deCODE scientists have discovered a single SNP that confers increased risk if inherited from the father, but is protective if inherited from the mother

Scientists at deCODE genetics, Inc. publish in the journal Nature the discovery of a version of a common single-letter variant in the sequence of the human genome (SNP) with a major impact on susceptibility to type 2 diabetes (T2D). The impact of the T2D variant is not only large, but unusual: if an individual inherits it from their father, the variant increases risk of T2D by more than 30% compared to those who inherit the non T2D-linked version; if inherited maternally, the variant  lowers risk by more than 10% compared to the non T2D-linked version. Nearly one quarter of those studied have the highest risk combination of the versions of this SNP, putting them at a roughly 50% greater lifetime risk of T2D than the quarter with the protective combination. This is the second largest effect of any genetic variant for T2D apart from SNPs in TCF7L2, discovered by deCODE in 2006.

“We could make this discovery beacause we are in the unique position of being able to distinguish what is inherited from the mother from what is inherited from the father. This we can do because of the large amount of data we have assembled on the Icelandic population. These data empower us in many ways. For example, using our ability to impute sequence data, we can multiply by 100 times the amount of information generated by sequencing one individual. We can use these tools to discover and integrate rarer variants into our tests and scans, identify drug targets for licensing, and put our know-how at the disposal of our service customers. We believe that this is an important advantage for conducting large-scale whole sequence studies over the next couple of years,” said Kari Stefansson, CEO of deCODE.

Because the risk is inherited and varies in this way, the SNP, located on chromsome 11, had never been linked to T2D even though it had been genotyped in large, traditional genome-wide association studies (GWAS). These do not distinguish between paternally and maternally inherited SNPs. But deCODE can track the parental origin of virtually any SNP in the genome of the tens of thousands of Icelandic participants in the company’s gene discovery work. In this study, deCODE used its population-wide genealogy database and proprietary statistical tools to determine the parent of origin of a number of SNPs in some 40,000 Icelandic participants in the company’s gene discovery programs. Some of these SNPs had previously been associated with different diseases and are located near “imprinted” genes – genes in which only the maternally or paternally inherited copy is “switched-on” to encode a protein. Five of these, one each in breast and skin cancer and three in T2D, showed that the parental origin of the variants affects the risk they confer.

The paper, “Parental origin of sequence variants associated with complex diseases,” is published online at www.nature.com, and will appear in the December 17 print edition.

deCODE genetics and Celera Corporation have announced the signing of agreements under which deCODE has granted Celera non-exclusive worldwide licenses to deCODE’s genetic markers for increased risk of major cardiovascular and metabolic diseases, including heart attack, stroke, atrial fibrillation (AF) and type 2 diabetes (T2D). These markers can be incorporated into laboratory tests for assessing and managing individual risk of these diseases.

“This is an excellent opportunity to broaden the clinical application and commercialization of our discoveries of high-impact genetic risk factors for major diseases. The markers included in these agreements are among the most widely replicated genetic risk factors for cardiovascular and metabolic disease, and they provide a natural complement to the biomarker services already offered by Berkeley HeartLab, Celera’s subsidiary.  In Celera we have a partner with a global reputation in human genetics and a large and effective outreach and sales force. We are pleased to have the chance to work with them to build upon our discovery and testing platforms and to accelerate the adoption of personalized medicine,” said Kari Stefansson CEO of deCODE.

“We believe access to these highly replicated markers, which complement our internal proprietary genetic discoveries in cardiovascular disease such as KIF6 and LPA, furthers Celera’s commitment to be a leading provider of genetic tests used routinely in personalizing disease management,” said Kathy Ordoñez, CEO of Celera.  “We expect Berkeley HeartLab to incorporate these markers into future laboratory service offerings, and Celera plans to ultimately commercialize them globally as new molecular diagnostic tests through our Products business.  We believe these markers that predict risk of coronary heart disease and drug response could produce highly differentiated, proprietary, and compelling tests that personalize cardiovascular disease management.”

As a deCODEyou reader, you have an active interest in how genetics can help to improve personal health and healthcare. If you are a deCODEme subscriber or have taken one of our DNA-based diagnostic tests, you have already followed up on that interest.

Then again, you may not have had your genome analyzed yet. You may simply be interested in taking part in research, having a scan, or simply in keeping up with the latest discoveries.

