Appearing today in the New England Journal of Medicine is a stealthily encouraging study for the use of genetic testing to improve the assessment of the risk of the common forms of breast cancer. Stealthily, I say, because the authors seem oddly determined to provide a gloomy interpretation of their own data. The study, entitled ‘Performance of Common genetic Variants in Breast-Cancer (sic) Risk Models,’ by Wacholder et al, uses data from several major breast cancer studies to answer an interesting question: does adding the measurement of common SNPs linked to risk of breast cancer add to the risk assessment provided by the traditional ‘Gail score’ criteria – age, family history, age at menarche, age at first live birth and the number of previous breast biopsies?

The answer is clearly yes, though the authors of the paper seem not to want you to know that. Most importantly, the authors define as elevated risk those women between the ages of 50 and 79 who are at a greater than 0.575% chance of developing breast cancer in any given year. Using the Gail criteria alone, 18.9% of study participants were considered to be at elevated risk. But with the addition of the genetic risk factors – which are ten of the twelve risk factors tested for by deCODE Breast Cancer test – another 9% of participants could be identified as being in the higher risk category. A 50% improvement.

Similarly, using an Area Under the Curve calculation (customarily used to evaluate the accuracy of methods for diagnosing disease) the Gail model yielded an AUC of 58%, and the Gail-plus-genetics model yeilded an AUC of 61.8%. In an AUC model, the amount over 50% (the baseline of a test that is no better than random) is the measure of relative discriminatory power. So an increase from 8 to 11.8 is, yes, a small number, but also an improvement of something in the neighborhood of 45%. The study also shows that compared to each other, the set of genetic risk factors were more accurate predictors of breast cancer than were the Gail factors that are the current mainstay of risk assessment.

So I can see why the authors wouldn’t want to celebrating these results too loudly – because we need to do better. But what this study shows is that genetics is already taking us in the right direction, and that the addition of genetic risk to current clinical practice can – right now, today – provide a substantial improvement in the crucial task: to better risk stratify the population, focus screening on those who should have it, pick up more cancers earlier and save lives. I can’t see anythig but good news in that. Our task is to keep discovering new risk factors that will continue to increase the power of these tests, and we are committed to doing so.

Dr. Kari Stefansson

Hypertension genetic risk now a part of the deCODEme Complete Scan

Hypertension, commonly referred to as high blood pressure, has been added to the deCODEme Complete Scan. Hypertension is defined as blood pressure of 140/90 mmHg or above on three consecutive measurements at least six hours apart. Blood pressure this high is a risk factor for many diseases. Over time, the increased workload on the heart weakens it and contributes to atherosclerosis (the thickening of the arteries due to fat and cholesterol depositions), thereby increasing the risk of coronary heart disease and stroke, which are among the leading causes of death in the United States. High blood pressure can also lead to other conditions, such as heart failure, kidney disease, and blindness. High blood pressure is especially dangerous because it often has no obvious warning signs or symptoms and can therefore remain undiagnosed and untreated long enough to cause damage. High blood pressure is common, but too often goes undetected. An estimated 1 billion people worldwide have hypertension, and this number is expected to increase to 1.56 billion people by the year 2025. This translates to about 1 in 4 adults being afflicted with hypertension worldwide. Currently, about 1 in 3 Americans are thought to have hypertension, and a third of them probably do not know it.

The deCODEme team has been busy working to update and improve your deCODEme experience.  Additions include ABO blood types, Kidney stones, Eye color and Statin-induced myopathy. We have also added  a section for feedback and research and a more detailed Male line analysis.

Here is a summary of the additions and changes:

FEEDBACK AND RESEARCH

Many deCODEme customers have contacted us, asking whether they could contribute to our research efforts and receive statistical feedback about the deCODEme user community. In response to these wishes, we have introduced optional survey questions about the various traits included in the deCODEme scans. To see the entire list of questions, click the “Feedback and Research” link on the home page that appears when you first log into your deCODEme account. Alternatively, you can see the questions for each trait when you view your results by clicking on the new “Research” tab. Participation is optional and entirely voluntary and you can, at any time, have the questions removed from your account by checking the box marked “I do not want to participate in feedback & research”.

Updates for deCODEme Complete Scan

ANCESTRY UPDATES

A new look for the Female Line and Male line ancestry analyses
The deCODEme web-design and ancestry teams have made several changes to the look and feel of the Female Line and Male Line ancestry analyses. Our aim was not only to make the presentation of your results clearer and more visually pleasing, but also to accommodate new features, some of which have already been introduced (link to More detailed Male Line analysis).

