New research suggests the primary genetic mutation that causes alpha-1 antritrypsin deficiency, a condition that results in liver damage and a wide variety of other problems, also affects risk for liver disorders associated with cystic fibrosis.

Cystic fibrosis is an inherited, childhood-onset disorder that causes the lungs, intestines and pancreas to become clogged with mucus, resulting in breathing and digestive problems. Between three and five percent of CF patients also experience liver disease, which leads to scarring that can block blood flow through the organ and increase blood pressure in surrounding vessels.

Liver transplants have been necessary in many of these cases, but the new genetic research may be able to help prevent them by enabling prediction and prevention of CF-associated liver disease.

A team of researchers at the University of North Carolina at Chapel Hill, led by Michael Knowles, analyzed genetic variants in five genes that have been proposed to be involved in cystic fibrosis-related liver disease. The study involved nearly 1,000 patients, both with and without liver symptoms.

The results, published last week in the Journal of the American Medical Association, identified one genetic variation that increases a cystic fibrosis patient’s risk of developing liver disease. Researchers found that each T at the SNP rs28929474 increases odds of liver disease in CF patients by 4.17 times. A T at both copies of this SNP causes alpha-1 antitrypsin deficiency.

Researchers are still searching for genetic variations associated with other complications of cystic fibrosis, including lung disease, intestinal obstruction and diabetes. Further studies on severe liver disease related to cystic fibrosis may reveal more risk factors for severe symptoms that can be detected early in life.

(23andMe customers can check their data for one of the most common CFTR mutations, Delta F508, in the Carrier Status Clinical Report for cystic fibrosis. Data for rs28929474 is available in the Browse Raw Data feature or in the Alpha-1-Antitrypsin Deficiency Carrier Status Report.)

ShareThis

A new report in the Journal of the American Medical Association adds to the mounting evidence that genetic variations impact the efficacy of clopidogrel (Plavix®), a drug used to prevent blood clots in people who have had a heart attack or stroke and also those with peripheral artery disease and unstable angina.

Previous research has shown that certain variations in the CYP2C19 gene prevent the body from converting clopidogrel into its active form. That reduces the amount of anti-clotting effect people get from the medication, increasing their risk for heart attacks, strokes and death from cardiovascular causes.

(23ndMe customers can learn how their data fits in with this research in a previous Spittoon post or in the Clopidogrel Efficacy Drug Response Report.)

The researchers, led by Alan Shuldiner of the University of Maryland School of Medicine, determined that BMI, lipid levels and age account for about 10% of the variation in clopidogrel’s ability to prevent blood clotting. Variation in the CYP2C19 gene accounted for another 12%, meaning that other factors, probably both genetic and non-genetic, are also at work.

For patients whose genetics may reduce the benefits of clopidogrel treatment, there are other options. Prasugrel (Effient®) was recently approved by the FDA and appears not to be affected by the same variations that impact clopidogrel efficacy, although there are some concerns about bleeding caused by this drug.  Several other drugs (ticagrelor, cangrelor, elinogrel) that could be used for clotting reduction in place of clopidogrel are currently in clinical trials.

Clinical trials have not yet been conducted to show if identifying people with variants of the CYP2C19 before prescribing clopidogrel actually improves health outcomes.  If such studies do show a benefit and this type of testing becomes routine, people with these variants might be steered away from clopidogrel by their doctors, which would seem to be a boon for the makers of newer medications.

But in an editorial accompanying the study in JAMA, Deepak Bhatt suggests that testing for these variations would also allow physicians to know for whom clopidogrel will work (probably). This would be an important piece of information considering that the patent on clopidogrel is set to expire in 2011, so cheaper generic forms of the drug will be available then.

“Although such testing currently is expensive, the cost will decrease and hopefully will coincide with supportive data.  Furthermore, if such testing allowed use of a less expensive generic anitplatelet drug, the test might essentially pay for itself,” he writes.

ShareThis

Treatment advances have dramatically increased the cure rate for acute lymphoblastic leukemia (ALL), the most common diagnosed cancer in children, from less than 10% in the 1960’s to more than 80%.

But even in those children who are cured, the response to treatment varies from patient to patient. For some, just a couple of weeks of chemotherapy can drastically reduce the number of leukemia cells in their bone marrow, while others continue to have high levels of disease even after six weeks of intensive therapy.

Now, researchers have discovered that these differences may depend on a patient’s genetics.

Much of the previous work aimed at understanding the variability in responses to cancer treatment has focused on differences between the cancer cells themselves. But researchers from St. Jude’s Children’s Research Hospital and the Children’s Oncology Group have taken a different approach, focusing on genetic variations inherent to the cancer patients and present in all cells of their bodies.

“Although the acquired genetic characteristics of tumor cells play a critical role in drug responsiveness, our results show that inherited genetic variation of the patient also affects effectiveness of anticancer therapy….Such variation may be factored into treatment decisions in the future,” the authors write.