But whoever you are, your genome is information about you. And at deCODE, we believe that your genome belongs to you. Over the past decade we have worked with hundreds of thousands individuals who have decided to use their genome to advance our gene discovery work, to understand their risk of a certain disease, or who want to have a broad and constantly updated look at their genome through deCODEme. In every case, we think it is the individual who has the right to decide to use their genome and learn about it as they wish.

Our job is to find the variations in the sequence of the genome that have an impact on risk of disease, and to report to those who use our tests and scans what those findings mean to them. We have done a lot of this – more than anyone else. And because we take your genome as seriously as you do, our tests and scans only detect genetic risk factors that have been validated in multiple populations and to very strict criteria. Many of the risk factors we have found and test for in diseases like heart attack, type 2 diabetes and breast cancer account for a large proportion of the occurrence of these diseases. Some have as big an impact on risk as do some of the major lifestyle and environmental risk factors that are already a standard part of risk screening.

So when we hear august voices argue that you shouldn’t have the right to look at your genome if you want to, or that we shouldn’t test for genetic risk factors until we know everything there is to know about the human genome, we feel obliged to disagree. In this week’s New England Journal of Medicine, we have heard again that it is “too early” to measure genetic risk factors for common diseases. Why? In essence because in the coming years we are likely to discover many more genetic risk factors that will help to round out our understanding of all of the risk factors that exist. To be sure, we will discover more risk variants in a great many diseases. Many will be common but with little effect on risk. Others will be rare but will confer a high likelihood of disease and thus likely be useful components in genetic tests.

But since we already know risk factors that can nearly double the risk of heart attack, diabetes or breast cancer, in a substantial portion of the population, we take the much clearer view that there is an ethical responsibility to make tests for these risk factors available as widely as possible. As our CEO, Kari Stefansson, was cited as noting in the New York Times yesterday, our tests can identify people who are at several times average risk of major diseases, and there is nothing trivial about that sort of increased risk.

After all, we believe that testing for cholesterol is a good thing, even though our understanding of just how LDL impacts risk of heart disease in incomplete. Similarly, we are only now learning how to optimize the use of statins (and that our heart attack risk factor on chromosome 9p21 has been shown to be helpful for finding the best dose for individuals). How many lives would have been lost if we had taken statins off the market until that elusive day when we thought we understood everything about them?

In our view the challenge is rather to try to bring genetic risk factors into clinical practice as swiftly as possible. As an article this week in The Times points out, a deCODEme scan has a lot of actionable risk information in it. But one of the things we need to do is educate doctors about how to use such results  and how to integrate genetic risk into everyday screening. Our own experience with doctors is that most are very eager to learn. Moreover, genetic information complements what they already do and helps them to deliver better and more personalized medicine to their patients.

In the past few years we have made rapid strides in identifying the key genetic risk factors for some of the most common diseases in our society. Very large independent studies have established that detecting these risk factors can help individuals to act to protect their health and to get the treatments that are best suited to them. This is precisely the sort of information that is going to make it possible to transform our healthcare system into one that is both more effective and efficient – focused on preventing disease and treating it early, rather than spending vast sums of money once people are already seriously ill.

You and your genome are already at the heart of this transformation. If someone tells you that you need to wait, or that they will decide whether and what you can learn about yourself, you need to set them straight. We’ll be there with you.

Dr Edward M Farmer
Chief Communications Officer
deCODE genetics Inc.

By Edward Weinman

With a simple swab from the inside of your cheek, deCODE genetics can scan your DNA, map your markers and assess your risk of developing 29 common diseases. Edward Weinman, self-described hypochondriac, wonders if he should look too closely at his possible future.

Fifteen hundred Americans will die of cancer today. Tomorrow, another 1,500 will perish. And the day after tomorrow: yet another 1,500.

While I’ve never had cancer (knock on wood) I know how the disease changes lives. My grandmother died from it. My brother has non-Hodgkin’s lymphoma, although thankfully it’s currently in remission after a lengthy round of chemotherapy. Cancer is scary. It accounts for one out of every four deaths. According to the American Cancer Society, cancer is the second leading cause of death in the US, behind heart disease.
Oh, yeah. Heart disease. The great American killer. Heart disease kills 652,486 Americans per year, according to the National Center for Health Statistics. Let’s not forget Alzheimer’s, no pun intended. This cruel disease that strips us of our memories is the sixth leading cause of death, and rising. Every 71 seconds, someone develops Alzheimer’s, including my mother. It’s hard to face the fact there is almost nothing we can do about some diseases, except prepare ourselves and our loved ones for the eventuality.
On the other hand, there are so-called killer diseases on which we can have a positive impact. We cut back on fatty foods and load up on vegetables. We increase our daily intake of fiber by eating cereal that tastes like bark dust. We pop vitamins. We spend time in the gym, going from workout station to workout station like a rat in a cage. Some of us work through crossword puzzles in the hope that mental gymnastics will keep plague from forming in our brains.

