Family History Tidbits

In my search for useful news today, I have come across something near and dear to my heart. Karen Lu at M.D. Anderson has posted on the importance of taking a family history. Her spin is obviously tilted towards cancer, but the benefits of family history or just as important in diseases like heart disease.

From the site:

“Family gatherings are the perfect time to ask family members detailed questions about their health history,” says Karen Lu, M.D., co-medical director of the Clinical Cancer Genetics program at M. D. Anderson.
“It is important to gather information about the health history of your parents, siblings, grandparents, aunts and uncles, and even your cousins.”

She points out that there are some red flags to watch out for in your family.

1. Early onset of Cancer. (I say not only cancer, any disease is important here)
2. Family member with 2 or more "related cancers" (These include things like breast and ovaries. For more info see here)
3. Two or more family members who have related types of cancers. (Too bad some insurers require 3 members to be afflicted in order to pay for BRCA testing)

If you find some of these red flags you should at a minimum ask your physician about genetic evaluation. If you live in the CT, NY, NJ area give Helix Health of Connecticut a call. Genetic Testing may be appropriate for you and evaluation is needed.

Genetic testing involves looking for abnormal genetic changes in a person’s blood sample. People who inherit abnormal genes from a parent may be at increased risk of developing cancer.

“The benefit for the cancer patient who tests positive for an abnormal gene is that doctors can use this information to determine if they are at increased risk for a second cancer and to help family members,” says Molly Daniels, a genetic counselor at M. D. Anderson.

For family members, the benefit to learning that a close relative carries an abnormal gene is that they too can be tested to determine if they are at increased risk for developing cancer.

Those who test positive may begin routine cancer screening exams at a younger age than what is usually advised for the public. High-risk screening enables health professionals to detect cancers as early as possible when there is the best chance of successful treatment and cure. Those who test negative can be reassured that they are not at increased risk because of family history.

The Sherpa Says: The major risk factor in both heart disease and cancer is family history. Perhaps more so in heart disease. Evaluation for these risks need to be done on an ongoing basis. Remember, your family history changes with time. So if you have taken your family's history, up date it yearly or when something you know has changed. A great tool for this is found at the HHS website!

Some times you don't need a genetic test.

Before I head home post call I want to talk about an important case I saw early this morning. I was in the emergency department admitting this poor gentleman who had developed something called angioedema. He had just started a new medication for his blood pressure called an ACE inhibitor. There is some thought that this reaction is brought about by a genetic predisposition. We do have examples of hereditary angioedema and the mechanism for this man's angioedema is likely very similar.

While seeing him and having the Ear, Nose and Throat doctor secure his airway with a cricothyrotomy (a hole cut into the neck to insert a breathing tube) an emergency room tech runs and hands me an EKG. He says "This patient is having a heart attack"

The hallmark findings of heart attack on ekg were indeed there, however there was something more. He was brought into the emergency department not for chest pain, but this 26 year old man came to the ED because he was involved in a bar fight and was drunk. He had a huge bump on his head. Normally the treatment for a heart attack is blood thinners like aspirin. If I hadn't looked at the EKG closely I would have given him these thinners.

No, what this young man had was not a heart attack. He had a condition called Brugada Syndrome (A genetic heart disease). This condition causes sudden cardiac death and placing an Automatic Intra-Cardiac Defibrillator can be lifesaving. Much more so than thinning his blood and risking a bleed in his head. But what would have happened if I didn't read the EKG? Brugada syndrome isn't rare (I saw 2 people with it last month) However, if you have not seen it. You can mistake the EKG for a heart attack. That would have been a costly error in this patient who did have some blood in his brain.

The Sherpa Says: If you have sudden death in your family, please go get an EKG. You never know what you might find. More importantly, what you might prevent. You never know when genetics will show up and the better prepared you are the better care you get. Even in an emergency, genes matter................

