“Ultimately, people need to know genetic makeup and lifestyle have the power to impact health and wellness,” said Nova. “Pathway’s goal is to educate and empower health care practitioners and patients through detailed personal genetic reports and individualized lifestyle recommendations.”

Ultimately, people need to know genetic makeup and lifestyle have the power to impact health and wellness,” said Nova. “Pathway’s goal is to educate and empower health care practitioners and patients through detailed personal genetic reports and individualized lifestyle recommendations.”

Held at the San Diego Convention Center, the ADA’s annual meeting brought together more than 10,000 registered dietitians, nutrition science researchers, health care providers, industry leaders and policy makers in an effort to address key issues affecting the health of the American people. Tackling the obesity epidemic was a clear highlight of the meeting.

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Most inherited diseases caused by single-gene mutations affect relatively few people, but are a major focus of research by scientists seeking to improve outcomes for patients and to learn more about the normal functions of the human body. Why is the study of these monogenic diseases so important?

Monogenic diseases provide a clear link between the disease and the molecule or structure affected by the gene. In the same way, you can prove that a battery supplies electricity for starting your car because removing the battery will prevent your car from starting.

Insights into the mechanisms of iron homeostasis, or how the body maintains just the right level of iron, have come from the study of monogenic diseases such as hereditary hemochromatosis (PMID 16409153, PMID 20542038), an iron overload disease which is included in Pathway’s Pre-Pregnancy Planning Test.

Iron — Necessary for Life, but Also Toxic

Iron readily gains and loses electrons: a property that helps it bind oxygen as a component of the hemoglobin molecule in red blood cells (PMID 17987043). On the other hand, this capacity for electron exchange also means that unbound iron can react with oxygen to produce free radicals that are very damaging to the cell. To prevent formation of free radicals, iron is always bound to a protective protein–ferritin inside the cell and transferrin in the plasma. Iron is also an essential component of the myoglobin in your muscle and of many enzymes including the cytochrome enzymes in your liver.

How is the Level of Iron in the Body Regulated?

The levels of iron in the body must be carefully regulated because too much or too little iron can cause iron overload disease (hemochromatosis) or anemia, respectively (PMID 17987043, PMID 21054916). The excretion of iron is not regulated, so iron homeostasis is maintained by controlling the amount of iron coming into the body. Iron from food enters through the small intestine, where it is absorbed by enterocytes–cells that line the lumen of the duodenum. Iron gets into the bloodstream via a protein in the enterocytes called ferroportin which exports the iron. A peptide hormone from the liver, called hepcidin, downregulates the amount of ferroportin. Thus the overall control of iron metabolism resides in the liver, where the synthesis of hepcidin is regulated in response to inputs about the need for more iron. For example, hypoxia or lack of oxygen signals a need for more red blood cells and reduces the synthesis of hepcidin so ferroportin is allowed to transport more iron into the body. On the other hand, if there is too much iron in the body, the synthesis of hepcidin will be stimulated, so that more ferroportin will be removed, resulting in less iron intake into the body. Hepcidin is synthesized in response to bacterial infections; this suppresses iron uptake and prevents the growth of iron-requiring pathogenic bacteria.

Monogenic diseases affecting iron metabolism

A key mechanism in iron homeostais is the downregulation of ferroportin in enterocytes by the peptide hormone hepcidin. The role of hepcidin and ferroportin in iron homeostasis is supported by the identification of mutations in the genes for hepcidin (HAMP), ferroportin (FPN), and by the identification of mutations in genes (HFE, HFE2, TFR2 and TMPRSS6) which regulate the synthesis of hepcidin (PMID 17987043, PMID 21150441). Mutations in these genes cause diseases of iron metabolism which result in excess iron absorption leading to iron overload or result in iron deficiency leading to anemia. Researchers investigating these genes have concluded that the molecular basis for hemochromatosis is insufficient hepcidin production (PMID 21150441). Mutations in the TMPRSS6 gene that result in too much hepcidin production cause an iron-refractory iron deficiency (IRIDA).

The Two Most Common Hemochromatosis Mutations

The excess iron in hereditary hemochromatosis can damage many organ systems including the liver, skin, pancreas, endocrine glands, joints, and heart. The only way to remove the excess iron is by bloodletting (therapeutic phlebotomy). If such treatment is started in time, the affected individuals will have a normal lifespan. Therefore, early diagnosis is essential.

