Surprise, Surprise, Genetic risks in Diabetes and Melanoma!

The Annals of Internal Medicine has a great article this week on genetic risks so does the ACMG Genetics in Medicine Journal for May.


The take home point is something which people may find interesting and it is something I feel is very real. I have begun to think that these Genomic tests act a lot like a placebo. They often don't add anything clinically. Hell, they may not even do anything to guide therapy (Pgx and high penetrance genes aside)


But they often act psychologically, either for good, or for bad.


First in the Annals of Internal Medicine; People have been arguing that perhaps testing only ONE snp and representing its risk is for disease is silly and in fact taht the REAL way to represent these risks is with a multiSNP panel. In Fact, this is what has been perhaps the selling point of some DTC genomics companies.


Even with this possibilty, the CDC and NIH are not satisfied with what the DTC companies are representing as risk.......Psychologically, that could be devastating to the would be consumer. Lack of public trust is a BIG DEAL......even in this era of lack of trust in everyone.


So let's look at what a multiSNP panel would do. The deCode/DNADirect T2 test looks at TCF7L2 (rs12255372), CDKAL1(rs7756992), PPARG( rs1801282),, CDKN2A(rs564398)





The Annals did a scientific study looking at these SNPs as well as loci including HHEX (rs1111875), IGF2BP2 (rs4402960), SLC30A8 (rs13266634), WFS1 (rs10010131), CDKN2A/B (rs564398, rs10811661) and KCNJ11 (rs5219).





What did they find?

The GRS significantly improved case–control discrimination beyond that afforded by conventional risk factors, but the magnitude of this improvement was marginal: Addition of the GRS increased the AUC by only 1%.






This is why I love science. The Journalists and Public read the word SIGNIFICANTLY different than I. In this case, statistical significance (which this word connotes) is essentially a useless guidepost. Becaue the enhanced effect was ONLY 1% better rates of prediction.....But my guess is that a crafty PR propaganda firm would USE the word Significantly in a far different way to manipulate the public.






Hence, placebo effect by hyped study results. The result? Buying more tests? Ask DeCode or DNADirect about that one.







But in this case if the results caused a patient to lose weight and exercise, that would be great. I am STILL waiting for that study.






It seems though as if the genetic risks gods have answered my request, at least with melanoma.

What if we could identify risk and the clinical or medical things we could do to prevent offered no benefit?






Hence the case with testing for Melanoma risk genes. Myriad said that Melaris testing would cause a patient to get more skin exams which would ultimately "reduce incidences and detect melanoma earlier." The data for that are not there to make any judgement on its ability to reduce disease.

But what about the psychological effects? Well, in an article to be published in May's edition of Geneitcs in Medicine it turns out that people with a family history of the skin cancer melanoma show reductions in anxiety and depression after getting tested for a high-risk gene mutation.

Over one hundred patients with a FAMILY HISTORY of melanoma were offered testing for CDKN2a, yes one of the diabetes genes.....







Myriad has this test and it is called Melaris. It turns out ONLY 25 got tested.....so this is not exactly what I call a very powerful study...nonetheless....patients who found they carried the high-risk gene had a significant reduction in scores for anxiety at two weeks after testing. Depression scores were also decreased, and remained so at one-year follow-up.






The Australians are particularly sensitive about Melanoma and it turns out it this case like to "feel" proactive.







Hence, Placebo effect, as we aren't sure if clinical exams prevent disease. But also perhaps some therapeusis if the begin to start wearing sunscreen. Something you hoped they would have done based merely on their family history...If the risk was ever conveyed to that member







The Sherpa Says: Placebo effect works, we know this in medicine. The real question is whether it is worth 99,000 USD.......or even 399?

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.

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!