MS genes and GWAS.

Today I want to once again cool the hype from the media. There recently was a study in the New England Journal of Medicine as well as a candidate gene study in the journal Nature Genetics which identify new risk factors for Multiple Sclerosis.

First what we know
Candidate-gene studies have validated associations between multiple sclerosis and polymorphic variants within the major histocompatibility complex (MHC), but no other loci with a definitive association with the disease have been found.

30 years ago scientists found that immune system proteins called HLAs (human leukocyte antigens) are partly responsible for the genetic factor. HLAs are like identity tags, all cells of the body carry them and the immune system "inspects" them so it knows not to attack them when it's seeking out foreign cells or pathogens to destroy. The gene that codes for them is called HLA-DRB1 and having this variant increases one's chance of getting MS by four times.

Second let's take a hard look at the data

From the NEJM Article

A number of allelic variants had a significant association with multiple sclerosis. Of these, two SNPs in intron 1 of the IL2RA gene encoding the alpha chain of the interleukin-2 receptor (also called CD25, located at chromosome 10p15) are notable: rs12722489 (P=2.96x10–8; odds ratio, 1.25; 95% confidence interval [CI], 1.16 to 1.36) and rs2104286 (P=2.16x10–7; odds ratio, 1.19; 95% CI, 1.11 to 1.26)

A nonsynonymous coding SNP (rs6897932) in exon 6 of IL7RA, a gene located on chromosome 5p13 that encodes a transmembrane domain of the IL7R chain of the interleukin-7 receptor (CD127), also showed highly significant evidence of association with multiple sclerosis (P=2.94x10–7; odds ratio, 1.18; 95% CI, 1.11 to 1.26)

The HLA-DR locus was unequivocally associated with multiple sclerosis (P=8.94x10–81; odds ratio, 1.99; 95% CI, 1.84 to 2.15)

Analysis of the 925 SNPs from the MHC region (positions between 29 and 34 Mb on chromosome 6) conditional on HLA-DRB1*1501 revealed a highly significant residual association signal peaking at rs9270986 (P=1.83x10–17; odds ratio, 5.80; 95% CI, 3.53 to 9.53), which lies close to DRB1. A portion of this residual signal is probably related to allelic heterogeneity at DRB1

The study in Nature found similar findings. Before I say shame on the media for hyping this association I would like to put these numbers called odds ratios into context.

An odds ratio of 1 indicates that the condition or event under study is equally likely in both groups. An odds ratio greater than 1 indicates that the condition or event is more likely in the first group. And an odds ratio less than 1 indicates that the condition or event is less likely in the first group. In this case the odds ratio of having MS would be more likely if you carried the studied polymorphisms mentioned above. But not by much!!!

Let me give you an example. In patients who carry a single change in one of their clotting factors, Factor V Leiden the relative risk of developing a blood clot is 7. Yet when combined with other rsik factors like smoking and obesity, only a whopping 10% ever develop blood clots!

Granted relative risk is slightly different than Odds Ratios. It does tend to measure on the more conservative side... since relative risk is a more intuitive measure of effectiveness, the distinction is important especially in cases of medium to high probabilities. If action A carries a risk of 99.9% and action B a risk of 99.0% then the relative risk is just over 1, while the odds associated with action A are almost 10 times higher than the odds with B.
In medical research, the odds ratio is favored for case-control studies and retrospective studies. Relative risk is used in randomized controlled trials and cohort studies. For more explanation click here

I hope you are still following me. What this means is that an Odds Ratio less than 2 is not impressive. In fact it gives misleading data.

The Sherpa Says: Even with the most tightly linked data discovered over 30 years ago, we still have no curative therapies for Multiple Sclerosis. What that means to me is that we have no clue as to the true molecular mechanisms of this heterogeneous disease. Stay away from the DTC tests that will likely spring up from these studies. Never take a test for risk without the Odds Ratio being at least 2. Now shame on you media, for just publishing press releases and not doing the due diligence regarding these findings!

