Wednesday, March 13, 2013

Gene expression over mutation

The main utility of genetics in health care may be in gene expression not mutation. We have this idea that by knowing our genetic profile we know our genetic disease destiny and can do something special about it. But disease causing mutations tend to either be rare variants with a strong ability to cause a disease or common variants that only slightly increase your risk of disease. If one of this rare strongly disease causing mutations runs in your family you probably know it and you could get tested to see if you inherited it, if you want to know and if there is something you can do about it. But most of us will have the other kind that increase risk slightly.

For example about 4-5% of people will develop an intra-cranial aneurysm, an artery balloons in the brain and has a risk of rupture, during their lives. About 1% of aneurysms rupture a year so most people will live a long life and die of something else, more likely heart disease, than die from the aneurysm. If you come from a high risk family that have a genetic predisposition to aneurysms you have double, 8-10%, life-time risk of developing an aneurysm. And you may also live out your life with the aneurysm still intact. Smoking may quadruple the risk of developing an aneurysm to 16-20% life-time risk, an even stronger risk factor than the genetics.

So what should you do if you have a high genetic risk factor for intra-cranial aneurysms? Don't smoke, control your blood pressure by exercising, eating more fruits and vegetables and less salt, and get regular check-ups. What should you do if you have a normal genetic risk for aneurysms and don't want a 16-20% chance of developing an intra-cranial aneurysm? "Don't smoke, control your blood pressure by exercising, eating more fruits and vegetables and less salt, and get regular check-ups." Sound familiar?

If you have the common mutations that slightly increase disease risk, which is more likely than the rare strong effect mutations, and want to avoid disease (and you actually do want to avoid these diseases) you will do the same things if you have normal risk and don't want these diseases. Prescreening for genetic risks may not make much difference to healthcare.

Many mutations that cause disease happen after we are born. Cancers often start from DNA damage, from the sun, smoking, pollution, diet, viruses, aging, and some may appear to be spontaneous. The immune system may stop many of these cancers early on before we even know we have a tumor. But once they get established tumors often have distinct gene expression profiles.

In a disease like the metastatic cancer glioblastoma certain genes are commonly over expressed and corresponding microRNAs are under expressed. MicroRNAs are short nucleic acids that suppress  genes. Many genes and microRNAs work in balance with the gene up and the corresponding microRNA down. By measuring the gene over-expression profile of a disease and corresponding under expression of microRNAs we could develop treatments by giving the patients small interfering (si)RNAs that mimic the under expressed microRNAs to down regulate the over expressed genes. These patterns of over-expressed (or under-expressed) genes and corresponding microRNA expression patterns could be a key avenue for use to develop highly targeted disease treatments.

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