The Olanzapine Example

Suppose you have a device that will not only tell you the diagnosis but also tells you the best treatment for a patient you have never seen before.   I suspect that it would be very handy, especially in a busy practice.
Now suppose that not only does this device tell you about the medication needed but it also helps determine if the patient will suffer from a significant side effect that may permanently cause physical damage. 
Lastly, this device does not cause pain nor does it require blood, just saliva.  Imagine how useful that would be.
In the real world, such a device would take years to develop and millions of dollars to become a reality.  It would also require significant time and money to pass the FDA barriers in place to protect society.
On the other hand, if you could elicit information from the patient that did the same thing via your interview and observation, the cost would be minimal.
This is the dilemma of genomics in medicine.  The information this there, it is 98%-99% accurate, and it is cheap.  The research for a lot of the uses of this information is still in its infancy but there are some papers that are well researched and practical that are not only intriguing but probably very useful if we could find a way to utilize them.
One example are the genomic studies that involve the anti-psychotic olanzapine.
Olanzapine was first introduced as Zyprexa in the United States as an atypical anti-psychotic that also has mood regulating capabilities.  It went generic in 2011 and is a standard drug for psychotic illness.  The drug has numerous side effects including massive weight gain and a proclivity towards hyperglycemia.  It has proven to be a useful drug but the weight gain issue often requires that the patient switch to another drug before permanent problems occur.
There have been a number of studies on the relationship of certain SNPs to olanzapine in regard to   weight gain and effectiveness.  A study of 88 subjects showed that those with the ancestral variant (C;C) in the rs6280 SNP were more likely to respond to olanzapine that those with the T;T variant.
A study of 67 subjects with the ancestral variant of rs7412 (C;C) who  took olanzapine showed significant weight gain as opposed to the T;T variant.  Two other SNPs, rs5092 and rs4765623 were also implicated in weight gain with olanzapine.
This sounds great, you might think, but there are significant limitations to these studies that need to be clarified.  First, the numbers in these studies are very small.  This could easily been an outlier and a study with thousands of patients might come up with a totally different result.  Second, this is a study of a single group, Caucasians in this case, and we know that various geographic groups have different ratios of responses to a variety of medications.
Third, genes are not disease.  There was a significant tendency for those patients with the variants mentioned to gain weight so there is a risk factor that has to be taken into account but it is not 100% predictive.
Nonetheless, if you have a number of medications you can use that appear to be of equal value, it probably would not hurt if you looked at these SNPs to help you decide whether or not to use olanzapine.
You can bet that if we had the technology in 2007 (the date the paper was published with government money) that Eli Lilly would have had a med rep on your doorstep touting Zyprexa and offering free 23andMe assays.  I understand that it is becoming a standard part of the testing for some researchers to correlate SNPs with their subject drug.  Gene-Wide Association Studies are becoming more available both for drugs and diseases these days.
So if you have a patient with the 23andMe assay, a computer with access to SNPedia, Firefox and an add-on called SNPTips, you could look this up very easily and be able to use the information to make a decision about the use of Olanzapine.
For instance, my rs6280 is T;T, the variant that is less responsive and my rs7412 is C;C correlated with weight gain.  This does not mean that I will have a poor response to the medicine and grow immense in the process, but the likelihood of both is much higher than if I was on another anti-psychotic.
All of the SNPs I mentioned happen to be in the exome analysis from 23andMe (and other vendors, they all use the same lab/chip) which makes the studies available helpful allowing for the warnings about power and scope mentioned above.   Olanzapine/SNP correlation is only one example of what is available so long as you know to  take it with a grain of salt.   Because this type of research is getting cheaper and easier ( GWAS  is often done with available data bases, no humans were harmed in these studies) we will see more and more possibilities like this to help our patients.
Mayo Clinic, Vanderbilt University, and a host of other well known medical centers are already employing these tools in order to individualize medicine.  Many of these centers are still using expensive specific studies but it appears that there are cheaper alternatives that are as accurate, at least as far as the SNPs are concerned.   The trick is to get the analysis correct and that will take some time.  I suspect that that time is short, however and learning to find your way around the confusing genomic landscape is not all that difficult if you work at it a little.

Here is a little cheat sheet for olanzapine.

The Olanzapine Cheat Sheet

Here is a quick précis of the SNP/olazapine relationships.

rs6280 (the “rs” stands for research sequence.)

The ancestral allele is C;C (cytosine.) If a patient has C;C then they are more likely to have greater remission of positive symptoms of schizophrenia.

If the allele is C;T or T;T (thymine) then the response is poorer. This is because there is a substitution of another amino acid on the D3DRD3 receptor.

Rs7412

The ancestral allele is is C;C. Those with the ancestral allele are more likely to gain weight on olanzapine than those with the T;T variant.

So, if you have a patient that has the C;C on the rs6280 he or she is a good candidate for olanzapine (with the usual warnings about the power of the study) but if he or she is C;C on rs7412 then they might gain a lot of weight.

Ideally the patient is a great candidate for olanzapine with rs6280 (C;C) and rs7412 (T;T)

Michael J Keyes MD
Fond du Lac, WI