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?