But are these healthy habits enough? Is there something more I can do to protect myself from these killer diseases?

For about $1000, deCODE will scan my genome for genetic markers linked to such killers as heart disease, diabetes, certain types of cancer and Alzheimer’s. All that’s required is for me to order a kit, swab the inside of my cheek, drop the swab into the mail, wait a few weeks and then log on to decodeme.com to view my results.

According to deCODE, discovering an inherited propensity toward a particular illness can motivate individuals to get more frequent checkups, take preventive medicines or make lifestyle changes to try to ward off the specter of disease.

But is it really a good idea for a hypochondriac like myself to know my own DNA? What if I discover that I have a high risk of heart disease? Will I soon be hauling myself off to the ER complaining of chest pains? Until recently, my view is that it would have been better to live and hope for the best rather than discover I have a high probability of developing a fatal condition. Ignorance is bliss.

Then my mother fell ill. And my brother got sick. As far as my own health, I exercise like a banshee. However, despite all the hours logged in the gym, I’ve taken more than one trip to the ER because of chest pains. I’ve had EKGs, stress tests, even a CT angiogram which all revealed that my heart was strong. The cause of my chest pains: stomach ulcers and, later, anxiety. But that helpless feeling of lying in the ER as doctors connect EKG leads to my chest sometimes returns. I worry about my health more than most 41-year-olds. So maybe a genetic test is exactly what I need to put my mind at rest.

Yes, I want to arm myself with as much information as possible in order to fight what might be coming, or at least prepare for what might await me on the horizon.

“We need to empower people,” says Dr. Robert Superko, author of the book Before the Heart Attacks, and executive director of the Center for Genomics and Human Health at the St Joseph’s Translational Research Institute. “If a genetic test prompts people to do what’s right for them then we have accomplished our goal.”
I order the kit.

Sitting at my laptop, logged on to deCODEme.com, the genetic secrets to my future health are only a mouse click away. I can click to see my inherent risks of contracting all 29 of the diseases deCODE tests for, or click on the results one disease at a time, leaving the scary diseases for later, or not at all. It’s my choice.

I’m not really concerned about whether or not I’m lactose intolerant. I’m not too worried about Celiac disease, or restless-leg syndrome. No, I’m sweating over the Alpha diseases: Prostate Cancer. Alzheimer’s. Heart Disease. What if my test results portend to a future weighted down by Chemo, or if I’ll one day take Arecept, or have a stent inserted into my arteries?

I demur. You know, no news is good news. The last thing a hypochondriac like myself needs is a fortuneteller mapping out my future in a pack of tarot cards. I understand that information is power, but what about Alzheimer’s? If my risk is relatively high, I can whittle down pencil after pencil working on the NY Times crossword and not really reduce my risk, even if I throw in a few Sudoku puzzles for good measure.
“The test is a way of bringing patient and doctor together,” says Dr. Jeffrey Gulcher, deCODE’s chief scientific advisor. “The test gives you a risk assessment, and then you and your doctor can figure out what to do about it.”

So the test is not definitive. It’s not a diagnostic tool in the usual sense. If I have a higher than normal inherited risk of heart disease that doesn’t mean I have to replace my artery clogging Ben & Jerry’s Chocolate Fudge Brownie with apple slices. If my risk of Alzheimer’s is high I’m not going to have to purchase an identity bracelet with my name, address and phone number engraved on it in case I get lost.

“The genetic test is analogous to a cholesterol test,” says Dr. Gulcher. “Just because you have high cholesterol, doesn’t mean you’ll have a heart attack. Just because you have low cholesterol, doesn’t mean you’re off the hook.”

I breathe a sigh of relief. I can look at my results without breaking out into a cold sweat. My DNA results aren’t going to say: “Tomorrow, Edward Weinman, you’ll contract cancer.”