The Pathway Pre-Pregnancy Planning Kit tests for the C282Y and H63D variants of the HFE gene, which are the most common cause of hereditary hemochromatosis. The C282Y mutation is thought to have originated by chance in a single Celtic (or Viking) ancestor in northwestern Europe about 2000 years ago. Homozygosity for the C282Y mutation is now found in approximately 5 of every 1000 persons of northern European descent. The carrier rate for C282Y is 1 in 9 for Caucasians, 1 in 33 for Hispanics, 1 in 43 for African-Americans, and 1 in 1000 for Asians. The H63D mutation is an older, more prevalent mutation with a worldwide distribution and a carrier rate of 1 in 4 for Caucasians, 1 in 6 for Hispanics, 1 in 17 for African-Americans, and 1 in 12 for Asians. About 60%-90% of individuals with HFE-related hereditary hemochromatosis (HFE-HHC) carry two copies of C282Y. 87% of individuals of European origin with HFE-HHC either carry two copies of the C282Y variant or carry one copy of the C282Y variant and one copy of the H63D variant.

Pathway‘s drug response panel includes aminoglycoside antibiotics and risk of hearing loss.  This phenotype may be of particular interest to couples planning a pregnancy.

The 1555 mutation and risk of antibiotic-induced hearing loss

For more than 60 years, aminoglycoside antibiotics such as streptomycin, gentamicin, neomycin, paromomycin, kanamycin, amikacin, netilmicin and tobramycin have been widely used, and continue to be used, especially in developing countries, for the treatment of severe bacterial infections. However, aminoglycoside use also carries the risk of hearing loss (also known as ototoxicity).

Pathway tests for a mtDNA mutation, called 1555A>G, which is the most frequent cause of inherited aminoglycoside-induced ototoxicity. The “1555 mutation” occurs in all ethnic groups and has been found to occur in approximately 1 of every 500 people of European descent (PMID 19196684, PMID 19196685). Newborn screening for the 1555 mutation has been suggested in China, where aminoglycoside antibiotics are more commonly used (PMID 21324532, PMID 21329993).

Pathway screens for a mutation in mtDNA, called 1555A>G, which is the most frequent cause of inherited aminoglycoside-induced hearing loss.

There are other mutations that are associated with antibiotic-induced hearing loss, but the 1555 mutation is the most prevalent. Carriers of the 1555 mtDNA mutation who undergo even a single course of aminoglycoside antibiotic therapy can suffer a severe and irreversible loss of hearing (PMID 20301595).

There is no report of a 1555 mutation carrier receiving aminoglycosides and not suffering a significant loss of hearing.

For individuals that carry the 1555 mutation, the recommended action is simple. Avoid aminoglycoside antibiotics. There are many alternatives to aminoglycoside antibiotics, and your physician can decide which is best for you.

There is no report of a 1555 mutation carrier receiving aminoglycosides and not suffering a significant loss of hearing.

However, individuals who carry the 1555 mutation and avoid aminoglycoside antibiotics are still at some risk of hearing loss.A few 1555A>G carriers who were not exposed to aminoglycoside antibiotics have developed hearing loss, suggesting that there might also be other environmental or genetic “triggers” that cause hearing loss in carriers (PMID 20301595).

Why is the 1555 mutation important for prospective mothers?

If you are female and pregnant or planning a pregnancy, we encourage you to be tested for this mutation. If you are female and your test results show that you carry the 1555 mutation, your child is likely to inherit the mutation.

In the US, aminoglycoside antibiotics are often prescribed in the neonatal intensive care unit to treat newborns with bacterial infections (PMID 15846011). For a newborn that carries the 1555 mutation, the risk of hearing loss can be avoided, simply by prescribing a different type of antibiotic (PMID 19192037).

Male carriers, on the other hand, will not pass the 1555 mutation on to their children. The 1555 mutation is mitochondrial and thus is transmitted maternally.

How does the 1555 mutation and aminoglycoside use cause hearing loss?

Aminoglycoside antibiotics wield their antibacterial effects by binding to bacterial ribosomes, the protein making machinery in cells, and thus disrupting protein synthesis in the bacteria.  Even though these antibiotics are usually administered so that all the cells in the body are exposed, they tend to accumulate in the fluids of the inner ear (PMID 3044302).

The 1555 mutation occurs in a molecule that is part of the mitochondrial ribosomes in the hair cells of the inner ear – these are the cells that sense sound vibrations, and allow you to hear. The 1555 mutation permits aminoglycoside antibiotics to bind to hair cell mitochondrial ribosomes, where they disrupt protein synthesis (PMID 19687236, PMID 18308926). The disruption in protein synthesis leads to the death of the hair cells in the inner ear, and eventually, irreversible hearing loss.

