Convincing evidence revealed for disease-causing effect of third type of cholesterol

New research from the University Oxford, funded by the British Heart Foundation (BHF), shows that a type of cholesterol, Lipoprotein(a) - known as Lp(a) - definitely plays a role in causing heart disease. Published in the New England Journal of Medicine, the findings could add new medicines to doctors' 'toolkits' for preventing heart disease, and open new avenues of research for treatments.

Lp(a) has been associated with heart disease since the 1990s, but until now it has not been possible to distinguish whether it actually causes heart disease. Now a study analysing the genes of nearly 16,000 people from the UK and across Europe has provided evidence that two variations of the gene for Lp(a) are strongly linked to heart disease risk, indicating a causal role in disease development.

Professor Hugh Watkins, BHF Chair of Cardiovascular Medicine at the University of Oxford and a lead author of the study said:

"We all know about 'good' HDL cholesterol and 'harmful' LDL cholesterol, but this is a third class that we should pay attention to. Diet and exercise have little effect on Lp(a) levels, but some existing drugs such as Niacin - and others coming onto the market such as CETP-inhibitors - lower Lp(a) as well as LDL cholesterol.

"Now that we know that Lp(a) is actually a cause of heart disease, testing whether  treatments that lower it actually prevent heart attacks should become a priority."

Using 'gene-chip' technology, the researchers at Oxford's Wellcome Trust Centre for Human Genetics (WTCHG) searched within regions of DNA that they knew from previous studies were potential 'hotspots' for heart disease risk. This meticulous analysis revealed the two genetic culprits.

Professor Martin Farrall, Chair of Cardiovascular Genetics at WTCHG and a lead author of the study, said:

"One in six people carry one or more of the culprit genes, which raises their risk of having a heart attack by 50%. However, the increase in risk to people from high Lp(a) levels is significantly less severe than the risk from high LDL cholesterol levels. So Lp(a) doesn't trump LDL, which has a larger impact and which we can already control pretty effectively. The hope now is that by targeting both we could get even better risk reduction."

Lp(a) exists in many different sizes - or 'isoforms' - and the research findings indicate that the small isoforms are more strongly linked to heart disease. Professor Peter Weissberg, Medical Director at the BHF said:

"Measuring Lp(a) in blood is tricky, because many different sizes of Lp(a) exist. Blood tests can give results that are difficult to untangle, and at present they're not part of standard cholesterol tests. According to this study, analysis of individuals' DNA code could give a better indication of risk but this application is a long way off.

"In the short-term the findings are useful because they highlight the importance of trying to lower Lp(a) - which will spark new efforts to design a medicine to achieve this effectively - and they reveal clues that open a new avenue for research to decipher how heart disease develops.

"Small versions of Lp(a) seem to be more important, so we need to find out what is it about their size that makes them bad news."

One hypothesis for how Lp(a) causes disease, is that it might interfere with the natural break-down of blood clots in our circulation.

Prof Weissberg continues: "Lp(a) 'looks' a lot like an enzyme called plasminogen, which is vital for clearing blood clots from the circulation. If Lp(a) gets in the way of plasminogen, that could be part of the reason for its link to disease."

The research doesn't change the BHF's current advice that everyone can reduce their risk of heart disease by eating a healthy balanced diet, being physically active and avoiding smoking. People over 40 can request a heart disease risk assessment from their GP, which tests the major measurable risk factors including LDL cholesterol, blood pressure and body mass index.

Lp(a) association diagram


Image:  SNPs show strong and consistent association
with Lp(a) levels and coronary artery disease (CAD)‏









For more information on Prof Farrall's research, click here.


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