Harry Potter and Pediatric Grand Rounds

What I love about grand rounds is that no one gets pimped. Walter hosts this edition at Highlight Health. I have a post describing the shortcomings of genetic testing via Otolaryngologists.

From PGR.

"At midnight just over a week ago, the seventh and final edition of the children’s wildly popular Harry Potter series, “Harry Potter and the Deathly Hallows”, was officially released.
To commemorate the occasion, each section of this week’s PGR begins with a quotation or some dialogue from the story. A total of 25 blog articles are included in this edition, each one just as magical as the next, and I hope you enjoy reading them all as much as I did. I intentionally kept my comments short so that you can focus on the content of each article.
So, without further delay, I present to you Pediatric Grand Rounds 2.8"

Do you think in 20 years that the Potter series will be studied in Brit Lit classes?

What good is a map?

Imagine being stranded on a raft......An object is floating in the water. You paddle hard to get it. Once you do, you realize its a map. Hooray, you can finally find some land. Or can you?

There are some significant questions to ask yourself prior to having any utility gained from that map.

1. Can you read the map? I used to be in the Navy. We learned how to read nautical maps. But my father, a retired colonel in the Army, would have no clue where to begin. Imagine someone who had no training......


2. Where are you on that map? If you have no orientation, how could you hope to navigate. Where does the sun rise? Simple question. However, when asked almost 15% of Americans do not know the answer.


3. What is on the land you will be paddling to? If you paddle hard to get there only to find out that there are man eating natives, how good was your choice? Did you really want to find that land?

A map of your personal genome is much the same. Jason Bobe over at the Personal Genome comments on some of these topics. Who should be able to read the map? Should everyone have a Tom-Tom or Garmin? Should there be age limits on querying ability. And what if we find out something we didn't want to know? These are serious questions.

The Sherpa Says:

There will soon be a personal genome option. Everyone will be able to have an economically priced copy. We need some guidance on its interpretation. Personally, computers can only do so much. With all apologies to my colleauge Tim Arimond, we cannot program our way out of needing human interpretation. A computer cannot tell when you are scared, confused, upset......yet. I think that personal genome sequencing holds tremendous promise.........But it is only a map.

Why Can't We Be Friends?

A recent study in the New England Journal of medicine implicated a gene called FTO (Fatso) in increased risk of obesity. If you had one copy, then you had a 33% increased risk of being obese. 2 copies? 67% increased risk. On average people with FTO weighed 7 pounds more.

It is true that we know of some increased risk due to genetics. However, a study published this week in the NEJM suggests perhaps your friends may play a larger role than your genes.

In this study, if you listed someone as your friend, and your friend became obese during the time they were studied, then your risk of becoming obese would be 171%. Much greater than the risk of carrying 2 copies of FTO.

What about the 6 degrees of separation effect? Wht if it was a friend of a friend? Well they found that the increased risk was less than that of FTO's effect. However, there still was increased risk.

The Sherpa Says: This study was performed on the famed Framingham Heart Study offspring. They attempted to control environment by evaluating neighbors. It does turn out that there is no relation between neighbors and obesity.....Unless they are friends...This tells us that social networking is an indicator of risk of disease. Intuitively this makes sense. Smokers hang together, as do illicit drug users, and perhaps as this study shows over-eaters. Why can't we be friends? Because you are fat.

Oscar and Predictive, Personalized Death

I just had to post on this today. In the New England Journal of Medicine there was a brief article on an Uncanny ability by a unique cat.

From the article:

Oscar takes no notice of the woman and leaps up onto the bed. He surveys Mrs. T. She is clearly in the terminal phase of illness, and her breathing is labored. Oscar's examination is interrupted by a nurse, who walks in to ask the daughter whether Mrs. T. is uncomfortable and needs more morphine. The daughter shakes her head, and the nurse retreats. Oscar returns to his work. He sniffs the air, gives Mrs. T. one final look, then jumps off the bed and quickly leaves the room. Not today.