Their study, published online yesterday the Journal of the American Medical Association, identified more than 100 SNPs linked to the number of leukemia cells that survive after initial treatment. A significant number of these same variations were also associated with early response, relapse and drug metabolism.

Children receiving different types of chemotherapy were studied to increase the chances that the SNPs identified by the study would be associated with treatment response in general, and not just response to a specific drug. A total of 487 kids, each receiving one of three different treatment regimens for ALL, were genotyped at more than 400,000 SNPS.

In all, 102 SNPs were associated with “minimal residual disease” (MRD), a measure of the number of leukemia cells that survive after the initial phase of treatment. Some of these SNPs are very close to each other and are likely markers of the same effect, but the researchers say that they identified 72 unique regions of the genome associated with this trait.

There are differences in ALL prognosis between different racial groups. For example, African American children have been shown in some studies to have lower survival rates than white children. The researchers suggest that this could be due to differences between the two groups in the frequency of the protective versions of SNPs identified in this study. In the future, the researchers write, findings like theirs could lead to “race-neutral” treatment decisions that are based on an individual’s unique DNA make-up instead of unreliable assumptions based on ancestry.


Photo of bone marrow cells from an ALL patient by Furfur.

ShareThis

It’s a situation that would leave many physicians at a loss. A 55-year-old man with a family history of dementia asks his doctor about genetic testing for Alzheimer’s disease. Is there a test? Which test should be used? Is testing even appropriate?

This week the Journal of the American Medical Association published the final installment in a three-part series of user’s guides that aims to help doctors who face these kinds of situations. Given the dizzying pace at which genetic association studies are being published and the increased availability of genetic tests, both through physicians and direct-to-consumer providers, these guides could not have come at a better time.

In the introduction to the series, the authors say that although genetic association studies may one day produce numerous benefits for both science and medicine, the most likely short-term use of this type of information for clinicians is in identifying the most at-risk people in a population and providing patients with information on the likely courses their diseases will take.

Although the user’s guides are intended for physicians, they are written in such a clear and concise manner that anyone interested in understanding more about genetics and how it applies to their health will find them helpful.

(Unfortunately these guides are not freely available. They may be available at a local city, county or university library. They are also available for download for $15 per article.)

Summary of the three user’s guides:

A. Background Concepts

The first article summarizes the key genetic concepts that clinicians must be familiar with to understand genetic association studies. There is a glossary of commonly used terms, a review of the components and structure of DNA, an explanation of human variation and a summary of the different forms that genetic association studies can take.

B. Are the Results of the Study Valid?

The second article takes the reader through the major issues that need to be addressed in judging whether a genetic association study is valid, presenting a series of questions physicians should ask themselves while reading an association study. Topics addressed include determining whether the participants used in a study were chosen correctly, how to tell if the technology being used to genotype study participants worked correctly, several statistical considerations that need to be addressed (including multiple testing) and whether the results have been replicated and are consistent with those of other studies.

C. What are the Results and Will They Help Me in Caring for My Patients?

The concluding article of the series offers guidance on evaluating the magnitude and precision of a study’s findings and determining what to do with these results, based on both the study and the patient’s family history and personal characteristics.

ShareThis

Diabetics have to be worried about more than just their cholesterol when it comes to the health of their arteries. They also have to watch their blood sugar to help prevent the build up of fatty plaques that can block blood flow.

But new research from the Joslin Diabetes Center and Harvard Medical School shows that high blood sugar may be more dangerous to some diabetics than others.

Dr. Alessandro Doria and colleagues found that a genetic variant on chromosome 9 previously associated with coronary artery disease (CAD) risk in the general population has an even greater effect in diabetics with poor blood sugar control. These results, published online today in the Journal of the American Medical Association, could someday help doctors identify people with diabetes who are at higher risk of CAD earlier, allowing them to aggressively target these patients for intervention.

People with diabetes are at least twice as likely as those without to have heart disease. Some studies suggest that middle-aged diabetics have the same high heart attack risk as people without diabetes who have already suffered a heart attack.

The first of two study groups was composed of 322 diabetics with coronary artery disease and 412 without. The researchers found that the risk for CAD was about the same in people with either the AA or AG genotype at rs2383206, even if they had poorly controlled blood sugar.

Having the GG genotype at rs2383206, however, increased the odds of CAD by about two-fold for diabetics with well-controlled blood sugar. And when high blood sugar was thrown into the mix, the odds of CAD for people with two Gs went up higher still – about four times compared to the lowest risk group.

In people with the GG genotype and a long history of high blood sugar, the odds of CAD were increased about seven times compared to diabetics with a history of well-controlled blood sugar.

(The study looked at rs2383206, which is available to 23andMe customers who were genotyped on the second version of our custom chip. But people who were genotyped on the first version can use rs2383207, the SNP we feature in the Health and Traits research report on Heart Attack, as a substitute. The G version is riskier for both SNPs.)

In a separate study group of 475 diabetics who were followed for 10 years, people with the AA or AG genotype at rs2383206 had the same risk of dying in general, or from cardiovascular disease in particular, regardless of their blood sugar. But for people with the GG genotype, the risk of death went up by a factor of two when blood sugar was not under control.

