1950s, there has been disagreement over how these people were related to others that crossed the Bering Strait into the New World.  By analyzing Inuk’s DNA and comparing it to modern populations, the researchers determined that the Saqqaq are most closely related to the Nganasans, Koryaks and Chukchis of Siberia.  The long-gone Saqqaqs most likely left Siberia for the New World about 5,500 years ago, independently from the ancestors of present-day Native Americans and Inuit.

Now that his team has shown that full genome sequence analysis of ancient samples is feasible, Willerslev expects that there will be an explosion of work in the field.  He says that sequencing of DNA from South American mummies could help illuminate the population history and genetic diversity of Native Americans from before the arrival of Europeans.  Willerslev also suggests that sequencing ancient human DNA could reveal when certain genetic diseases become prevalent in different populations.

Do you share genetic characteristics with Inuk?  The table below lists the SNPs the researchers used to come up with their physical description of the ancient man.  SNPs currently covered by 23andMe are linked to the Browse Raw Data feature, where Complete Edition customers can check their own genotypes.  Inuk’s genotype at each SNP is presented in the format used on the 23andMe website, which may not match the original paper.  The notes column lists 23andMe content related to each trait and/or SNP.

* The genotype the study authors listed for this SNP (which was originally listed in this tabel) actually indicated that Inuk would have had type O blood.  We contacted the authors and they confirmed that this was simply a typo.  The table now reflects Inuk’s true genotype.

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The list of participants includes:

• Elizabeth Alexander, professor and poet
• Mario Batali, chef
• Stephen Colbert, comedian
• Louise Erdrich, novelist
• Malcolm Gladwell, journalist
• Eva Longoria, actress
• Yo-Yo Ma, musician
• Mike Nichols, director
• Her Majesty Queen Noor
• Dr. Mehmet Oz, television host/heart surgeon
• Meryl Streep, actress
• Kristi Yamaguchi, figure skater

Sneak peaks of each participant’s unique story are available on the Faces of America page at pbs.org.

All four episodes promise to be very interesting.  If you’re a fan of 23andMe, be sure to catch the episode featuring genetic ancestry analysis by our scientists on March 3.  Each participant was offered the same maternal and paternal ancestry and global origins information we give every Complete and Ancestry Edition customer.  And now that Relative Finder has had its official launch, these famous Americans can also use their DNA to connect with living cousins from all around the world.

Faces of America with Henry Louis Gates, Jr. premieres nationally Wednesdays, February 10 – March 3, 2010 from 8-9 p.m. ET on PBS.  Check your local listings here.  The first full-length episode will be available online on Thursday, February 11.

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