Making his way back up the hallway, Oscar arrives at Room 313. The door is open, and he proceeds inside. Mrs. K. is resting peacefully in her bed, her breathing steady but shallow. She is surrounded by photographs of her grandchildren and one from her wedding day. Despite these keepsakes, she is alone. Oscar jumps onto her bed and again sniffs the air. He pauses to consider the situation, and then turns around twice before curling up beside Mrs. K.

One hour passes. Oscar waits. A nurse walks into the room to check on her patient. She pauses to note Oscar's presence. Concerned, she hurriedly leaves the room and returns to her desk. She grabs Mrs. K.'s chart off the medical-records rack and begins to make phone calls.
Within a half hour the family starts to arrive. Chairs are brought into the room, where the relatives begin their vigil. The priest is called to deliver last rites. And still, Oscar has not budged, instead purring and gently nuzzling Mrs. K. A young grandson asks his mother, "What is the cat doing here?" The mother, fighting back tears, tells him, "He is here to help Grandma get to heaven." Thirty minutes later, Mrs. K. takes her last earthly breath. With this, Oscar sits up, looks around, then departs the room so quietly that the grieving family barely notices.

On his way back to the charting area, Oscar passes a plaque mounted on the wall. On it is engraved a commendation from a local hospice agency: "For his compassionate hospice care, this plaque is awarded to Oscar the Cat." Oscar takes a quick drink of water and returns to his desk to curl up for a long rest. His day's work is done. There will be no more deaths today, not in Room 310 or in any other room for that matter. After all, no one dies on the third floor unless Oscar pays a visit and stays awhile.

Note: Since he was adopted by staff members as a kitten, Oscar the Cat has had an uncanny ability to predict when residents are about to die. Thus far, he has presided over the deaths of more than 25 residents on the third floor of Steere House Nursing and Rehabilitation Center in Providence, Rhode Island. His mere presence at the bedside is viewed by physicians and nursing home staff as an almost absolute indicator of impending death, allowing staff members to adequately notify families. Oscar has also provided companionship to those who would otherwise have died alone. For his work, he is highly regarded by the physicians and staff at Steere House and by the families of the residents whom he serves.

The Sherpa Says: Perhaps this cat is just "sucking the breath" out of the patients.............

WikiPedia Meets Genetics

I just received an email from one of my readers today. Trip said " am med student at Univ of KY, interested in medical genetics and have been reading your blog.........I am recommending http://www.snpedia.com/ for a blog post on the gene sherpa" Well Trip....You Asked for it, You got it..... As they say on that old Toyota commercial....

First I would like to mention that my friend Bertalan over at ScienceRoll commented on this Yesterday. He did an excellent job. Also SNPedia has their own blog although there are only 2 posts so far.....

So Single Nucleotide Polymorphisms (SNPs) are little genetic changes, much like letters in a word. There is some data out there which shows taht when readign a senetnce letters in the middle of a word do not alter the readers undertsanding. This could be the case for a SNP, it may result in no change in the protein function. Or it could be the case that a SNP may change the word altogether.

Even crazier is when a SNP isn't even in the coding region of a protein. This may affect a protein as well. When we make mRNA there is a process called splicing. This splicing could be altered by a SNP located in an intron (noncoding region of a gene) or it could be located in an another gene and affect the protein by epistasis........

Listen, this is all confusing. Much like SNPs are...... It reminds me of other "genetic markers" like HLA haplotypes. No one knows what role HLA B27 has in ankylosing spondylitis....it is just linked to an increased likelihood of having the disease.

So what about SNPedia. This is a catchy idea. There exist several databases out there including OMIM. However, the more databases, the better. If we can cross reference these for validity it certainly would be nice.

In reviewing SNPedia I performed searches on several SNPs including in TCF7L2 and CCR5. The database has listed some but not all of the associations within each of these "genes" in fact CCR5 is not only an HIV associated gene, it is also implicated in abdominal aneurysms.

The Sherpa Says:

Any database is only as good as the data in the base. I feel that opening it up to public contribution through wiki is a great idea. However, we must assure the public that SNPedia will be monitored by a knowledgeable set of curators.

