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13/11/2014 - Press release

Genetic mutations inactivating the function of a gene reduce the risk of infarction by 50%

The results open the door to developing new drugs

A study by the international consortium The Myocardial Infarction Genetics (MIGen) with the participation of researchers from the Hospital del Mar Medical Research Institute (IMIM) has analysed the genetic characteristics in more than 110,000 people and has identified, for the first time, 15 mutations in gene NPC1L1. The existence of any of these mutations has been associated to a reduction in the levels of LDL cholesterol or “bad cholesterol” as well as protecting against the risk of having an acute myocardial infarction. The results are published on-line in the prestigious journal The New England Journal of Medicine.

Gene NPC1L1 produces a gene with the same name that, in the intestine, absorbs cholesterol in the food we ingest. According to Roberto Elosua, a researcher from the IMIM Research Group on epidemiology and cardiovascular genetics, “the task was to look for mutations that inactivated this gene, meaning that the protein produces was not active and, therefore, absorbed less cholesterol in the intestine, and thus reduced the level of LDL cholesterol circulating in blood”.

The study analysed this gene in detail in around 21,000 people (14,000 of which had not suffered an infarction and 7,000 of which had) and identified the 15 mutations aforementioned. At a later stage, their presence was studied in some 90,000 people more. These genetic mutations are rare, are present is one in every 650 people and occur naturally. “A person with any of these mutations showed around 12 mg/dl less LDL cholesterol, compared to persons with no mutations. The presence of any of these mutations was associated to approximately half the risk of experiencing a myocardial infarction”, says Jaume Marrugat, a researcher from the same research group.

At present, there is a drug used in clinical practice to reduce the levels of cholesterol, ezetimibe, which reduces the activity of protein NPC1L1. Until now, there was no study showing that this drug also reduces the risk of experiencing an infarction. "The results of our study suggest that blocking protein NCP1L1, as does the drug ezetimibe, could be a good strategy not only to reduce the level of LDL cholesterol, but also to prevent myocardial infarction” comments Roberto Elosua. The researcher adds that “However, the big difference that may affect the efficiency of the treatment versus the mutation lies in the fact that the mutations identified are active since birth and throughout one’s life, while this drug is only used if needed in adulthood and, therefore, during a shorter period of time”.

The scientific community is interested in these mutations that inactivate the gene not only because of what they can reveal on the biological foundations of the disease (infarctions are the leading cause of death in Spain), but also because of their potential as possible therapeutic targets. From a pharmaceutical point of view, it is much easier to develop new drugs that inactivate a gene or its protein than drugs that activate them.

"LDL cholesterol is one of the greatest risk factors of experiencing a myocardial infarction. It is estimated that, this year, some 120,000 people will suffer from a coronary disease in Spain, and these results open the door to a new strategy to prevent this disease”, concludes Jaume Marrugat.

Article of reference

“Inactivating Mutations in NPC1L1 and protection from Coronary Heart Disease”. The Myocardial Infaction Genetics Consortium Investigators. The New England Journal of Medicine. DOI: 10.1056/NEJMoa1405386.

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