Where from here?

This is the question I am asked so often.

1. We have the steady progress towards cheap genomes.
2. We have the biggest supporter of personalized medicine running the NIH
3. We have "some" clinical awareness of personalized medicine
4. We have the government aware of the shenanigans of some unscrupulous DTC advertising, etc
5. We have several milemarkers under our belts with genome science..... We are moving in the "right" direction, but where do we go from here

There are several areas we need to investigate. I would like to sum a few of them, both basic science and clinical. Basic Science first.

1. We need to understand precisely how gene regulation occurs in the face of certain common environmental exposures. Trans Fat, Tobacco Smoke, Alcohol, Stress. Is it RNA? Is it Methylation? What precisely is it? Maybe it is all of them and more. But the quicker we understand that, the quicker we can look for signs of these ill effects.....and stop them molecularly

2. We need a good CNV/Indel etc database. Toronto sure, I have heard that. But seriously. We need this and we need it now. Give me Normals, Give me abnormals, Give me phenotypes......This is a very key missing piece of the puzzle which neds to be completed in the next 2 years

3. Junk DNA investigation. This will come once we have a database like the one in Iceland......I am certain this will come. I think that next to nuclear fission, the investigation into the "junk dna" will prove to be one of the most fruitful works of governmental science. Yes, you can quote me on that one.

4. Systems biology. This is one of those areas where we will eventually realize the Greeks were right with phlegmatic systems vs bilious systems.......

Now onto the top 3 Clinical Science targets

1. A complete revamping of the current risk stratification system. What do I mean? We need to develop a process for efficiently introducing genotypic risks into current clinical risk stratification. We need to evaluate the with and without and change in AUC......
1b. We need to evaluate the role of integrating family history in some risk stratification models. I know Dr. Khoury/Scheuner et.al are working on these things, but it sure would be nice to have odds ratios and RRs/HRs for adverse drug outcomes, common autoimmune disease risks, COPD, Alcoholism, Suicide, etc. types based on fam hx integrated with current models.

2. Pharmacogenomics......end of story, we need more science here for more drugs. There is not nearly enough clinical study weight on outcomes. I understand why from the Pharma end, but the US government cannot ignore its utility, especially with the pain they feel from Medicare part D
This area has tremendous promise, but has not seen the will from genetics departments, mine looked at my cross eyed when I wanted to do a PGx study. There has to be a will in basic medical science departments like pharmacology and cell biology to understand the processes and polymorphism which really screw up a drug's effect.....or really enhance it. And there has to be a will in clinical departments to study the outcomes with different therapies based on genes.....

3. I want to know what behavioral outcomes are likely with knowledge of one's family history risk versus genome scan risk vs both together vs with no knowledge.

These are some low hanging fruit that could get accomplished and probably already are........

The Sherpa Says: These are not stretch targets, these are do-able things in the next 5 years or so. If we can accomplish most of these, we will be well on our way to evidence based personalized medicine, which is where we need to be........

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!

Sherpa quoted on About.com

Today I was just informed that I had been quoted on About.com, Dr Glenn Gandelman is an excellent cardiologist working in Greenwich, Connecticut and in New York City. More importantly, he is the lead author of HeartAttacks.about.com.
From the article

"Who can help me obtain a thorough family history?
A basic family history is part of a complete physical examination and should be updated on a yearly basis. It's also a good idea to let your doctor know of any new illness that occurs in your family. In some cases more specialized genetic counseling is required. Your doctor may refer you to a geneticist in such cases. According to Dr. Steven Murphy, a physician with Helix Health of Connecticut, “there are specialists in medicine such as geneticists and genetic counselors who are trained to take and interpret family histories.”

The Sherpa Says: This site is an excellent resource for cardiovascular health and information. Make sure you check it out often.

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?

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!