More detailed Male Line analysis
The deCODEme ancestry team has recently updated and expanded the classification of Y-chromosomes in the Male Line analysis. We have added two new Y-groups to our Male Line classification system, bringing the number Y-groups to 24. More importantly, male deCODEme customers can now have their Y-chromosomes classified into one of over 105 Y-subgroups. This provides a much more detailed picture of your genealogical relationship to other people through the male line. Thus, for example, if your Male Line result previously assigned you to Y-group R1b, you can now find out which of the 15 different R1b subgroups you belong to. You are much more closely related to other members of your subgroup through the male line than you are to those who do not belong to that subgroup – even if they belong to the same Y-group as you. Click on the “subgroup tree” tab on your Male Line results page to learn more about your Y subgroup.

HEALTH WATCH UPDATES

New diseases and traits in Health watch

Kidney stones
Kidney stones are small crystals formed of dissolved minerals, mainly calcium, that form in the kidneys. Smaller stones can simply be passed through urination, though larger ones can block the urinary tract, causing considerable pain and bleeding. Kidney stones affect some 5% of women and 10% of men in the industrialized world. We are proud to announce that our scientists at deCODE genetics have just published new scientific results that shed light on genetic variants that affect the risk of developing kidney stones. Within hours of the first report of this exciting new discovery in the scientific literature [link to manuscript on Nature genetics website], deCODEme customers can log into their Complete Scan accounts and examine an estimate of their genetic risk for developing kidney stones! The discovery involves a common genetic variant in the CLDN14 gene on chromosome 21 that is associated with increased concentration of urinary calcium, which in turn leads to an increased risk of developing kidney stones.

ABO blood types
There are four different ABO blood types, named A, B, O and AB. Many people know their ABO blood types, because they are typically assessed by healthcare workers when a person receives blood or donates blood or an organ. This is because it is critically important to match ABO blood types of donors and recipients of blood or organs. Your ABO blood type depends on which kind of glycoprotein or antigen is found on the outside of your blood cells. These glycoproteins come in three forms and are referred to as A, B and O. The gene that determines your ABO blood type is found on chromosome 9 and is called ABO glycosyltransferase. In the simplest terms, this gene may be said to come in three different forms, that is, it has three different alleles. These alleles are also named A, B and O, because each is responsible for the production of its namesake glycoprotein (antigen). It is therefore the combination of alleles that you inherited from your parents that determines which glycoproteins are found on your blood cells and thereby your ABO blood type. The deCODEme genetic scan determines which combination of the three ABO alleles you carry on chromosome 9 and therefore which blood type you are likely to have.

Eye color
Eye color refers to the color of the iris. The color of the iris is determined by the amount and distribution of melanin, a dark brown pigment, which is produced by a special type of cell called the melanocyte. In simple terms, a brown iris contains abundant melanin, whereas a blue iris contains much less melanin. Albinos have an almost complete lack of melanin, resulting in a red or pink iris color (due to the greater visibility of blood vessels through the almost transparent iris). The vast majority of people in the world have brown eyes. It is primarily those of European descent that we find normal variation in eye color, in the form of blue, grey or green colored eyes. While eye color is a trait determined by several genes, some genes seem to play a more important role than others. The deCODEme Genetic Scan identifies a genetic variant associated with blue and brown eye-color in the HERC2 gene on chromosome 15. The results provide an interpretation of the associated likelihood of blue/grey or brown eye color in individuals of European descent.

Statin-induced myopathy
Statins are a group of compounds that are commonly prescribed by physicians for individuals with high cholesterol to reduce risk of cardiovascular diseases. While statins are generally safe and effective, there are some known side-effects. One that affects a minority of those taking statins is a muscle disease called statin-induced myopathy, the symptoms of which include muscle pain and weakness.

As always, we welcome your comments and suggestions and encourage you to visit your deCODEme account frequently to take advantage of regular updates and new features.

Click on the image to watch the 60 Minutes Australia segment on genetic testing

The Killer In You

60 Minutes Australia recently visited the deCODE genetics labs in Iceland and interviewed deCODE’s CEO Dr. Kari Stefansson. Among the people who did the deCODEme genetic test were journalist Liz Hayes, world surfing champion Layne Beachley and Australian television’s favorite builder, Scott Cam. To watch the 60 Minutes Australia segment click on the image above. To read the transcript of the webchat with Professor Bob Williamson click here. To learn more about deCODEme genetic tests and order your personal genome scan visit www.decodeme.com.

deCODEme calculates your genetic risk for Multiple Sclerosis

The Multiple Sclerosis Association of America (MSAA) encourages Multiple Sclerosis (MS) Awareness during March 2009.

