ANRIL, Chromosome 9p21 and Coronary Artery Disease

I had just attended a talk by Dr Ruth McPherson on the topic of “Genetic Insights into Coronary Artery Disease”. She spoke about her genomewide association study (GWAS) which she had recently published in Science. For a quick review of the recent developments in GWAS of CAD, you can refer to my editorial in the European Heart Journal.

GWAS have consistently pointed to chromosome 9p21 and its robust association with CAD. Several replication studies have confirmed this fact. Approximately 25% of Caucasians carry 2 copies of the risk allele and have a 1.5 fold higher risk for CAD. The increased risk associated with this allele is independent of all known CAD risk factors. Thus the identification of region suggests that a novel biological pathway may be involved in atherosclerosis.

The 9p21 locus overlaps a newly annotated antisense noncoding RNA in the INK4 locus splice variant (ANRIL or DQ485453). ANRIL spans 126.3kb and overlaps at its 5’end with CDKN2B (p15INK4b). It consists of 19 exons, of which the first 12 exons are conserved whereas exons 13-19 are subjected to alternative splicing.

It would be exciting to see how the investigations of the 9p21 region would unfold in the near future!

Breckenridge

After more 24 hours of flying and in transit, I have finally arrived in Breckenridge, a small highland town in Colorado, USA to attend the Keystone Symposium on Metabolism and Cardiovascular Risk . It was a pity that I had arrived late in the evening and was unable to see sceneries of the mountains on the way here. Nevertheless, I had some time this morning to take a walk around The Great Divide, the lodge where I am staying. A picture is worth a thousand words. So here are the pics!

Aerial shot while on flight from San Francisco to Denver.

Can anyone tell me what are those disc-like vegetation in the midst of the desert? I saw a few clusters of these.

Sky view of Colorado

Breckenridge
Breckenridge

My research interests

I have two major research focuses

I. Genetics of Coronary Artery Disease

This aspect of my research involves studying genes related to coronary artery disease (CAD). It includes genetic epidemiological studies of how genes influence plasma risk factors such as lipid levels and blood coagulation factors, as well as clinical outcome such as atherosclerosis.

In the process of studying the genes, we have also built up a sizable database of about 3000 CAD and healthy individuals with information on more than 32 genotypes, environmental risk factors and family/medical histories. We have capitalized on this by developing an algorithm with the help of statisticians to predict CAD risk. The algorithm has since been patented and we are now validating it with more test cases.

The ultimate aim of our research is to be able to assess an individual’s risk of heart disease through family history, biochemical factors and genetic tests, especially for the neonates, so that preventive measures can be implemented early in life in order to delay the occurrence of CAD significantly or prevent it from occurring altogether.

Recently, we have also conducted some studies in the mouse and human cell line models to elucidate molecular mechanisms involved in dietary and acute phase protein responses.

II. Development of Lab-on-a-Chip Devices for biomedical applications

Another aspect of my research is in the development of biochips or “Lab-on-a-Chip” (LOC) devices for use in molecular diagnostics. LOC basically serves to miniaturize all the functions of regular bench-top equipments in the laboratory onto a chip no larger than the size of a credit card. We have successfully developed silicon biochips that can automatically extract nucleic acids (DNA or RNA) from blood. In essence, at the push of a button, blood goes into the chip and out comes pure DNA or RNA for carrying out genetic testing after about 1 hour. This breakthrough was made possible by combining the expertise from a highly dynamic team of engineers and biologists. There are three key advantages of LOC over conventional methods. These include i) Portability - the ability to be used at point-of-care or anywhere without the need to send samples to the laboratory, ii) Full Automation - does not require skilled operator, iii) Small Reaction Volume - thereby reducing reagent cost. Coupled with another of our invention, the microPCR for DNA amplification and other commercially available portable detection systems, the full capability of the LOC could be realized. We believe there is tremendous potential of our invention in shaping the way genetic tests are going to be carried out in the near future in diverse fields such as clinical, veterinary, forensic and medicine; agriculture; animal husbandry and biodefence.

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CK