Personalized Service Leaving Insurers

Today I want to pose a question. This has nothing to do with personalized medicine per se. However, some think that the "concierge" model will allow for a truly personalized service. Why? Well for one, the doctor will be able to spend the time to gather a good family history. Secondly, by working less the physician will be able to devote more time to continuing medical education. Here's what some physicians think

What do you think?

Pediatric Ear Nose and Throat but Not Gene Specialists

In the Archives of Otolaryngolgy last month a questionnaire was sent to pediatric Ear, Nose and Throat (ENT) doctors. These physicians frequently evaluate things such as recurrent ear infections or even childhood hearing loss.

A significant amount of this hearing loss can be attributed to genetics. This survey intended to see how many ENT's used genetic testing, whether they were able to handle results as well as counsel properly.

Here's what they found

1. 69% indicated that they use genetic testing of the connexin 26 (Cx26) gene (GJB2) as an initial test in their workup of prelingual sensorineural hearing loss
   
2. 71% reported that they provide genetic counseling for their patients and their families


3. 45% answered questions regarding recurrence risks incorrectly or stated that they did not know the correct response

The Sherpa Says: This is precisely why we need genetic counselors and geneticists. 45% is not a small number, but I was surprised it wasn't 75%. At a minimum we need a good curriculum in medical school which teaches the principles in this ever changing field. Too bad you can't just pick up genetics on the job. Trust me, you can't. I warn you to run away from any physician who states that they have!

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................

Restless Legs and deCODE

In the New England Journal of Medicine next week there will be an article on yet another study done at deCODE. Their model may be that of the next wave of pharma companies. Personally, not a bad model, but imagine Pfizer sending press releases on all of their Phase one data. It would result in a lot of "white noise" that may or may not have some future health news. That seems to be what is going on in Reykjavik. At least they are getting their money's worth for the Icelandic genome.

In this study the research team conducted genome-wide scans of nearly 1,000 Icelanders and 188 Americans. A new chip technology was applied along with genome wide association methods. This approach allowed Drs. Rye and Stefansson to probe more than 300,000 small regions (single nucleotides) distributed across the entire genome for differences more common to RLS sufferers as compared to population-based controls.

The expedition was to find a gene linked to Restless Leg Syndrome. Sleep is often interrupted in these patients and can lead to a terrible lifestyle. There is a high prevalence of this disease in North America and Europe. Seemingly a Caucasian disease it was natural to look for this linkage in the Icelanders.

Here's what my Head Genomic Counselor had to say:
"They found an intronic SNP in the BTBD9 gene that has an OR of 1.7 for PLM (heterozygotes) and an OR of 2 – 4 for homozygotes for the A allele (vs. the wild type G allele).
The interesting thing is that it seems to be associated with PLM alone and RLS with PLM, rather than RLS without PLM.
They replicated the association in three independent patient groups – two in Iceland and one in the US. Seems like a good study from a design perspective."

What does that mean? Let me translate. The searched the genome of these Icelanders for genes linked with restless leg syndrome versus periodic leg movement disorder in sleep. RLS is a common neurologic disorder which involves both sensory and movement components. Identification of the genetic under pinnings in RLS has been difficult because of several confounding variables including other medical conditions. Periodic limb movements in sleep are a component of RLS. These movements can also be absent in the presentation of RLS.

The group found and replicated a non-coding change in a gene called BTBD9. This gene was also correlated with depleted iron stores. RLS has been long linked to iron deficiency and this makes this whole study "seem" to be correct.

The Sherpa Says: All this is fine and Dandy, but what clinical use will this finding hold. Personally, I feel that this is a confusing issue. The predisposition test would let us know something that we currently cannot prevent. Testing for this???? I wouldn't recommend it. But I am certain they will market this test just like the risk for atrial fibrillation. Not a bad model over there......too bad it could lead to misguided healthcare in the wrong hands. Why? Because who would tell you to take a blood thinner, just because you have a predisposition to atrial fibrillation? Only those doctors looking to get sued........