Both groups of diabetics Doria et al. studied were of European ancestry.

“While good glucose control is important for all people with diabetes, testing for this predisposing variant may help doctors identify patients for whom better control is an absolute necessity,” said Doria in a statement. The authors estimate that 30% of diabetics will have two Gs at rs2383206.

The probability of clinically significant CAD is about 30% for type 2 diabetics in general. The authors say this number could shoot up to 60% for diabetics with the GG genotype at rs2383206 and poorly controlled blood sugar.

The authors admit that this is a small study that will need verification. They also note that their findings are at odds with a previous report that found no difference between the risk conferred by SNPs in the 9p21 chromosomal region (where rs2383206 lies) in diabetic vs. non-diabetic subjects. Due to a number of methodological differences between the two studies, Doria et al say that no direct comparison of the results is possible.

ShareThis

The connection between obesity and cancer is well established. As many as 25 to 30 percent of several major cancers – colon, breast (postmenopausal), endometrial, kidney, and esophagus – may be accounted for by obesity and physical inactivity. Some studies have also found links between obesity and cancers of the gallbladder, ovaries, and pancreas.

It is not yet clear to scientists, however, how obesity increases the risk for certain cancers. Part of the answer may lie in a hormone released by fat cells — adiponectin. Decreased blood levels of this hormone, which are found in obese people, have been linked with breast, endometrial, prostate and colon cancer.

A new study published today in the Journal of the American Medical Association provides further evidence for adiponectin being the link between obesity and cancer. Researchers have demonstrated that a variant in the gene that encodes the hormone influences the risk of developing colorectal cancer.

Kaklamani et al examined several SNPs in the adiponectin and adiponectin receptor genes in a total of 629 people with colorectal cancer and 855 people without the disease. All subjects except for 37 cases and 37 controls were of European ancestry. The researchers found that people with one or two Gs at rs266729 in the adiponectin gene had 27% lower odds of developing colorectal cancer compared to those with two Cs.

(23andMe customers can look up their data for rs266729 using the Browse Raw Data feature)

According to the report’s senior author, Dr. Boris Pasche, these research findings could help identify people who would benefit from increased colorectal cancer screening.

“Our hope is that we can significantly improve the screening and early detection for this disease, and open new avenues for better understanding the genetic and lifestyle factors that influence colon cancer risk, “ he said in a statement.

Pasche went on to caution that additional studies are needed to confirm whether those without the adiponectin variant that appears to protect people from colorectal cancer will benefit from cancer-prevention lifestyle changes such as diet and exercise.

A different variant in the adiponectin gene was recently identified as a modifier of breast cancer risk in a study co-authored by Pasche. Understanding how variants in this gene influence breast and colorectal cancer risk, and whether the variants affect the risk for other cancers, will require more research.

Colorectal cancer is the second-leading cancer killer of Americans. According to estimates from the American Cancer Society, 149,000 people will be diagnosed with the disease and 50,00 will die this year alone.

ShareThis

The journal points to the incredible pace of recent discoveries associating specific genetic markers to various diseases and conditions. It even adds a few new revelations to the mix, including:

• a study that found certain variations of the stress-related gene FKBP5 increase the chances that a person who is abused as a child will later develop post-traumatic stress disorder.
• the first evidence of a causal link between the gene PON1, the antioxidant activity of a substance known as paraoxanase and a person’s chances of having a severe heart attack.
• a paper demonstrating that variations in the gene LRP5, which has previously been linked to osteoporosis, can affect bone density and risk of fracture.

More provocative is a commentary by National Human Genome Research Institute director Francis Collins and two colleagues that envisions a not-too-distant future (the year 2020) when doctors and patients will be able to tailor their health care to individualized genetic information.

The question is, how do we get from here to there? Even allowing for the incredible amount of progress that is being made, it will take an enormous amount of research to incorporate genetic information into medical practice – and even more to demonstrate that doing so is beneficial.

23andMe wants to be involved in that research effort. Though some (including the author of another commentary in the JAMA special issue) have argued it is too early to offer personal genetic information directly to the public, we believe our company can contribute to realizing the “2020 vision” advanced by Francis Collins and his co-authors.

In giving our customers access to their genetic information, 23andMe is helping to organize a group of motivated, educated people around the goal of achieving truly personalized medicine. And once we have enough customers we plan to enlist their help in research studies designed to find more associations between genes, disease and drug response – and to learn how people might benefit from having knowledge about their genomes.

It’s true that there isn’t enough evidence yet to justify taking medical action on the basis of genetic information, and we make that clear to our customers that they shouldn’t make health-related decisions based on what early research results might indicate. But if anything, that’s an argument for the existence of companies like 23andMe – by educating our customers and the general public about the potential value of genetic information, we can enlist their help in achieving the common vision of personalized medicine.

Image courtesy of U.S. Department of Energy Genome Programs (http://genomics.energy.gov)

ShareThis