Genetic testing can help you or your child avoid hearing loss

Testing for the 1555 mutation is not currently part of any standard newborn or fetal screening test.  Pathway’s test for the 1555 mutation can give you actionable information about your risk of aminoglycoside-induced hearing loss. If you are female, testing for the 1555 mutation can also give you information about your child’s risk of aminoglycoside-induced hearing loss.

Genetic counselors from Pathway attended the American College of Medical Genetics (ACMG) meeting in Vancouver this past weekend. Below are some highlights from the conference.

A plenary session on hereditary connective tissue disorders included discussions of phenotypic and genotype correlations in connective tissue disorders, including the possible co-inheritance with cardiac problems that are not part of the disease spectrum, and how to sort this out.

A short course prior to the meeting entitled “Preparing for an Expanding Range of Adult Consultations” described the issues surrounding accurate diagnosing of adult patients with disease. Cases presented included Marfan syndrome, homocystinuria and vascular Ehlers-Danlos syndrome. The take-home message was that by old-fashioned clinical assessment, including pedigree information, testing for known biochemical analytes in associated pathways, and sometimes sequencing for known genes, more accurate diagnosis can be made when there are overlapping syndromes and/or associated conditions in a patient or family history. Cautions included the potential of missing a case when a SNP test did not include the causative gene variant.

Robert Green from Boston University announced the initiation of a study by the Impact of Personal Genomic Services consortium (IPeG) to understand individual response to personal genetic testing. The IPeG consortium, which includes Pathway Genomics and 23andme, will assess whether individuals make lifestyle changes in response to personal genetic testing, and also how well individuals understand their personal genetic test results.

The IPeG consortium, which includes Pathway Genomics and 23andme, will assess whether individuals make lifestyle changes in response to personal genetic testing, and also how well individuals understand their personal genetic test results.

The IPeG study is expected to add to the data generated from the Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) study on reactions to genetic testing for Alzheimer’s disease. In the REVEAL study, those found to have high genetic risk for Alzheimer’s disease were found to have made some positive lifestyle changes, including increased exercise and changes to diet.

“His achievements have made it possible to treat infertility, a medical condition afflicting a large proportion of humanity, including more than 10 percent of all couples worldwide,” the Nobel medicine prize committee said.   

Edwards, who is currently a professor emeritus at the University of Cambridge, began working on IVF as early as the 1950s.

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With the assistance of gynecologist surgeon Patrick Steptoe, Edwards succeeded in turning his vision of IVF into a reality with the birth of Louise Brown in 1978, the first “test-tube baby” – thus marking a historic moment in the annals of medicine and a vital turning point in the way we view human reproduction.   

While the methods have been refined, the fundamental core of IVF remains, and is an accepted and established practice across the globe.   

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Pathway would like to give a heartfelt congratulations to Professor Robert Edwards. We believe that pivotal advancements in science and medicine, such as in-vitro fertilization, should be rewarded, and Pathway is grateful to play a part in assisting those who continue to push forward these developments.   

Learn more about Robert Edwards, IVF, and the 2010 Nobel Prize in medicine.

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THE STEPS

For Patients

Step 1: First, ask your doctor about Pathway Genomics’ personal genetic reports. In addition, you can easily notify your physician of your interest in Pathway’s services, by visiting www.pathway.com/physicians/notify and simply filling in the blanks!
Step 2: Using Pathway’s Saliva Collection Kit, you provide a small amount of saliva. Your physician will mail your saliva sample to Pathway Genomics, along with the ordering information.
Step 3: You will need to go online to provide profile information, consent to the testing, and pay any laboratory processing fees.
Step 4: Wait for instructions from your doctor.

For Physicians

Step 1: First, you should meet and discuss Pathway’s services with your patient.
Step 2: Next, you will need to contact Pathway Genomics to arrange for a Saliva Collection Kit to be sent to your office.
Step 3: Then, using Pathway’s Saliva Collection Kit, arrange to collect a saliva sample from your patient.
Step 4: Lastly, simply complete and fax the physician order form to Pathway.

Dr. Eric Topol is the Director of the Scripps Translational Science Institute in La Jolla, California.

