Plenge Lab
Date posted: November 15, 2014 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Precision Medicine

At the Harvard-Partners Personalized Medicine Conference last week I participated in a panel discussion on complex traits. When asked about where personalized medicine for complex traits will be in the future, I answered that I envision two major categories for personalized therapies.

(1)Development of drugs based on genetic targets will lead to personalized medicine; and

(2)Large effect size variants will be detected in clinical trials or in post-approval studies and will lead to personalized medicine.

This answer, I said, was based in part on current categories of FDA pharmacogenetic labels and in part on how I see new drug discovery occurring in the future.  But did the current FDA labels really support this view? 

The answer is “yes”.  In reviewing the 158 FDA labels (Excel spreadsheet here), my crude analysis found that 31% of labels fall into the “genetic target” category (most from oncology – 26% of total) and 65% fall into the “large effect” category (most from drug metabolism [42% of total], HLA or G6PD [15% of total]).

A subtle but important point is that I predict that category #2 (PGx markers for non-oncology “genetic targets”) will grow in the future.  In other words, development of non-oncology drugs will riff-off the success of drugs developed based on somatic cell genetics in oncology. …

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Date posted: November 12, 2014 | Author: | No Comments »

Categories: Drug Discovery Embedded Genomics Human Genetics Precision Medicine

I have come across three reports in the last few days that help me think about the question: How many genomes is enough?  My conclusion – we need a lot!  Here are some thoughts and objective data that support this conclusion.

(1) Clinical sequencing for rare disease – JAMA reported compelling evidence that exome sequencing identified a molecular diagnosis for patients (Editorial here).  One study investigated 2000 consecutive patients who had exome sequencing at one academic medical center over 2 years (here).  Another study investigated 814 consecutive pediatric patients over 2.5 years (here).  Both groups report that ~25% of patients were “solved” by exome sequencing.  All patients had a rare clinical presentation that strongly suggested a genetic etiology.

(2) Inactivating NPC1L1 mutations protect from coronary heart diease – NEJM reported an exome sequencing study in ~22,000 case-control samples to search for coronary heart disease (CHD) genes, with follow-up of a specific inactivating mutation (p.Arg406X in the gene NPC1L1) in ~91,000 case-control samples (here).  The data suggest that naturally occurring mutations that disrupt NPC1L1 function are associated with reduced LDL cholesterol levels and reduced risk of CHD.  The statistics were not overwhelming despite the large sample size (P=0.008, OR=0.47). …

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