CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Ali J. Marian, MD*
* University of Texas Health Science Center—Houston, Institute of Molecular Medicine, Center for Cardiovascular Genetic Research, 6770 Bertner Street, Texas Heart Institute at St. Luke's Episcopal Hospital, Suite C900A, Houston, Texas 77030 (Email: Ali.J.Marian{at}uth.tmc.edu).
I thank Dr. Iakoubova and colleagues for the information (1–4). They cite King et al. (5), who described detection of messenger ribonucleic acid (mRNA) expression by microarray in coronary segments isolated from explanted hearts of 22 patients, mostly with ischemic heart disease. The main findings were decreased expression levels of smooth muscle cell genes and increased levels of immune/inflammatory markers. However, I did not find any reference to KIF6 (5). The microarray data, which requires validation by another technique, is posted at NCBI-GEO at http://www.ncbi.nlm.nih.gov/sites/entrez. It shows increased mRNA levels of KIF6 in some coronary segments but reduced or unchanged levels in others. The data do not specify expression of KIF6 in normal coronaries, a prerequisite for establishing the causality, as the cause (expression) has to precede the effect. Dr. Iakoubova and colleagues indicate that they analyzed 26 additional single nucleotide polymorphisms (SNPs) at the KIF6 locus in 1 of the 3 study populations. All were in linkage disequilibrium (LD) not only with the Trp719Arg but also with 117 additional SNPs. In this scenario, Trp719Arg may not be the true susceptibility SNP or KIF6 the true risk gene. The LD structure of the region should be analyzed, preferably in all 3 study populations, to identify other putative candidates. Mechanistic studies are necessary to distinguish the true susceptibility allele (gene) from those in LD with the risk allele (gene).
The most important impact of the findings, if proven to be true, would be in implicating a new pathway for the pathogenesis of coronary atherosclerosis and, hence, novel therapeutic targets. Most susceptibility alleles for complex traits, because of a small effect size on absolute risk, are unlikely to portend meaningful impact on pre-clinical diagnosis, early risk stratification, early intervention, prognostication, or individualization of therapy. Dr. Iakoubova and colleagues have a tremendous opportunity to rise to the challenge by delineating the molecular mechanism(s) by which Try719Arg in KIF6 predisposes to coronary atherosclerosis, its clinical complications, or response to statins. By doing so, they could make an endurable impact in the care of millions of people worldwide. Otherwise, I humbly submit that the findings are unlikely to fulfill the late Dr. Koshland's Cha-Cha-Cha theory of scientific discoveries (6).
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References
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1. Iakoubova OA, Sabatine MS, Rowland CM, et al. Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE IT-TIMI 22 study J Am Coll Cardiol 2008;51:449-455.[Abstract/Free Full Text]2. Shiffman D, Chasman DI, Zee RY, et al. A kinesin family member 6 variant is associated with coronary heart disease in the Women's Health study J Am Coll Cardiol 2008;51:444-448.[Abstract/Free Full Text] 3. Iakoubova OA, Tong CH, Rowland CM, et al. Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials J Am Coll Cardiol 2008;51:435-443.[Abstract/Free Full Text] 4. Marian AJ. Surprises of the genome and "personalized" medicine J Am Coll Cardiol 2008;51:456-458.[Free Full Text] 5. King JY, Ferrara R, Tabibiazar R, et al. Pathway analysis of coronary atherosclerosis Physiol Genomics 2005;23:103-118.[Abstract/Free Full Text] 6. Koshland J. Philosophy of science: the Cha-Cha-Cha theory of scientific discovery Science 2007;317:761-762.[Abstract/Free Full Text]
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Association of the 719Arg Variant of KIF6 With Both Increased Risk of Coronary Events and With Greater Response to Statin Therapy
- Olga Iakoubova, James Shepherd, and Frank Sacks
J. Am. Coll. Cardiol. 2008 51: 2195.
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