SACGHS and DTC testing

The SACGHS met this month and alloted 15 minutes to the CDC presentation on awareness to DTC tests. The CDC funded three states to study awareness of DTC testing as well as utilization of DTC testing. They also performed a national study. The presentation reviewed this data and of note there were some intersting findings

1. Only 0.6% of the national population has used DTC tests (BTW that's 1.8 milllion people)


2. 14% of the US population is aware of DTC testing


3. 73% of those who were aware, heard through the media


4. Yet over 60% who used the tests were directed by DOCTORS!!!!!!

In addition a survey was administered to physicians. This DocStyles study had 555 physicians who were aware of DTC testing. Of Those

1. Only 4% of MDs report >10% of their patients asking for DTC testing


2. And an amazing 93% of physicians report <1%>
   
3. 96% of physicians report Journal Articles as the most trusted source for Genetic Testing Information. ONLY 6% report that other health professionals are a trusted source for Clinical Testing! (Does this include CGCs or Geneticists?)


4. The majority of info physicians receive on DTC testing is from the media, not Journals.

The Sherpa Says: There are some limitations with the public studies. One thing is for sure.....The media has a powerful lock on distribution of this information. Did you hear that Mr Murdoch? I am truly scared that the physicians do not find other physicians knowledgeable or trustworthy. YIKES!!!!

Weekend Off, But Genetics Never Rests.

I took the weekend off from posting because I was in the hospital 3 days in a row. It is truly amazing how little you know when you start internship. I am frankly amazed that there aren't more problems during July. The statisticians must have been crazy.

Rule number 1-Don't get elective care in July
Rule number 2-Don't go to a training hospital in July
Rule number 3-Always ask about the medications a nurse gives you

Enough public service.....Back to genomics and personalized medicine.
I was sent an email the other day from a company called Genelex. You may have heard of them. They have been offering pharmacogenomic testing since 2000. Yes that is correct. I thought we should take the time to review what this company offers.

The first tool is called GeneMedRx.
According to the site : GeneMedRx is the first software tool available to prescribers that predicts drug-drug interaction risk based on both cytochrome P450 metabolism and genetic testing. This allows for enhanced understanding of metabolism-based adverse drug interactions or lack of efficacy.

I would say that after reviewing this tool it is a very good resource that should be considered. In addition, a company such as Revolution Health or even an EMR would be smart to snap up a tool such as this. It has over 2000 drugs and metabolites as well as significant links to PubMed. For a demo.

I will continue to review this company throughout the week. They have some very useful and some debatable services as well.

The Sherpa Says: Sorry for the weekend off. I know.........But like C3PO says "Please don't deactivate me" There is alot going on this week and I hope to cover it all. Keep Climbing.

This week in NEJM

So I have been reading about how the new article in the New England Journal of Medicine shows that BRCA gene mutations are not worse than sporadic breast cancers due to non-BRCA mutations.

If you look at the article you will see that there are many reasons why this is flawed thinking. But more importnatly it flies in the face of another study which actually showed and increased risk in worse outcomes with BRCA1 mutations.

So on closer inspection what was the NEJM article about?

They took all breast cancer specimens available in Israel's National Healthcare repository and looked for 3 I repeat 3 FOUNDER MUTATIONS....... This immediately makes the study invalid to comparison on women who have non ashkenazi mutations, especially if they are not founder mutations.

Secondly they analyzed outcomes retrospectively. This is a notorious way to get confounding results as well.

Thirdly this study did not have interpretable data regarding estrogen or progesterone receptor status.......This is a big deal!!!

And Lastly,
"We had 16-year follow-up data on mortality and incident cancers, but information on the cause of death was available from the Central Bureau of Statistics only for deaths that occurred before 2000." None from after 2000........

The Gene Sherpa Says: Before bloggers and press go off half cocked in this interpretation we need to be careful in how we evaluate this study. This ONLY means if you are an ashkenazi jew from Israeli heritage and have one of 3 founder mutations, then you are not more likely to have adverse outcomes than ANYONE else who is Israeli and Ashkenazi with non founder mutation breast cancer....That's IT. Nothing else can be extrapolated here. To those who are.....tread carefully...Because you are misleading the public!

