GeneSequence™ Blog

A recent study published in Circulation found that women with genetic predispositions to thrombosis had a whopping 49% reduced risk of venous thromboembolism (VTE) when given vitamin E supplements. What’s the big deal? VTE can lead to pulmonary embolisms and deep vein thromboses and indicates a generally hypercoagulable state which is also associated with heart attacks and strokes. The study compared the use of 600 IU of natural vitamin E to placebo in 40,000 female subjects with and without the Factor V Leiden (G1691A) or Factor II (G20210A) mutations.

All women in the study who took Vitamin E had a reduced risk of thrombosis, but the study’s conclusion specifically stated that women with a previous history of VTE or a genetic predisposition to thrombosis could particularly benefit from vitamin E therapy. This is the kind of research that is building the up and coming field of “nutrigenomics.”

What I particularly like about this study is that they used a natural source of vitamin E, whereas previous studies used a synthetic version that inherently performs poorly. Foods high in vitamin E include: seeds and nuts, whole grains, egg yolks, and leafy green vegetables, wheat germ oil and unprocessed vegetable oils. Sadly, it is not practical to get 600IU per day from foods alone, so supplements are the way to go.

Conclusion: If you or your family have a history of thrombosis, consider getting tested for hereditary thrombosis indicators like Factor V Leiden and G20210A. If the test determines that you are at increased risk, taking a natural vitamin E supplement every day can reduce your risk of thrombosis. Simple as that.

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The Gilbody Study published in the American Journal of Epidemiology last January found that the MTHFR C677T variant was associated with an increased risk of developing not only schizophrenia but also depression and bipolar disorder.

For those of you without biochemistry backgrounds, MTHFR is shorthand for the enzyme Methylenetetrahydrofolate-reductasean enzyme that helps the body recycle the B-vitamin folic acid and process the metabolic waste product homocysteine. The C677T variant is a single nucleotide polymorphism (SNP or SNiP) where gene that codes for the MTHFR has a base substitution in the DNA at position 677 where cytosine is replaced with thymidine. The result is more fragile enzyme which causes decreased activity and predisposes the subject to having low levels of the folic acid and high levels of homocysteine which itself is associated with heart disease. Of note is that the Gilbody Study specifically mentioned the possibility of using folic acid in the treatment and prevention of the associated mental health disorders. Exciting stuff!

It is also important to note that having this genetic variation does not mean that one will necessarily develop mental illness. These conditions are well known to have highly multifactorial causes, and there are many more examples of people with these genetic variations without the disorders than those with the disorders. In an ideal world, diagnosis of these MTHFR variants will enable environmental, behavioral and nutritional interventions that can not only assist in the treatment of these mental health disorders, but also help prevent susceptible patients from developing them in the first place.

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Syndromes with poorly understood causes, inconsistent presentations, and ineffective treatments are the bane of practicing physicians. The main hope for these conditions is that eventually incremental scientific advances will help divide them into more predictable, preventable, identifiable, and treatable diseases. My guess is that schizophrenia (literally divided heart) is headed for functional divisions itself. Roffman and colleagues published a study in Biological Psychiatry last Spring indicating that genetic variations of the MTHFR gene influence what symptoms will predominate in schizophrenia.

Lets back up a bit. Psychologists divide the symptoms that diagnosed schizophrenics present with into positive and negative groups. Positive symptoms (not to be confused with desirable) are additions to normal experiences that people without schizophrenia diagnoses rarely experience. Examples of positive symptoms include hallucinations and delusions such as paranoia and delusions of grandeur. Negative symptoms are those that involve degrees of absence of normal experience and behavior including loss of interest, energy, warmth, humor, expressiveness, being slower to think, talk and move.

With regard to schizophrenia, the Roffman study states that having the C677T MTHFR variant increases the risk for negative symptoms in schizophrenia, while reducing severity of positive symptoms.

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With the FDA’s recent relabeling of warfarin, the real clinical challenge in determining appropriate dosage is understanding which genetic warfarin dosing panel to order. There are different tests in application. It is important to order a test that takes into account all of the ethnic variants in the sequence. This is a critical point for providers to understand when ordering these dosing tests.

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Right out of medical school, while I was studying for my board exams, I took a job at a hospital laboratory in the Ballard district of Seattle. After proving myself by getting blood out of the needle addicts on the top floor I was shipped down to the outpatient lab. During the day the waiting room was often overflowing with clients waiting for blood draws. On average, I’d say that nearly half of the patients were on warfarin and having their prothrombin times tested on a monthly basis. Most of them were not happy campers. For a warfarin patient, bumping your shin on a coffee table can be a major event, so a blood draw is the last thing you want to do. After the blood draws, we had to wrap the patients up very carefully lest they run the risk of returning five minutes later with blood running down their arms from the tiny venapuncture holes.

Why are we testing these patients so often? Warfarin has a very narrow therapeutic window—too much leaves the patient at risk for bleeding, too little leaves them at risk for a heart attack or stroke. That bad situation gets worse when you consider the fact that there is a 10-fold inter-patient variability in the dosing required to attain a therapeutic response in terms of the INR range (International Normalized Ratio target is 2.0-3.0).

Despite all the extra monitoring, warfarin is still the second most common drug (after insulin) implicated in ER visits for adverse drug events. Major bleeding events occur in half of patients during the first 90 days of warfarin treatment. Clinicians and patients alike have been asking for a long time “what can we do about this?”