Forbes and Genetic Part 3...The Genes

So after that long and drawn out search I am most interested with the genes that these guys chose and why they chose them. I am surprised this article wouldn't have been written by a scientist or maybe a clinician. They would probably be in a better position to say how these gene polymorphisms/tests will perform.

1. Complement Factor H LOC387715; In people with bad copies of these genes, chances of macular degeneration progressing from an early, mild form to a severe one increase 10-fold to almost 50%, according to a study in the Journal of the American Medical Association. Ok so this is true. There is another gene HTRA1 that should have been included. Together these two gene polymorphisms increase your risk of AMD by 40 fold! Also there should have been some mention of the fact that there is some preventative measures you can take now with this disease including eye drops, antioxidants and diet (Fish). Also carotenoids (so eat your carrots!) Or you once you get AMD you could get injections into your eyeballs to prevent progression...Carrots are sounding a whole lot better! 1st round.......Forbes 1 Sherpa 0
2. The next up Apolipoprotein Epsilon 4 variant. The problem...Alzheimers Disease, we have gone over this problem before here. Jim Watson PhD knew that this predisposition was iffy at best. But as I state in my previous post perhaps with analyzing GAB2 we can come up with a clearer picture. But if Dr Watson doesn't want the results....Why should you. I gotta say this pick is pretty poor...for now. Especially because they don't even mention the possibility of modifier genes or Prevention (any ideas?) Round 2......Sherpa 1 Forbes 1
3. Number 3 isn't even a gene. It is a linkage locus. Chromosome 9p21 and the name deCODE shows up! OMG, this one has got me hopping mad. There are so many other linkages, why does this one show up? This increases your risk by 30% only if you are a Caucasian Perhaps a genetic panel should be mentioned. Well, I could name 4 polymoprhisms that show greater risk. And a family member with a heart attack at any age increases your risk 250% take that deCODE! Round 3 goes to the Sherpa, ....Sherpa 3 Forbes 1

The Sherpa Says: I think breaking these up into groups of 3 will be better for all of us. Tomorrow I will write about 4-6. Are you already getting the sense that these guys had no clue what they were talking about?

The Problem with Avandia

Warning....This is a non-genetics post (for now)

Yesterday in the media and the New England Journal of Medicine an article was released. This meta-analysis implicated a PPAR gamma activator named Rosiglitazone in the increased risk of heart attack, and death from heart attack. The risk fo heart attack was increased by 43% and the risk for death from cardiovascular causes was increased by 64%. Now before you get too crazy let's do some data analysis.

1. The study is a meta analysis of 42 articles. This methodology is fraught with problems.
2. The second result....64% increased risk of death is not even statistically significant P value of 0.06 with a confidence interval which includes REDUCED RISK OF DEATH.
3. This study is a policy play, based on the fears of Vioxx.

The Gene Sherpa Says: Don't get me wrong, if you have risk of heart disease in the family, then you should not take this drug now. At least until a full proper study can be done. But please, don't freak out. Just talk to your doctor about this risk!

DNA mutation....Not so fast my friend.

Today results were released from a Genome Wide Association Study. This revolutionary type of research does promise to bring us closer to true personalized medicine. That being said........
The study published in Science today by DeCode and several academic institutions (U Penn, Duke, Emory) shows that a loci on Chromosome 9 (long arm) 21 has been linked to an increased risk of heart attack. This study was almost simultaneously replicated by Dr McPherson in Canada at the Ottawa Heart Institute. The study links are not up yet. I will post the abstracts when they are. This is exciting news, however.

1. This is just in a block of genome, not a gene per se
2. The risk with this polymorphism is 1.6-2 fold
3. In Scheuner's analysis of family history, the risk with one afflicted sibling is approximately 2.8 fold
4. As my good friend Dr Lei at Eye on DNA suggests, this will not change the way we practice medicine....yet. First we need to start teaching doctors how to take a family history, then we can move to QTLs and genotyping.

I hate to be the lead balloon but,

The Gene Sherpa Says: While interesting and it should help discover further causes of heart attack this DNA "test" is not even close to ready for prime time!