“Eric Topol, the cardiologist who helped establish the effectiveness of several important blood thinners and who raised early concerns about the risks of the arthritis drug Vioxx, has a wonderful piece in the current issue of Science Translational Medicine, a research journal, speculating about how new genetic technologies could enter the health care system.” Click here to read more…

“We are all biologically unique, even those of us who have an ‘identical’ twin. The way we respond to a medication varies considerably, from being unresponsive, hyper-responsive, or developing serious side effects.” Click here to read more…

The current American political and social context is perfectly aligned with this line of discourse, because it is with this misunderstanding that the U.S. Government Accountability Office (GAO) questions the value of genetic testing when its report to the Subcommittee on Oversight and Investigations revealed, “Donor 4 had a pacemaker implanted 13 years ago to treat atrial fibrillation. However, [23andme] and [Decode] found that he was at below-average risk for developing atrial fibrillation, and [Pathway] and [Navigenics] claimed that he was at average risk.” The implication is that our collective analysis of his genetic risk must be wrong, simply because he has worn a pacemaker for 13 years. The problem with this conclusion is that genetics does not work in a vacuum, and environment and lifestyle pose a large role in the development of a health condition such as atrial fibrillation.
 
The first item to address is that this dialogue is focused on genetic testing to estimate risk for complex health conditions, such as colon cancer and atrial fibrillation, and is generally not applied to carrier status testing, drug response, or other types of genetic testing. Complex conditions have multiple possible causes in addition to genetics, including environment, lifestyle, and family history. The risks for many complex diseases can be mitigated by making informed personal health choices.

The Genetic Misperception
It seems probable that much of the misunderstanding originates from science fiction and entertainment media, where omnipotent governments or diabolical scientists manipulate genetics to exercise greater control over the world. This can make for great entertainment and thoughtful consideration of our future, but in this context, reality is much different from fiction. When used for assessing risk of complex health conditions, genetic information is more accurately considered as an additional tool to be used in making more informed health assessments and plans for prevention. While a family history of heart disease does not guarantee that every child and grandchild will get the disease, it is a valuable tool in encouraging future generations to make lifestyle changes for better health.

Perhaps the best way to poignantly illustrate the difference between predictive and deterministic is through an analogy. Every evening, meteorologists on the local news inform the community of the weather to expect for the coming days. Based on a scientific analysis of weather patterns and meteorological conditions, these educated meteorologists might tell us there is a “60% chance of rain on Tuesday,” or to “Expect sunny and 70 over the weekend.” Is this prediction to be used as fact? Not necessarily, as that particular Tuesday may very well bear no rain, and the weekend may turn out to be partly cloudy and a chilly 60 degrees. Collectively, it is safe to conclude that we would agree that weather reports are to be used as predictors to inform, and not to be seen as foretelling the precise future. The point here is that while these meteorologists may have been slightly incorrect in their predictions, it does not make the meteorological predictions useless – we still pack umbrellas and plan events with friends and family based on the best information that we have.

Bringing this back to complex health conditions and genetics, learning that one does not have known genetic risks that contribute to cardiovascular disease is not an excuse to enjoy a cigarette with every helping of red meat. On the other side of the spectrum, learning that one has an increased risk of cancer is no reason to throw in the towel and surrender to your ultimate destiny. The information from personal genetic testing can and should be used as a motivational tool to encourage people to make good health decisions.

Transcending Tradition
Some critics claim that there is nothing in a genetic test that cannot be determined from a comprehensive analysis of one’s family history. This assertion is clearly an appeal to tradition and can only serve as a catalyst for stagnation. Only a few decades ago, the common medical practice was to not inform patients of the diagnostic details surrounding a terminal illness, such as cancer. Either out of respect or out of lack of knowledge, many people were reported as having died of old age or something broad such as heart problems. The consequence of this practice has led to a lack of understanding. It has not provided the people of this current generation, who are largely concerned with preventive health, with the information to understand their individual risk of conditions such as breast cancer, heart attack or Alzheimer’s disease. That said, the medical community’s current role in responsibly informing patients of these matters has dramatically improved. Using a person’s genetic information to further investigate the propensity for a complex disease is another piece of the health and wellness puzzle, which can be integrated in preventive health care.

Conclusion
The Oxford English Dictionary defines predictive medicine as “the branch of medical science or practice concerned with the prediction of the occurrence or course of disease in individual patients.” It is with this definition that we, as a culture, and our government need to view personal genetic testing.

Simply stated, as it relates to complex health conditions, personal genetic testing is predictive, and not deterministic, and it can be used as an additional piece of the puzzle. The perception that genetic testing is not useful because of its predictive nature is a fallacy.

Finally, this brings us back to the GAO report’s “Donor 4,” the colon cancer survivor who also had a pacemaker implanted 13 years ago. While the predictive nature of our genetic testing may have been imperfect for atrial fibrillation, Pathway, 23andme, and Navigenics each interpreted his genetic data to suggest an “Increased Susceptibility,” “Elevated,” and “Above Average” respectively for colon cancer. In respect to this individual’s privacy, we will not reveal what his lifestyle survey and family history suggested about his risk for this health condition, but the reports from all three companies clearly and consistently indicated increased genetic risk.