Multiple sclerosis (MS) is the most common neurological disorder diagnosed in young adults.  It is an inflammatory disease of the central nervous system; the brain, nerves and spinal cord, that damages the protective insulation (known as “myelin”) surrounding the nerves. As a result, nerve impulses carrying messages from the brain and spinal cord are disturbed, causing a variety of symptoms such as visual disorders, weakness, dizziness, and various movement disorders, to name but a few.

The causes of MS are not fully understood. With better understanding of the disease, more effective ways will be found to treat it in the future, and hopefully prevent it from occurring in the first place. Significant steps towards better understanding of MS have however been made.

Researchers have for example found that although the disease is not directly inherited, genetics play an important role in who gets the disease.  Studies have revealed that the risk of developing MS for an average person is 1/750 but the risk rises to 1/40 for a person who has a first-degree relative (parent, sibling, child) with the disease. Even though identical twins share the same genetic makeup, the risk for an identical twin is only 1/4, showing that factors other than genetics are involved.

The deCODEme Complete Genetic Scan includes a test that calculates a person’s genetic risk for MS according to the best scientific data available to date. While the test cannot determine whether you will or will not develop MS, it can, on the basis of a comparison of your personal genetics to the genetics of large groups of people with and without MS, give you an estimate of your lifetime risk of developing this disease. This, combined with other risk factors, can give you an estimate of your overall risk.

Other factors involved in the development of MS that have been identified are

• MS is more common in people of Northern European descent than in people of other ethnicities, and more common in women than men.

• Viruses and bacteria have been suspected of contributing to the development of MS because patients with MS typically have a higher number of immune cells than a healthy person. Some researchers theorize that MS may develop in genetically susceptible people, after they have been exposed to a viral or bacterial infection.

• MS is more common in countries with temperate climates, including Europe, southern Canada, northern United States, southeastern Australia and New Zealand. The reason for this is unknown, but geographic studies suggest that it may be due to environmental factors, genetic factors, or both.

Visit The Multiple Sclerosis Association of America for more about the disease
Visit deCODEme to learn more about the Multiple Sclerosis Genetic Test.

deCODEme takes on Heart Disease in February

February is American Heart Month. With heart disease being the leading cause of death in the United States it is important to assess your genetic risk of developing Cardiovascular conditions. To mark this we have decided that during the month of February our deCODEme Cardio Scan™ will be offered for a promotional price of $100.

deCODEme Cardio Scan enables individuals to better understand their inherited risk of heart attack, stroke and atrial fibrillation, intracranial and abdominal aortic aneurysm, and venous thromboembolism.

Genetics contribute to the risk of Coronary heart disease and heart attacks

Coronary heart disease is a progressive disease that begins early in life but symptoms generally do not appear until middle age or later. Coronary heart disease is the main cause of death in the developed countries and it is estimated that over 1.35 million North Americans will as a result of coronary heart disease, have a heart attack in the year 2008.

Several studies have found evidence of a genetic contribution to CHD and heart attacks. Two common genetic variants have been discovered that are associated with an increased risk of heart attack; one variant near the CDKN2A/2B genes on chromosome 9 and another in the CELSR2/PSRC1 genes on chromosome 1. The variant near the CDKN2A/2B genes is a particularly strong risk factor for early-onset heart attacks (occurring earlier than 50 years of age in men and 60 years of age in women).

Adopting a heart-healthy lifestyle can reduce risk

Even though age, gender, and family history are unmodifiable risk factors for coronary heart disease and heart attacks, the risk of developing CHD and eventually a heart attack can be reduced with a lifestyle that includes physical activity, a heart-healthy diet, and no smoking.

deCODE customer rep Larus Jon Gudmundsson and genetic counselor Kris Kristjansson MD

Tapping the vast resources of deCODEme scientists

The users of deCODEme show great interest in their results and are not afraid to ask questions. deCODEme customer support welcomes all questions and inquiries and taps the vast knowledge base and resources of its research teams to respond to all emails as comprehensively and quickly as possible. Among the more general questions we receive is the following.

Question
“I’m seriously thinking about doing the DNA test. Now I only have to decide from which company. How does your test compare with tests from other companies?”

