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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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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Today at the American College of Cardiology conference in Atlanta, researchers from the Mayo Clinic and Medco Health Solutions, Inc., presented results showing that using genetic testing to guide dosing of the commonly used blood thinner warfarin reduces hospitalizations.

Overall there were 31% fewer hospitalizations within six months of beginning warfarin therapy in those who received genetic testing compared to those who didn’t. A 28% drop in hospitalizations due specifically to bleeding or blood clots was seen.

“Warfarin represents an excellent example of how to take the modern science of genetic testing and apply it to making an older drug more effective and safer to use,” said Dr. Robert S. Epstein, lead author of the study and Medco’s chief medical officer and president of the Medco Research Institute, in a press release.  ”These results show that we can greatly reduce hospitalizations, and their significant costs, by making genetic testing routine early in a patient’s therapy with warfarin.”

Although a variety of factors influence a patient’s ideal dose of warfarin, variations in the CYP2C9 and VKORC1 genes play an important part.  The FDA has mandated that information about these variants be included in the labeling information of the medication since 2007.  In February of this year they updated the drug’s label to include specific dosage recommendations.

Genetic testing before administration of warfarin, however, is not mandatory.  There has been significant disagreement over whether or not health outcomes are actually impacted when genetic information is available to physicians.  In fact, the Centers for Medicare and Medicaid Services, the federal agency that makes decisions about what Medicare, Medicaid and the Children’s Health Insurance Program will cover, decided last year that there was not sufficient evidence to justify covering genetic testing before warfarin administration for Medicare beneficiaries. It will be interesting to see if the new study, which will soon be published in the Journal of the American College of Cardiology, will change this stance.

theheart.org has more on this story, including comments from researchers critical of the research.  The PowerPoint slides used in the researchers’ presentation are also available for download. (Free registration required)

You can also read more here.

23andMe Health Edition and Complete Edition customers can view their data for genetic variations in the CYP2C9 and VKORC1 genes in the Warfarin (Coumadin®) Sensitivity Drug Response Report.

Only a physician can determine whether warfarin 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.

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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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Researchers have identified several genetic variations associated with the timing of a baby’s first tooth and the number of teeth at age one. The results, published recently in the journal PLoS Genetics, could be important for understanding more about human health than just this rite of passage all babies must go through.

Nascent teeth form in the womb, but for most babies the first one doesn’t poke through the gums until sometime between four and seven months of age. Some little ones, however, begin teething as early as three months, while others may take a year or more to sprout their first pearly whites. Although the genetic bases for many syndromes involving serious problems with tooth formation have been discovered, until now not much work has been done to understand how our DNA impacts the normal variation in teething seen in the population.

British and Finnish researchers analyzed the DNA of about 6,000 people (approximately 1,500 from the U.K. and 4,500 from Finland) who had been followed by epidemiologists since early in their mothers’ pregnancies. Genetic variants in 10 different regions of the genome had at least a suggestive link to age at first tooth eruption and/or number of teeth at one year. Those SNPs with statistically significant associations with at least one of the traits are shown in the table below.

*= association not significant for tooth eruption; **= association not significant for number of teeth at age one.

Subjects are classified by the number of delayed tooth eruption alleles. SNPs are chosen so that they had the strongest signal for number of teeth at each locus. Mean time of first tooth eruption is plotted in red and number of teeth by the age of one year in black. The bars represent the number of individuals for each count of ‘delayed tooth eruption’ alleles. The line through points is a linear regression fit. doi:10.1371/journal.pgen.1000856.g002

Much as has been the case for genetic associations with height, another highly heritable and complex human trait, the variations the researchers linked with teething characteristics explain only a tiny fraction—about 3-4%—of the total variance seen in the population. More studies, with larger samples, will be needed in order to identify more SNPs, including those with smaller effect sizes and rare variants.

Based on the significant SNPs listed above, the authors defined a summary statistic called the “delayed tooth eruption measure,” which is calculated by adding up how many copies of the “delayed” version of each SNP a person carries. For women the total possible is 10 (two copies of each of five SNPs). Because one of the SNPs is on the X chromosome, for men the total possible is nine.

Based on the Finnish sample, the researchers calculated that individuals with a delayed tooth eruption measure of eight or more have an average of 1.5 fewer teeth at 12 months of age, and later tooth eruption by 1.1 months, compared to individuals with a score of three or less.