Then again, Dr. Gulcher’s recent health issues suggest that comparing the deCODEme genetic test to a cholesterol screening is not all together an accurate analogy. Months ago, Dr. Gulcher took the swab, and his genetic profile revealed that he had a 30 percent lifetime risk of contracting prostate cancer. At 48, Gulcher was still two years away from when most medical experts believe prostate screening should begin.
How did Dr. Gulcher take the news? He was empowered. Dr. Gulcher took a standard blood test measuring his prostate-specific antigen, or PSA, which showed he was at the high end of normal. This data, combined with Dr. Gulcher’s DNA test, compelled his doctor to refer Gulcher to a urologist who performed an exploratory biopsy. The biopsy’s result? “A fairly aggressive form of cancer,” Dr. Gulcher recalls. Thankfully, Dr. Gulcher’s cancer had not spread to other parts of his body, and he underwent surgery to remove the cancer. Dr. Gulcher has just had his catheter removed when I ask him if deCODE’s genetic test saved his life.
“I can’t say for sure, but it’s likely it did. I had a tumor at the time of diagnosis. There is a good chance that tumor would’ve already spread” by the time he went in for a normal PSA screening at the age of 50.
Okay, I’m convinced. Time to decode my DNA. I click on the link and my test results are revealed:
My relative genetic risk for Alzheimer’s is 1.74, translating into a lifetime risk of 10.5 percent.

Not so bad, right? Not exactly. The average risk of contracting the disease is 6.4 percent. So I’m higher than average. But what stands out like a scar on a model’s face is when I look at the percentage of the population at a less or equal risk to me: 97.2 percent. In other words, only 2.8 percent of the population has a higher risk of contracting Alzheimer’s than I do.

So what does this mean?

“We emphasize that these are not determinative factors. They reflect risk. Relative risk,” Dr. Gulcher tells me.
He’s got a point. When I look at my risk of becoming obese I realize these results must be taken with a grain or two of salt. My DNA says that my relative genetic risk for obesity is .80, translating into a 31.6 percent chance of becoming fat. I chuckle, because I work out four to five days a week, and I’m what you might call skinny, or as I prefer, lean and toned. Plus, my metabolism works at hyper speed. At 41, I can proudly say that I have a six-pack. So a 31.6 percent risk of becoming fat? I don’t think so. (There’s no need to elaborate more because this grain or two of salt is refuted below, in that the test is necessary, and one that can improve health. One must always present the counter argument to make the argument stronger.)
Again, deCODEme only provides me with information on my “relative” risk of contracting common diseases. It’s not definitive. But can’t I just look at my parents’ and grandparents’ health and the health of my siblings to decode what diseases might afflict me when I grow older? Do I really need to pay $1000 for a genome scan?

“That would work well for certain diseases, like certain types of breast cancer, but common diseases tend to skip generations. Most of us don’t keep track of our genealogy. But that’s what’s going on when we find these common variations.” Dr. Gulcher continues: When we run a test “we are percolating the risk through your family’s history of disease.”

Dr. Gulcher then asks me a question. He curiously wants to know what my top two diseases are in terms of risk. I figure Alzheimer’s is number one, until I scan down my gene profile and learn that I have a 2.3 relative genetic risk of developing Type 2 Diabetes, translating into a 57.5 percent lifetime risk, double the average lifetime risk.

Not a chance. No way is it possible that I’m at risk for diabetes. I’m healthy. I eat right. I exercise. I’m not even close to being overweight. My BMI is perfect. I went so long during my last stress test that the cardiologist asked if I ever ran cross-country competitively. How can I be at risk for Type 2 Diabetes? Surely this proves deCODEme’s genetic test must be taken with many grains of salt. Perhaps this invalidates all my other results.

The doctor draws my blood and ships it off to the lab.

A few days later, I find out that my fasting glucose level is 96 mg/dl. That’s the high end of the normal range but a lot higher than I expected. One indication of pre-diabetes is a fasting glucose level that is between 100 and 125 mg/dl. Talk about a wakeup call. Despite my healthy lifestyle, my glucose levels are too high and that can be nothing other than genetic.

I remember Dr. Gulcher’s words: “The test is a way of bringing patient and doctor together. The test gives you a risk assessment, and then you and your doctor can figure out what to do about it.”
There’s no need to panic, but it is time to make an appointment to see my doctor. It’s time to trade in my Ben & Jerry’s for those apple slices.

Edward Weinman is a freelance writer living in Los Angeles, and a contributor to deCODE’s News Blog. He spent eight years in Iceland, working as a journalist and he co-wrote the film A Little Trip to Heaven.