Kalirin Gene and CAD
Kalirin Gene and CAD
April 12, 2007 (Durham, NC) - Researchers at Duke University have identified a new gene that appears to put individuals at greater risk of developing cardiovascular disease. The gene, known as kalirin (KALRN), is located in chromosome 3 in a region that has been previously implicated in the development of coronary artery disease.
"We used an iterative approach to find a genetic association of kalirin with CAD," investigator Dr Simon Gregory (Duke University Medical Center, Durham, NC) told heartwire. "The approach involved testing an increasing density of genetic markers from a previous linkage region on 3q13-21 within a population of unrelated case-control individuals. Markers that showed suggestive significance within the first CAD population were then typed in a second case-control population to establish replication of the initial results. Statistical analysis showed that kalirin was associated with CAD, particularly within individuals with early-onset CAD."
The results of the study, led by Dr Liyong Wang (Duke University Medical Center), are published in the April 2007 issue of the American Journal of Human Genetics [1].
Studied in more than 4000 individuals
In a previous genome scan of a group of families with at least two siblings who had early-onset coronary disease, the researchers identified a small section of chromosome 3 where genetic variations appeared to be linked with disease. To map the chromosome 3 linkage peak, the Duke investigators conducted an association mapping study using single nucleotide polymorphisms (SNPs) in two independent case-control data sets.
Using DNA from 500 patients who had volunteered to be studied while being examined at the cardiac catheterization laboratories at Duke University Hospital, the researchers identified one SNP, in the kalirin gene, that differed between individuals with CAD and those without. The experiment was repeated in two additional patient populations, scanning the DNA of 3500 individuals, and similar results were found. Furthermore, in a study of 145 human aortas, the investigators also found this SNP to be significantly correlated with the degree of atherosclerosis.
The investigators then tested markers within genes directly adjacent to kalirin on 3q13. These genes, MYLK and CDGAP, were also associated with CAD in multiple populations and, interestingly, were also in the same functional pathway as kalirin, the Rho-GTPase signaling pathway, said Gregory.
"The markers that we used to identify genetic association of kalirin, MYLK, and CDGAP with CAD could be used as assays to determine an individual's genetic risk of developing CAD," Gregory told heartwire. "Although the markers from these three genes don't underlie the complete contribution of genetics to the development of CAD, they add to the growing number of markers that are being associated with this common, complex disease."
Ultimately, he added, the goal will be to develop a panel of genetic markers that, together with evaluation of lifestyle and environmental influences, will allow for an accurate determination of an individual's risk of developing CAD.
With the discovery that kalirin, MYLK, CDGAP, and the Rho-GTPase signaling pathway are implicated in CAD, investigators hope next to determine underlying biological mechanisms. To do so, they plan further genetic analysis to identify the causal nucleotide markers that alter gene function and to determine what impact these might have on Rho-GTPase signaling.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
April 12, 2007 (Durham, NC) - Researchers at Duke University have identified a new gene that appears to put individuals at greater risk of developing cardiovascular disease. The gene, known as kalirin (KALRN), is located in chromosome 3 in a region that has been previously implicated in the development of coronary artery disease.
"We used an iterative approach to find a genetic association of kalirin with CAD," investigator Dr Simon Gregory (Duke University Medical Center, Durham, NC) told heartwire. "The approach involved testing an increasing density of genetic markers from a previous linkage region on 3q13-21 within a population of unrelated case-control individuals. Markers that showed suggestive significance within the first CAD population were then typed in a second case-control population to establish replication of the initial results. Statistical analysis showed that kalirin was associated with CAD, particularly within individuals with early-onset CAD."
The results of the study, led by Dr Liyong Wang (Duke University Medical Center), are published in the April 2007 issue of the American Journal of Human Genetics [1].
Studied in more than 4000 individuals
In a previous genome scan of a group of families with at least two siblings who had early-onset coronary disease, the researchers identified a small section of chromosome 3 where genetic variations appeared to be linked with disease. To map the chromosome 3 linkage peak, the Duke investigators conducted an association mapping study using single nucleotide polymorphisms (SNPs) in two independent case-control data sets.
Using DNA from 500 patients who had volunteered to be studied while being examined at the cardiac catheterization laboratories at Duke University Hospital, the researchers identified one SNP, in the kalirin gene, that differed between individuals with CAD and those without. The experiment was repeated in two additional patient populations, scanning the DNA of 3500 individuals, and similar results were found. Furthermore, in a study of 145 human aortas, the investigators also found this SNP to be significantly correlated with the degree of atherosclerosis.
The investigators then tested markers within genes directly adjacent to kalirin on 3q13. These genes, MYLK and CDGAP, were also associated with CAD in multiple populations and, interestingly, were also in the same functional pathway as kalirin, the Rho-GTPase signaling pathway, said Gregory.
"The markers that we used to identify genetic association of kalirin, MYLK, and CDGAP with CAD could be used as assays to determine an individual's genetic risk of developing CAD," Gregory told heartwire. "Although the markers from these three genes don't underlie the complete contribution of genetics to the development of CAD, they add to the growing number of markers that are being associated with this common, complex disease."
Ultimately, he added, the goal will be to develop a panel of genetic markers that, together with evaluation of lifestyle and environmental influences, will allow for an accurate determination of an individual's risk of developing CAD.
With the discovery that kalirin, MYLK, CDGAP, and the Rho-GTPase signaling pathway are implicated in CAD, investigators hope next to determine underlying biological mechanisms. To do so, they plan further genetic analysis to identify the causal nucleotide markers that alter gene function and to determine what impact these might have on Rho-GTPase signaling.
Wang L, Hauser ER, Shah SH, et al. Peakwide mapping on chromosome 3q13 identifies the Kalirin gene as a novel candidate gene for coronary artery disease. Am J Hum Genet 2007; 80:650-663.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
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