Response
There are a few key differences between the services of deCODEme and its competitors.
deCODEme is provided by a company called deCODE genetics. Scientists at deCODE genetics have been carrying out research on human genetics for over a decade and have already produced a very large portion of validated discoveries of variations in the human genome that confer risk for common diseases. Our mission at deCODE genetics is to use genetics to help people to improve their health, and one of the ways we do that is by offering the deCODEme service. The same scientists, statisticians and geneticists who actually discovered the genes engaged in making that information useful to the public. At the same time they are continue to publish the results in the best scientific journals and have been doing so many years. Now, additionally, they simultaneously make those articles available on the deCODEme customer’s profiles.

However, it is also important to note that not only do we use our own internal expertise to develop our products, process your sample and analyze the resulting data , but we also give you direct access to this expertise, should you have any clinical or scientific questions. Our clinical support team includes an MD medical geneticist and genetic counselors that you will have access to at no extra cost. In contrast, most other companies offering DNA analysis are only acting middle-men and have to outsource much of the sample processing.

Another key difference is that the deCODEme analysis consists of information on 1 million markers, while our can only offer less than two thirds of that total. This means that if you have a deCODEme profile we can provide you with higher coverage now and significantly higher quality analysis of future research findings as we make new discoveries.

Our strategy is to offer a product that is as good and as useful as possible, which is how we provide real and long-term value to deCODEme customers. We have posted an entry on this subject on our blog.

The results are presented in a simple and clear format.
deCODEme provides a report on your sample on the www.decodeme.com website that you can unlock with your password. The report will contain your actual genotypes for the SNPs in question. Additionally, you will be provided with the raw data of the complete scan, i.e. about 1 million SNP genotypes. Reference to published scientific findings relevant to your results are also a part of the report, and are individually linked to each marker that is analyzed.

The report contains a disclaimer that although a SNP is individually associated with disease risk in deCODE´s own population studies, deCODE cannot predict how that SNP will interact with variants at other SNPs in any particular person.

There is a Site Tour available now on the website under “What is deCODEme” on our website. In addition there is a FAQ (frequently asked questions) section on the website.

The deCODEme browser.
We have recently introduced the deCODEme Genome Browser, a highly sophisticated on-site tool that enables to explore your results in detail. The Genome Browser is accessible on on the deCODEme website.

Best regards,

deCODEme customer support.

On October 8th MSNBC published an article by Arthur Caplan, Ph.D. on genetic tests for breast cancer.
The following is a response by Jeff Gulcher, M.D., Ph.D, Chief Scientific Officer at deCODE Genetics.

Arthur Caplan stresses caution in the application of the new genetic risk tests for common diseases and I certainly agree that genetic testing should be applied with care. However, he goes too far when he says that the new deCODE BreastCancer genetic risk test is only useful for women who have two or more close relatives with breast cancer, is not based on large enough studies to be accurate, and is not regulated.

There are two major types of breast cancer: the rare, early onset form that occurs in certain families and for the detection (for which the Myriad Genetic test is well suited), and the common form which accounts for 95 percent of breast cancer. The vast majority of women who develop breast cancer do not have the conventional risk factors of family history, pregnancy history or breast density. Unfortunately, many of these women were likely considered to be of average risk before their cancer was found. Therefore, they were not even offered screening with breast MRI which detects two to three times more cancer at an earlier stage than mammography alone, or preventive measures such as tamoxifen treatment which can cut down cancer rates by 40 to 50%.
To date, the healthcare system has not been as good as it would like to be at predicting which women are at higher risk of the common forms of breast cancer: But we at deCODE and others have invested years of research and tens of millions of dollars to find other factors that can complement the conventional factors. Our efforts have paid off, because there are 7 genetic markers, easily and accurately measured from a cheek swab, that define most of the genetic risk for the common forms of breast cancer. The test defines risk from 0.4-fold to 4-fold compared to the general population risk (the average woman of European ancestry in the US has a lifetime risk of 12%). Based on this test alone, 10 percent of women have risks ranging from 1.4- to 4-fold, and would account for about 17 percent of breast cancer cases. Five percent of women are at more than 2-fold average risk, and the 1 percent are at 3-fold risk, so the risk is substantial for a significant portion of the population.