Heart Risk Genes in Question

In the April 11th issue of JAMA Tom Morgan and Rick Lifton report a large "Replication" Study intended to identify at risk polymorphisms. I remember Tom running all over Yale collecting samples while I was a medical student rotating through genetics there. Personally I am surprised that the press did not jump all over this study. They evaluated 85 previously studied markers and found absolutely none were linked to increased risk of heart attack.
However family history of MI was higher in cases than controls, the racial subtype was Caucasian, the study identified each gene polymorphism individually. What this alerts me to is the shortcoming of candidate gene analysis (looking for genes based on mechanism of disease process). More importantly it puts an ALERT out that testing for MI predisposition is not ready for prime time quite yet, at least in a pan screening form. Perhaps nuanced testing in specific groups like ALOX5AP in Icelandic and Scottish patients will be the best way to stratify care.
The Gene Sherpa says- Hold on to testing for MI for now. Subgroup analysis will need to be done....again. Soon we will have whole genome analysis of risk genes and that will help solve this mystery. I hope Tom is doing well at Wash U St Louis. If anyone sees him tell him Steve Murphy says hi.

Menopause, Hormones, and You

In the Wall Street Journal today there is a review article regarding recent literature published on menopausal hormone replacement. This article summarizes the debate regarding hormone therapy but does not get to the meat of an article published in the Journal of the American Medical Association(JAMA). The article has some controversy swriling around it. Mainly, that the p-value (likelihood of chance association) was adjusted after the analysis in response to a JAMA request. This is not usually standard practice for publishers as the p-value is usually accepted at 0.05. In this case it is 0.01. Either way the findings are what is interesting.

Traditionally the thought was that menopause and estrogen deficiency was a disease state. As such the "old time" doctors thought that hormone replacement helped prevent stroke and heart attack risk. This was flipped on its head in 2002 when the WHI released some findings which stated that you are actually at increased risk of heart attack or stroke while on the therapy!
This new study points out that there is a window of new onset menopause where therapy does lower risk, however in the elderly >70 years old there is an increased risk. I think that this study has some merit. However, the results can only be interpreted through a genomic eye. Recently data were released regarding ESR1(estrogen receptor alpha) and increased risk of heart attack in men. Currently there are no definitive data on whether estrogen PLUS some gene polymorphism put you at increased or decreased risk. When that data comes, rest assured that labs will be lining up the postmenopausal women. And when that data comes, you will hear it here First!

Genes for Heart Attack Risk/Prostate Cancer Risk

This week in the American Journal of Human Genetics 2 articles about genetic risk for heart attack are published. The findings raise hope of future therapeutic targets and identification of risks. The first study implicates the KALRN gene and an intronic(noncoding) SNP. This polymorphism(change in a gene) was found in almost all Caucasians with early heart attack. What does this mean? Very little so far. The results need to be replicated... But more importantly this gene operates in a totally different system than cholesterol in creating atherosclerotic plaques! The second study is more limited in scope and is less important for pan-ethnicity and only applies to French Canadians.

The news is just as exciting for African Americans as new studies implicated and corroborate other findings that a gene polymorphism could be responsible for up to 2/3rds of prostate cancer in this ethnic group. This set of data may lead to early detection or even prevention. This is the goal of all Personalized Medicine specialists....including myself!

This Week in New England Journal of Medicine

This week in NEJM Armanios et al post a study on telomere repair and Idiopathic Pulmonary Fibrosis. They found that <10% class="blsp-spelling-error" id="SPELLING_ERROR_7">telomere repair genes hTERT/hTR. This condition, as the name idiopathic (or as I like to call it IDIOT-Pathic) states has no known etiology, and no effective treatment. Even worse, by the time you are symptomatic it is nearly too late, as median survival is 3-5 years after diagnosis.

In January the specter of short telomeres was brought up implicated in heart attack. Perhaps telomere testing is the new marker. These studies require replication, but I am convinced that the system of telomere repair is involved in both disease processes.
Stay Tuned.