The researchers also evaluated whether or not any of the SNPs found in their study of infant teething were associated with the need for orthodontic treatment by age 31 in their Finnish sample. The only significant finding was a SNP that showed only suggestive evidence for an association with timing of first tooth eruption and number of teeth at age one (i.e., it is not in the table above). Each G at rs6504340 increased the odds of requiring orthodontic treatment by 1.35 times.

All of the SNPs identified in this study are in or around genes known to have roles in organ formation, growth and development, or cancer. The authors suggest that studies of teething and other aspects of infant development may have far reaching implications.

“The discoveries of genetic and environmental determinants of human development will help us to understand the development of many disorders which appear later in life. We hope also that these discoveries will increase knowledge about why fetal growth seems to be such an important factor in the development of many chronic diseases, ” said Professor Marjo-Riitta Jarvelin, the study’s senior author, in a press release.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

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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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People chronically infected with the hepatitis C virus currently have only one treatment option:  a combination of polyethylene glycol (PEG)-ylated interferon alpha and ribavirin (RBV).   Not only does this drug regimen fail to eradicate the virus in about half of all patients who receive it, but even when it does work the side effects can be so bad that treatment has to be scaled back or abandoned altogether.

In up to two-thirds of all hepatitis C patients, RBV treatment leads to the destruction of red blood cells and a decrease in the amount of oxygen that can be transported throughout the body, a condition called hemolytic anemia.  New research, published online yesterday in the journal Nature, shows that genetic variants that cause a normally benign enzyme deficiency actually offer some protection against this condition.

Duke researchers Jacques Fellay, Alexander Thompson and Dongliang Ge, along with colleagues from the Schering-Plough Research Institute and the Johns Hopkins School of Medicine, studied about 1300 European-Americans, 200 African-Americans, and 100 Hispanics receiving hepatitis C treatment.  The patients had their hemoglobin (the oxygen-carrying protein in red blood cells) levels measured at the beginning of their treatment and at the four-week mark, the point when many patients must begin treatment to stimulate red blood cell production due to RBV-induced anemia.  The researchers also analyzed the patients’ DNA to look for genetic variants associated with hemoglobin level changes.

Several variants on chromosome 20 showed a significant association with maintenance of good hemoglobin levels after RBV treatment.  Deeper analysis of this DNA region revealed that the effect could be traced to two variations in the ITPA gene.

The ITPA gene encodes an enzyme that helps breakdown a substance called inosine triphosphate in cells.  The less common versions of the two variations the researchers identified (A at rs1127354 and C at rs7270101) both reduce the function of the ITPA enzyme.  In most people this isn’t a problem.  For people taking drugs called thiopurines, which are used to prevent organ rejection in transplant patients and to treat leukemias and autoimmune disease, reduced ITPA activity may lead to toxicity.  What the new study found is that for people receiving treatment for hepatitis C, less ITPA enzyme function is actually a good thing.

Of the people in the current study predicted to have less than one-third of the normal ITPA activity due to their genetics, none ended up with hemoglobin levels below the level traditionally set as a threshold for RBV dose reduction.  Of those with normal ITPA levels, 11.7% had their hemoglobin levels dip into the danger zone.

(23andMe does not currently provide data for rs7270101.  But we do provide data for rs1127354.  Complete Edition customers can use the Browse Raw Data feature to see their genotype for this SNP. Each SNP was shown to have an independent effect on hemoglobin levels in the face of RBV treatment.)

More research into the genetics of RBV-induced anemia will be needed.  Although the exact effect varied among the different populations studied, the researchers estimate that about 20-30% of the variability in hemoglobin level reduction in response to RBV treatment was explained by rs1127354 and rs7270101.  There was no significant association between these SNPs and the efficacy of hepatitis C treatment.

(Other SNPs have been associated with treatment outcomes; see here and here in the Spittoon, or the 23andMe Response to Hepatitis C Treatment Drug Response Report.)

Because having low levels of ITPA enzyme activity does not seem to cause any problems for most people, the authors suggest that drugs that inhibit this enzyme could be developed so that people receiving RBV treatment for hepatitis C could be protected against anemia, even if they do not carry the protective genetic variations.

Illustration of ITPA protein structure: Emw

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

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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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