No More Skin Biopsies????

Imagine going to your dermatologists office and instead of getting biopsied for your funny looking mole, the dermatologist places a little sticker on the mark.

He sends it off in the mail and later that week you are told that it is just a mole....phew......

That is the promise of a new technique called EGIR or epidermal genetic information retrieval. A new company called DermTech has just developed the technique. So what is the technique and how does it work?

The tape collects RNA from the skin sample. The sample then was amplified as cDNA and a microarray checked for the 117 gene analysis. This technique was studied and a 5 gene profile was adopted and accurately differentiated melanoma from benign skin changes. This technique is being evaluated at University of California San Francisco.

The Sherpa Says: In general only 3-10% of suspicious lesions are actually melanomas. The traditional method to detect includes a scalpel excision.....Tape......Scalpel... You decide. However, this is only a small study that determined proof of concept. There is a replication study underway and despite being great for the patient, the dermatologist can't exactly bill for RNA extraction. They do get paid very nicely for skin biopsies though. Not quite for prime time, but it does demonstrate how ubiquitous genetic soon will be in the office.

The Danger in Genetics

My great friend Adam Messenger just sent me an article which I can't believe I missed. Late June in the New York Magazine there was an article entitled "The Science of Gaydar"

Has anyone read this article? After I did, I was very frustrated....

From the article-

"If sexual orientation is biological, are the traits that make people seem gay innate, too? The new research on everything from voice pitch to hair whorl"

I do not remember a time when sexual orientation was classified as a disease.......However that is only because I am young. Ask a host of physicians and they will tell you that until 1973 the American Psychiatric Association viewed it as a mental illness along the lines with bipolar disorder.

"Back then, many psychiatrists treated homosexuality with shock therapy, detention, or a mind-twisting intervention called “aversion therapy”—a practice that was still in vogue in the late seventies, when a lumpy-faced psychiatrist put me through a regimen of staring at Playboy centerfolds."

The author talks about how classical morphology is being used to evaluate for sexual orientation. I feel this is almost as if they are discovering a new "syndrome". If you examine all first print literature of genetic syndromes you find much the same associations.

In fact there is a book that lists standard and accepted measurements for moprhology. This book used to be a mainstay for skilled clinical geneticists. There is another textbook called Smith's Recognizable Patterns of Human Malformation. The piece made me feel as if sexual orientation was soon to be listed in this book!!!! I am certain this will make the public feel similarly.

"A large-scale study within the next year is expected to determine more conclusively if a gene (or genes) is linked to sexual orientation. Alan R. Sanders, a psychiatrist from Northwestern University, is enrolling 1,000 pairs of gay brothers in one of the largest sexual-orientation studies ever undertaken. With the experiment, funded by an NIH grant of over $1 million, Sanders will attempt to map genes that influence sexual orientation."

This will create the first data in a long time on the subject. The Xq28 stuff is really suspect and I am certain there will be a much different take once this "study" completes.

But I agree with the author on his final assumption.

"It’s bizarre to think some value systems might lump gayness in with—say—sickle-cell anemia or Down syndrome. As Matt Foreman from the Task Force put it, “It’s not playing with the number of toes you have; it’s really manipulating your very essence. So many people see gay people only in terms of sexual behavior, as opposed to what sexual orientation is really about, which is how you fit into the world. I don’t want to get mushy, but it’s about your soul.”"

The Sherpa Says: What I have a hard time with is the simple fact that morphology analysis is being used. Even worse is the use of the term "gay gene" Yes genetics will impact everyone's life, but must we go at sexual preference. Aren't there bigger things to answer? Yes there should be some study of things considered deviant: child molestation, rape, etc. But I thought homosexuality was declassified in 1973......I guess I was wrong. If deCODE or any other DTC company markets a "gay test" please do not go out and take it!!!!!!!! Please!!!

