Wednesday, June 4, 2008

14 years and still no good genes!

I am preparing a talk for the Connecticut Geriatric Society and I am just can't get over it. We haven't found good genes for Late Onset Alzheimer's Disease since 1994. Sure we have SORL1, GALP and MAPT from the sexy Genome Wide Studies....but nothing increases risk like APOE Epsilon4.

In fact when you look at all the other genetic risks, NONE top an Odds Ratio of 1.5. Why do a I always harp on Odds Ratios? It's simple. If you can't beat the family history risk increase (300-500%) for a first generation relative, then you can't have much clinical significance, unless you have a multiple gene panel that does.

Why is clinical utility so important? Why not just test everyone with everything. I see several problems with this.

1. False Reassurances, patients are led to believe they won't get some devastating disease and thus fail to plan appropriately. And in some cases take preventative measure...This is called Harm to Patient and it is malpractice.

2. Inappropriate Action, there are several modifiable risk factors in many diseases. This often is argued as the reason FOR testing everyone. But this only assumes that modifying behaviors are actually good things. But, did you know some things like vitamins can actually be bad and promote things like cancers? So you mega dose on Folate and end up promoting breast or colon cancer because you found out that you "Process Folate poorly" on a Nutrigenomics test. And that is just Folate, what about preventative medications? Even more dangerous!

3. Exposure to Discrimination, as I stated in previous posts GINA has passed, but will not go into effect until 2009. In addition, GINA does not cover disability, life, or long term care insurance. Nor does it cover any form of discrimination outside of workplace or health insurance. Medical records can be subpoenaed. However, in most states it is illegal to ask for health records without good cause. Unlike corporate information, which can be bought and sold without YOUR permission! This includes identifying factors Ladies and Gentleman!!! This is why this testing should be done in the realm of healthcare protection.

These are merely 3 of the many reasons I see that we should not be applying SNP scans to everyone. There has to be some clinical significance for actions. If you want consumer enabled research, then you have to protect the consumer. Just as if they were a subject under the protections of an Institutional Review Board.

The Sherpa Says: I could go on a diatribe about this forever. But I have a talk to prepare. Imagine this 80% heritability and only 1 gene for Late Onset Alzhemiers....we must not be looking in the right place.


Anonymous said...

Quote: "....but nothing increases risk like APOE Epsilon4."

Maybe we already have all there is? Maybe not?

Check out TRPC4AP on chromosome 20. May 2008 issue American Journal of Medical Genetics Part B: Neuropsychiatric Genetics.

Steve Murphy MD said...

Genome screen of late-onset Alzheimer's extended pedigrees identifies TRPC4AP by haplotype analysis.Poduslo SE, Huang R, Huang J, Smith S.
VA Medical Center, Augusta, Georgia.

Alzheimer's disease is a complex progressive neurodegenerative disorder with profound cognitive decline. Multiple susceptibility genetic variants have been identified with equivocal replication. While rare, collections of extended pedigrees with multiple affected family members are invaluable for genome-wide screens. We have used two extended pedigrees, having 14-15 siblings with four to five affected late-onset Alzheimer's disease patients in each, to identify the gene, transient receptor potential cation channel, subfamily C, member 4 associated protein (TRPC4AP), on chromosome 20q11.22, as relevant for the disease. Multiple significant SNPs in this gene were found with the initial genome scan (after Bonferroni correction). Additional SNPs were assessed in the families and in the controls which were also significant by haplotype analysis. Moreover, 36% of the patients' haplotypes in our collection of late-onset patients had the same haplotype. These results suggest that TRPC4AP is involved with the disease in these late-onset Alzheimer's families. The results also confirm the use of the genome-wide association study for identifying new genetic variants of complex diseases. (c) 2008 Wiley-Liss, Inc.

Not Bad. I will take a read tonight

Anonymous said...

What about inherited epigenetic modifications? Standard genome-wide scans wouldn't find this...could account for inheritability and lack of clear associations in the genome itself.

Steve Murphy MD said...

What about Copy Number Variation. SNP scans poorly address these too. First to market may have advantages....but it definitely is not first to great product!


Kevin said...

Here is one DTC company selling tests for APOE ε4: CLIA Lab + mandatory genetic counseling.

Mike said...

Yesterday I left a comment (as anonymous) asking for examples of where self-initiated non-medical genetic testing caused harm. Today's post is very illuminating, but the first few examples I looked at were, unfortunately not examples of harm. There were examples of learned people expecting there to be harm or, even examples that (IMHO) are off topic.

For example, the UN Article 17 you cite, although written broadly, appears to be more narrowly focused against mandatory testing for employment or insurance needs. Your cited document refers to "Article 2, paragraph 2" many times for clarification, but the document you cited doesn't include Article 2. So I can only infer what the actual intent was.

Interestingly, it does go on to conjecture the case where a person may get a test themselves and then (perhaps) determine that they are at genetic risk for a disorder and modify their health insurance all w/o disclosing this to the insurance provider. That is indeed an interesting problem.

Some of your other examples cite psychological harm that may come to people who try to interpret the results of such testing w/o doctor supervision. I agree that this may become a problem, but you did not cite (nor am I aware of) any examples where it actually has caused a problem. Or... even if it has caused a problem that its magnitude and continuing threat to public health and safety is such that it's worthy of regulation in order to prevent.

Another type of example you cite is that the testing industry is not mature enough yet and that essentially quackery and fraud exists in this fledgling field. I'll concede that point (although some of your cited sources are from 10+ years ago), but think it's off topic as I believe we already have laws for dealing with this. If I understand the law that you're advocating here (and I admit, I may not) you're advocating mandating a doctor write a prescription to have a genetic test done (so as to enforce a learned person be on the receiving end of the results). The correct and already existing solution to quackery is to regulate the entity doing the work, not to regulate the entity requesting the work.

I'm in Washington state and we've just come off of a year where several winter season hikers were killed in mountain trips. This has prompted regulation-happy people to suggest banning such risky activities. Needless to say there are folks who think such a ban is crazy over-regulation government interference. IMHO the stance you're taking seems to be in-line with these people. We're all for safer mountain hikes, we're all for "safe and effective personalized medicine", we're discussing how best to achieve that w/o needlessly interfering with other liberties.