Pathway envisions a health system in which people such as GAO’s “Donor 4” use their genetic information, coupled with family history, lifestyle and environmental factors, to make informed health decisions and never have to suffer from complex health conditions that their genetic makeup has loaded in their guns.

We want the public, FDA and Congress to know that Pathway is not a direct-to-consumer (DTC) genetic testing company. We define DTC as allowing a customer to order and receive test results without the involvement of a licensed physician. New technologies have enabled expert physicians to facilitate this in ways that differ from a traditional physician-patient relationship, and we feel that this is an important trend in facilitating patient access to expert providers, lowering costs, as well as addressing some privacy concerns. Nevertheless, even though Pathway has always had expert physician and genetic counselor review and oversight over the ordering and delivery of our genetic testing services, Pathway voluntarily suspended the ability for customers to purchase a collection kit at our website or any retail outlets.

Furthermore, the GAO report released at the congressional hearing investigated 15 companies and identified some practices of DTC genetic testing companies that should not be tolerated and have no place within the scientific and medical community. As acknowledged during the hearing, none of the companies that testified engage in those practices, and only one of the other twelve was identified. As a result, media coverage following the hearing focused on Pathway Genomics, Navigenics, and 23andme, and it unfairly associated the scientific leaders of this emerging industry with what the GAO referred to as “bottom feeders” who are exploiting people’s misunderstanding of genetic tests.

We would be remiss if we did not recognize that the GAO report highlights some legitimate concerns that are relevant to Pathway. During the hearing, an audio clip was played that implied that one of Pathway’s genetic counselors encouraged a woman to submit her fiancé’s saliva sample in order to surprise him with a genetic report. It is important to know that the caller was talking to a customer service representative, and not a genetic counselor. Regardless, this occurrence was brought to the attention of our management team immediately after it happened, and long before we knew it was part of a GAO investigation. We addressed the issue with the customer service team to make it clear that we do not accept samples to be submitted on behalf of someone else. Furthermore, we require personal consent for every sample.

Moreover, the GAO highlighted different interpretations in risk of outcomes reported by the GAO. We appreciate how one concludes from this that these tests are unreliable, but it is important to recognize that only applies to the health conditions report, not carrier status or drug response and that this report provides an estimate of risk, not a diagnosis of disease or prediction.   Differences in interpretation of test results are not uncommon in medical care. This is why second opinions are often requested by patients, and it is why doctors differ in their opinions on how to guide patient treatment. It is for these reasons that we encourage our customers to use this information as one additional piece of information to be used in making health decisions, as an enhancement to and not a replacement for other risks including environment, lifestyle and family history. Pathway, 23andme and Navigenics all apply different rules for which genetic markers to use and which research paper to reference for odds ratio calculations, but that does not make them incorrect. To help offer transparency into how Pathway calculates results, we are developing a new web page laying out our processes for scientific curation, the criteria that we use in selecting research publications and the methods that we use to calculate risk for the health conditions report. Additionally, we support the common conclusion that regulatory bodies and industry need to agree on standards, and look forward to an ongoing dialogue with FDA and others to define those.

Moving forward, if this past week highlighted one thing for us it is that genetics and genetic information is significantly misunderstood. Some of this is because our knowledge is swayed by science fiction, popular movies and television shows that portray extreme scenarios, often emphasized for their entertainment value over their scientific credibility. Further, the field of genetics is broad, and it covers a variety of testing. The discussions about legitimate issues and concerns need to be focused more specifically to the types of testing and procedures being analyzed. The issues and concerns surrounding genetic risks for complex, adult-onset health conditions are very different from those surrounding carrier status testing, drug response testing, or other forms of testing. Given the complexity of these issues, in-depth objective analyses and discussion often do not occur, intensifying the potential for misconceptions.

As a leader in this emerging industry, Pathway Genomics does not seek to hide behind these realities or use them to brush off legitimate concerns. We believe that genetic testing holds the promise of fundamentally shifting the delivery of health care, allowing for more personalized treatment and proactive prevention of disease. While our understanding of genetics is still growing, it is no reason to postpone taking advantage of the best information we have today. To that end, this post marks the beginning of a multi-series project being initiated by Pathway to educate physicians, patients, policy makers, and anyone else interested in a greater understanding of the emerging field of genetics. This series will aim to be objective and informative, and will focus on a single topic at a time, allowing us to provide the depth and focus that are needed to establish a fair understanding of this industry, its promise and its risks. Our first post, which will be available here next week, will provide an in-depth explanation of why different genetic testing companies can produce different estimates of risk for complex health conditions.