Multiple Sclerosis Risk Passed Equally By Parents

Recently a phenomenon known as the Carter effect has been put in to doubt. At least for the horrible disease Multiple Sclerosis (MS).

A study published in the journal Neurology last week indicated that the transmission of MS risk is not skewed based on sex.

"Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. The precise nature of these factors and mode of inheritance remains unknown. A female predominance is universally found. Recently, offspring of affected fathers were reported to be more likely to have MS than those of affected mothers. This was attributed to the Carter effect, which is seen in polygenic disorders. The Carter effect predicts that affected parents of the sex lesser affected by a disease/trait are more genetically loaded for risk alleles and thus transmit these more often to their offspring."

The study found that both men AND women afflicted with MS transmitted the disease about 10% of the time to their offspring.

The Sherpa Says: This is a study which calls into question old notions of thinking regarding genetic predisposition. Unless this is a sex linked disease, we should not see skewing. This old thinking was much along the lines of "Only women pass on breast cancer". I am glad to see it go. However the critics of this study will note that 3 times as many afflicted mothers were studied. Also no genome wide association studies have identified any genes in this likely multifactorial disease. Patience......they will come.

Taking Appointments For August

After Much Ado, Legal Wrangling and Getting the Practice up, we are now accepting patients!!!! We have dates available in August. I have to tell you how very excited I am about this revolutionary style of medical practice. Heck, even when I talked with Dr Collins he was excited.

The biggest problem with genetic care as well as primary care is its true lack of continuity. Helix Health of Connecticut of CT will fix that problem and more. Yes, I know you may be thinking "Gosh, this is a shameless plug for his personalized medical practice"

You are correct it is completely shameless. It is a revolution. The future of health care is about to change in a big way.................

Diabetes Risk Model Without Help from deCODE!

A study was brought to my attention by Helix Health of Connecticut's Genomic Counselor Sarah Coombes. This study which was published in the journal Archives of Internal Medicine(a very respected academic journal for primary care physicians) showed that Parental diabetes, obesity, and a low good cholesterol were better predictors of diabetes risk than complicated algorithms and complex clinical models.

The incidence of type 2 diabetes is skyrocketing and predicting onset can help us guide interventions. In the public health schema it can have tremendous effects when anticipation guides development of preventative strategies. This is the case with heart disease and cholesterol lowering modifications.

Parental history of diabetes, obesity, HDL(good cholesterol) less than 40 predict diabetes onset at a greater rate than ANY GENETIC TEST OUT THERE!

Most importantly, your insurance pays for the HDL and glucose tests.

The Sherpa Says: This study which evaluates the offspring of the famed "Framingham Study" is excellent. The point with personalized medicine is not just sending genetic tests. True, this study needs to be validated in all ethnicities not just those who were found in a suburb of Boston (Caucasians). But, I would use this risk stratification tool on all of my Caucasian patients. True personalization comes not only from genetic tests, but also from other traditional labs AND family history!

Sherpa Posts Total 100!!!!

No I am not nearly as prolific as some of my contemporaries, but hey I have only been at this since March ;)

I hit the milestone of my 100th post today. In my championing, flaming, arguing, almost getting sued (Thanks San Fran!), and just plain out bashing quacks I have discovered some amazing people and some amazing sites. The following is a running tally of blogs I love. Some genetic, Some medicine, Some not so much.

• Scienceroll by Bertalan Mesko soon to be MD



• Bad Science by Ben Goldacre MD



• Eye on DNA by Hsien Lei PhD



• Highlight Health by Walter Jessen PhD



• Revolution Health's CMO Jeff Gruen MD



• The DNA Network and its littany of great blogs!



• Mashable the blog for social networks



• Buddhist thought by James Ray



• The Entrepreneurial MD



• Great Pics from around the World at Cosmos



• The latest and greatest at Science Friday



• The Wall Street Journal's Health Blog



• Wired's Science Blog



• NPR's On The Media
  

I know that this only 14 blogs but each is worth its weight in gold. It is Thursday and July so forgive me but I have to deal with some new interns :)

The Sherpa Says: Thanks to all of you. I look forward to the announcement when I hit 500 posts! Let's keep our eyes open and realize that there are a whole lotta people out there trying to oversell genetic tests. Or even worse. Knowledge is just a set of unorganized facts. Wisdom is knowing where to find the answer. I will strive to give you that answer or at least have the wisdom to find it.

