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Eagle Eye: New Gene Research Target

Posted Aug 26 2008 4:32pm

The 'Eagle Eye' is a new recurring blog item that will look at cutting edge research into the root causes and potential 'cures' for heart disease. The latest item is the research into the 'kalirin' (KALRN) gene and the 'Rh0-GTPase' signaling pathway. The abstract can be found at http://hum-molgen.org/NewsGen/03-2007/000023.html Let's break it down in layman's terms for all those who slept through Bio-Chem lecture with special thanks to University of Wisconsin Honors Bio-Chem major - and my daughter - Caitlin (you didn't really think I was that smart did you?).



Researchers looked at chromosome 3q13-21 (a specific section of a human DNA strand), a site already established as playing a role in early onset atherosclerosis. We remember (yeah, sure) that DNA is simply a 'biological program' for creating the basic proteins that make up living organisms. It is composed of a long sequence of nucleotides (a fancy word for a group of four chemical compounds adenine , cytosine , guanine , thymine abbreviated A, C, G, and T respectively) that are organized into what we know as 'genes'. These sequences of A, T, C, and G, our genes, determine what proteins are made (thousands of them) and ultimately determine what the end result of the process is (an artery for example).



The researchers also considered little glitches in our genes called ' Single Nucleotide Polymorphisms ' (SNP). SNPs are simply gene sequences where a single nucleotide (remember A, G, C, T) is replaced with another, incorrect, nucleotide. SNPs in genes sometimes code to produce the same protein, but they can also create subtle differences that are beyond the space in this blog to describe.



Finally, researchers used the '1-LOD-unit-down' method which is a statistical method of determining whether a gene is likely to be linked or associated with another gene in a given chromosome (wonks can review Genetic Linkage for a complete description and the math).



Now to the good stuff. Here is what they found.



A strong association between SNPs and heart disease was found in the KALRN (kalirin) gene. Three SNPs in the kalirin gene in particular were found in patients with early-onset heart disease. The kalirin gene is also responsible for the inhibition of 'inducible' (i.e. endothelial) nitric oxide synthase (iNOS/eNOS) which we all know regulates artery dilation (the body synthesizes endothelial nitric oxide from l-arginine which is why this is such a popular supplement). Finally, researchers discovered the kalirin gene is part of the Rho-GTPase signaling pathway that regulates behaviors such as clotting (see http://atvb.ahajournals.org/cgi/content/full/22/6/1029 ), reverse cholesterol transport (see http://www.jlr.org/cgi/content/full/47/1/78 ), and arterial stenosis (see http://ajpheart.physiology.org/cgi/content/full/278/6/H1733 )



What does this all mean?



The bottom line is that if you find ways to manipulate the kalirin gene or its manufactured proteins you may be able to do things like increase eNOS (like we do with l-arginine), improve the reverse-cholesterol transport efficiency of HDL, inhibit the formation of the clots associated with heart attack, and affect the process by which arteries accumulate plaques. One study (see http://circres.ahajournals.org/cgi/reprint/97/12/1232.pdf ) found that statins actually inhibit Rho-GTPases which might account for the additional or pleiotropic effects they have beyond LDL cholesterol reduction. Realistically, commercial applications of these findings are at least 5-10 years away. So work extra hard with what you've already got and buy that extra decade! There is more than this exciting research already in the pipeline. LET'S BEAT HEART DISEASE TO A PULP! The way to do it is one day at a time.



Regards,





HeartHawk

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