This risk is independent of family history and other conventional risk factors and therefore may identify some women as having higher risk even if breast cancer does not appear to be in their families. So Arthur Caplan is fundamentally incorrect in stating that only women with a family history of breast cancer would benefit from genetic testing. That may be true for traditional genetic diseases like Huntington’s disease and the rare highly familial form of early breast cancer addressed by the Myriad test, but the new tests for common diseases define risk beyond family history.

Each of the genetic markers in this risk test have been replicated in between 5 and 30 different populations in studies by deCODE genetics, the National Cancer Institute, and UK Cancer Research. These studies have been published in the most prestigious, peer-reviewed journals, including Nature Genetics and the New England Journal of Medicine. Altogether almost 100,000 patients and controls have been studied to define the marker risks. We made this test available for physicians to order for their patients through our reference laboratory which is regulated under CLIA by the US Federal government.

However, it is important to emphasize that the test does not diagnose breast cancer: it is simply a means of assessing personal risk of the disease, much more analogous to an LDL-cholesterol test for assessing heart disease risk than traditional genetic tests for purely genetic rare disorders like that for Huntington’s disease. That is, women at higher risk based on deCODE Breast Cancer are not destined to develop breast cancer. They may have a 20 to 36 percent lifetime risk for developing cancer (versus baseline risk of 12%). Women at lower risk are not immune from breast cancer and therefore would still be regularly screened with mammography. Women at higher risk above a certain threshold may benefit from more intensive screening using breast MRI on top of mammography, as recommended by the American Cancer Society. Also, certain medications such as tamoxifen which blocks the estrogen stimulation of breast cancer cells are approved by FDA to reduce breast cancer risk for women at higher risk.

In summary, this test may reclassify as higher risk some women who were previously considered to be of average risk, contributing to earlier detection and more focused prevention strategies. In fact, this test together with family history could define as higher risk the roughly 20% of women who may account for 35 to 40% of future breast cancers.

Looking at the big picture, about 5 percent of the health care budget is used for diagnostics and most of the rest is for therapeutics. Much money has been invested in the development and use of new expensive therapies for women with advanced cancer. But individual women and our healthcare system may both benefit from the increased use of risk diagnostics to help to focus on women at higher risk and thus diagnose cancers earlier rather than later, saving lives, suffering, and money.

Anyone who wants to hear some real stories from real people about how genetic tests like this may improve healthcare can find them on this blog.

Jeff Gulcher MD PhD
Chief Scientific Officer
deCODE Genetics

In a recent interview Dr. Kari Stefansson, C.E.O. of deCODE genetics talked about the future for genetic tests such as deCODEme and how he believes that they will drive the shift from intervention to prevention in medicine

As the founder and CEO of deCODE, I want to welcome you to our blog, deCODEyou. This is a place where you can learn not just about deCODE’s discoveries and products but what others are saying about our work and about the application of human genetics to healthcare. We also hope that it will become a place where we can hear from you.

We are at a fascinating juncture in the application of genetics to the practice of healthcare. When we set out to try to search for the genetic causes of common diseases more than a decade ago, we took the approach that what we were doing was fundamentally a data mining challenge. We were trying to find correlations between two datasets: diseases or other phenotypes on the one hand, and variations in the sequence of the human genome on the other. This was a task for which computers were ideally suited. This fundamental insight has served us well, and as we assembled very large population-based datasets on disease, genotypes, and genealogy, advances in genotyping technology, computing power and our own data mining algorithms have enabled us to discovery major genetic risk factors for dozens of the biggest public health challenges of our time.

The purpose of understanding the genetics of disease was to use that information to create new means of diagnosing, treating and preventing disease.

As you know, one of the things we at deCODE are focused on now is turning our discoveries into tests for better assessing individual susceptibility to many common conditions, and, through our pioneering genome analysis service deCODEme™, enabling individuals to put themselves in the context of all that we are learning about human genetics.

And once again, the technology is helping us to bring understanding of genetics to people around the world. Unlike a large number of other companies hoping to follow on our heels, deCODEme is not just a website that happens to be about human genetics; it is your portal into the world’s largest and most successful effort to understand the inherited risk of the most common diseases in contemporary society. And the same technology that enables us to give deCODEme subscribers a secure, constantly updated profile of how you fit into what we are learning about the genome, also enables us to launch this blog and to engage you in a conversation about how we should use this information as individuals, healthcare systems and societies, to make our lives healthier and more productive.

As we make discoveries we are, by definition, opening up new possibilities and breaking new ground. We are very excited to be at the forefront of this work and hope that you will join us in this conversation.

Yours truly,

Kari Stefansson