WCM-Q research named as one of the most significant studies of 2015
Research involving WCM-Q into how the body metabolizes fat and cholesterol has been named as one of the top ten most significant advances in heart disease of 2015 by the American Heart Association.
The research, which identified tiny particles of previously overlooked genetic material that can affect how the body deals with cholesterol and other fats, had already been published in the high-impact journal Nature Medicine. The latest accolade from the American Heart Association demonstrates just how significant the research is, potentially offering doctors new avenues for treating patients with abnormal cholesterol levels.
Dr. Hani Najafi, assistant professor of cell & developmental biology at WCM-Q, initiated the research project five years ago. He said it was gratifying that research conducted in the laboratory has the potential for direct and positive impact on the lives of patients by providing new strategies on how to combat abnormal cholesterol and fat levels in the body.
Dr. Najafi said:
“What one may think of as relatively insignificant can actually be of huge importance to the body and the way it reacts. This research is testament to the fact that although we are making huge advances in basic genetic research each year, we still have an awful lot to learn about its impact on medicine.”
In collaboration with other research centers including Massachusetts General Hospital, Harvard Medical School and Weill Cornell Medicine in New York, Dr. Najafi examined the enormous amount of data that has been generated from the genome-wide association studies (GWAS) that seek to identify and link specific genes with certain diseases. These studies have, for instance, identified genes that potentially contribute to the characteristics of conditions like high cholesterol/lipid levels, severe obesity, and other metabolic diseases. The studies take the gene sequence and look for SNPs (single-nucleotide polymorphisms). These are variations that happen within the gene sequence and some of these variations can affect the function of the gene. If there is a strong association between an SNP and a particular characteristic (phenotype) or disease, that SNP will stand out as being significant. The researcher would then identify genes that include or are close to that SNP.
But Dr. Najafi saw that alongside the protein-coding genes that were listed, there were also small non-protein coding genes known as microRNAs (miRNAs) embedded within the vicinity of the SNPs. MicroRNAs are known as novel inhibitors of gene expression with an emerging role in human metabolic diseases. Dr. Najafi and his colleagues asked if the miRNAs could be playing a role and contributing to lipid abnormality.
Dr. Najafi said:
“We found that overall 69 miRNAs were in close proximity to the signature SNPs associated with abnormal lipid levels. More surprisingly, we saw that more than 30 different genes that have a role in lipid metabolism are potential targets of the identified miRNAs.”
The research team analyzed four microRNA candidates that regulated two major key players in lipid metabolism that prevent abnormal blood lipid levels - LDLR (low-density lipoprotein receptor) - and ABCA1. LDLR clears bad cholesterol known as LDL, whereas ABCA1 generates good cholesterol known as HDL. The collaborating team of Dr. Timothy Hla and postdoctoral fellow Yi-Chien Lu at WCMC-New York interrogated their dataset of miRNAs that interact with lipid metabolism genes and also noticed that the same miRNAs regulated the LDLR and ABCA1 in mouse macrophages. Dr, Najafi and their colleagues found that microRNAs miR-128 and miR-148a could be used as therapeutic targets by using their antisense oligonucleotides as potential lipid-lowering drugs. This would then render the miRNAs useless, essentially correcting the level of miRNAs and in turn the lipid levels.
Dr. Najafi said:
“After we confirmed our discovery in human cells, we tested this in obese live mice and we saw an increase in HDL and a lowering of LDL. So this could potentially be used to alter the lipid levels in humans back into the normal range..
“The findings are extremely valuable. They could potentially lead to new therapies for high cholesterol, helping people to avoid heart and liver diseases.”