Happy Independence Day US!!!!

The Sherpa Family Would like to wish all of you A Happy Fourth Of July!

Even for my friends from every country of the world. Take this day to remember everyone who fought hard to give us the lives we now enjoy.

-Take Care

Which came first? The cancer or its chromosomes?

Every now and again I like to throw out the old paradigms and put in some new. Geneticists love this......The So Called "Paradigm Shift"

Back in 2005 this was done with Marfan's disease. It is an example I use to teach my students that what they may have learned is wrong. It is wrong because medical teaching is only built on science that has a very limited set of knowns and an immense set of unknowns.

This paradigm shift is already in the making.

The classical model of how a cancer develops is called the "two-hit" hypothesis. It states that in order to have uncontrolled growth of cells i.e. cancer, you need two hits to genes. Mostly you have to have at least 2 mutations. Sometimes you activate a gene by mutation and other times you may silence the genes. For the last 30 years the view of cancer is a very geno-centric. Just look at our so called targeted therapies. They block single gene proteins. Guess what. Even when these elegantly designed therapies are administered some cancers develop resistance. Why? I thought that the genes mutated were what caused the cancer. Shouldn't this wonderfully targeted therapy work for all cancers with this gene mutation? The answer is the same as for this question...

Shouldn't all persons with sickle cell have the exact same disease prognosis and complications? NO....no gene or genes are an island!

This new paradigm states just that. It says cancer is the result of 1000s of genes and the chromosome is really the master here. Screw up enough chromosomes and you get cancer. Let's face it. It is now known that gene expression arrays predict the response to chemo better than a single gene or even a microscopic cell type. This indicates that massive gene expression changes similar to those you may get from a chromosomal anomaly could be at play. Is this true? And what role will it play in the personalized therapy for cancers?

The Sherpa Says: This is very likely to be true. That is not to diminish the role of those rare cancers that are uniquely mono/bi-genic. This will lead to better therapies and earlier detection. It could eventually mean that every single case of cancer will truly be personalized and will require personalized medicine in the truest sense.......

Britain Needs A Sherpa!

I just received an email from a reader who pointed my attention towards a popular morning program in the UK. They interviewed a person who had taken a genetic risk test despite the significant cost (I am uncertain of the test). The costs online are up to 1000 pounds, almost 2000 USD!

She did this simply because she was concerned about pancreatic cancer (her father had died of it as age 69). She announced that she was free of the risk of pancreatic cancer but had learned that she shouldn't take HRT and had stopped it.

She had also learned that she was at risk for age-related Alzhemers' (although the discussion wasn't at all clear". The discussion ended with the enthusiasm for the testing from doctor who is associated with the TV show and a call from the lay-woman that such comprehensive screening should be made available on the NHS.

My reader did think that it was interesting that there was no discussion as to the considerable potential costs to the NHS of follow-ups that have to be ordered after such screening.

The company feature in this show was GeneticHealth and from the looks of it they are cashing in on the snake oil gravy train. Francis Collins has warned of this type of testing. You can tell what they aim to do by looking at their news headlines "Could your DNA hold the key to a wrinkle-free face and a great figure?"

Thanks To Shinga Xavier for the heads up on this madness.

The Sherpa Says: How come no one in the UK is railing against a company like this. In the US there are significant consumer protection laws. Still even here they fall short in protecting completely. This woman thinks she is risk free of pancreatic cancer........Doubtful. What kind of doctor do you have on the Boob-Tube speaking the benefits of this bogus testing? The answer....He's a boob on the tube! Direct To Consumer Testing for non binary tests is absolutely dangerous and must be stopped!!! The Sherpa is Hoppin Mad!!!