Before genetic tests were available, clinicians were essentially shooting in the dark with regard to the starting dose for warfarin patients. Recent developments in genetic testing have identified variants in two key genes related to warfarin metabolism: CYP2C9 and VKORC1. Though far from the whole story (depending on who you ask, estimates of the effect of these two genes on warfarin dose variation range from 39-56%) together identifying these two genes holds significant promise in helping health care providers dial in the right dose for patients starting warfarin therapy.

In August 2007, the FDA recommended genetic testing prior to initiating warfarin therapy. The Iverson Warfarin Dosing Panel satisfies this recommendation. Check out the FDA press release here.

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The U.S. House of Representatives passed the Genetic Information Nondiscrimination Act (GINA) in April of 2007. The Senate version of GINA (S.358) is still in process.

The Health Insurance Portability and Accountability Act (HIPAA) of 1996 was the first federal protection against genetic discrimination. The act prohibited health insurers from excluding individuals from group coverage due to past or present medical problems, including genetic predisposition to disease. The law specifically stated that without a current diagnosis of illness, genetic information in the absence of did not constitute a preexisting condition.

Sounds great, right? A closer look reveals that HIPAA left the door wide open for genetic discrimination. Specifically, It did not stop insurers from requiring applicants to undergo genetic testing, didn’t prevent charging higher insurance rates to people with genetic risk factors, didn’t stop insurers from collecting genetic information, and didn’t stop or limit the disclosure of genetic information about individuals to insurers. Pretty big holes if you ask me.

Later on, the (Bill) Clinton Administration supported Nationwide laws strengthening HIPAA protections, but they failed to pass congress. In February 2000, Clinton issued an executive order prohibiting federal agencies from obtaining or using genetic information in hiring and promotion decisions.

On April 25, 2007, the Genetic Information Nondiscrimination Act (GINA) of 2007, H.R. 493, was passed in the U.S. House of Representatives, by a vote of 420-3. The GINA Senate bill, S. 358, has yet to be voted on in the Senate.

In case you are curious about what protections are in place now, check out the National Human Genome Research Institute’s (NHGRI) Genetic Discrimination Fact Sheet.

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Many patients ask me: Does having a gene that predisposes you for a particular disease mean that you will get the disease? The simple answer is no, having a risk factor does not mean that you have a particular disease or that you will necessarily develop it.

To illustrate this point, this summer scientists published studies which showed that genetic variations of the IL-2 and IL-7 receptors each add about 20-30% chance to an individual’s risk of developing the nerve demyelinization disease Multiple Sclerosis (MS). While these numbers may seem impressive, it is important to note that the incidence of MS in the Northern United States is about 30 cases per 100,000 and so a 30% increased risk is not by itself jaw-dropping from a public health standpoint.

The new research about the interleukin receptors link to MS was a BIG breakthrough though. These were the first genetic links to MS found since 1972, when researchers discovered that having a variation in the HLA-DR which raises the risk of developing MS nearly six fold.

The million dollar question then becomes: Why do some people with these three genetic risk factors get MS while others with the same genetic risk facts do not? First, I’d say that we are a long ways off from knowing all the genetic risk factors for MS and even further from understanding the interactions between these genes. Genetics aside, my guess is that investigations into psychoneuroimmunology, environmental exposures and other lifestyle factors will fill in many of the blanks left behind by the genetic links.

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Many genetic diseases have gendered predispositions. Multiple Sclerosis (MS) is one of these sex-linked diseases where women are affected about twice as often as men. The “Carter effect” dictates that in these diseases one can expect that offspring of the less effected gender (males in the case of MS) might be more likely to develop MS than children of the more affected gender (females) due to an expected loading of genetic risk factors in the physiologically resistant gender.

Last year, Neurology published a Mayo Clinic, National MS Society and NIH funded study which “proved” that the Carter effect is demonstrated in MS. The Study’s conclusion states: “The authors have demonstrated the Carter effect in multiple sclerosis (MS). These observations may be explained by greater genetic loading in men that leads to relative excess paternal vs maternal transmission.” Ah certainty. Feels good, doesn’t it?

Well, not so fast. According to a Canadian-based study also published in Neurology this summer, there is “no evidence for the Carter effect” in MS.

This is an example of how new the field of personalized medicine is, and serves as a reminder to keep our beliefs flexible while we continue to refine our understanding of the causes of diseases like MS.

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Smoking is considered one of the hardest addictions to break. Ever wonder why some people have an easier time kicking the habit than others? One answer comes from research in a new field of medical research called pharmacogenomics from the National Institute on Drug Abuse (NIDA). Read press release here.

This research indicates that people who have a genetic variant of the CYP2B6 gene (which codes for one of the enzymes that metabolize bupropion in the human body) were less likely than those without it to have resumed smoking six months after treatment with bupropion (Zyban). How prevalent is this variant? The good news for smokers is that it is present in 45% of Americans of European descent, 50% of African Americans and 25% of Asian Americans.

Once genetic testing is available for this variant, health care providers may have a better idea of who will respond better to the bupropion and, perhaps more importantly, who will respond best at particular doses.

This is one example of the growing field of pharmacogenetics—which many expect to usher in a new era of medicine where treatments are personalized based on individual genetic profiles. For more information on pharmacogenetics check out the National Center for Biotechnology Information’s Science Primer.

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