A genetic analysis from three studies of people living in Denmark found that those who had higher levels of a cholesterol known as lipoprotein (a) due to genetic reasons were at higher risk of heart attack. The researchers suggested that although their findings were strong enough to support the idea that higher levels of lipoprotein (a) due to genetic reasons very probably cause higher risk of heart attack, only randomized clinical trials that show fewer heart attacks occur when lipoprotein (a) is reduced through therapy can prove it.
The study was the work of Dr Pia R Kamstrup, of Herlev Hospital, Copenhagen University Hospital in Herlev, Denmark, and colleagues, and is published in the 10 June issue of the Journal of the American Medical Association, JAMA.
Despite the fact that statins are now routinely used to lower levels of low-density lipoprotein (LDL, or “bad” cholesterol), myocardial infarction (MI or heart attack) remains a leading cause of illness and death, wrote the authors.
There is a need to identify other risk factors as targets for treatment they said. Lipoprotein (a), a cholesterol that is not included in routine cholesterol screening, has been suggested as a potential candidate, but there is not enough evidence of how closely it is linked to heart attack risk.
Lipoprotein (a) levels vary from person to person, sometimes the level in one person can be thousands of times higher or lower than the level in another person, the range is so vast. This is partly determined by genetics, and the variations in one gene in particular, known as the “Lipoprotein (a) kringle IV type 2 (LPA KIV-2) size polymorphism genotype”. The authors wrote in their background information that the number of KIV-2 repeats is already known to correlate inversely with levels of lipoprotein(a).
For the study, Kamstrup and colleagues looked at whether genetically elevated levels of lipoprotein (a) were linked to increased risk of heart attack (MI) in three studies covering about 45,000 white individuals from Copenhagen who started giving samples in 1976 until 2007.
The researchers found that risk of MI increased with increasing levels of lipoprotein (a), and with “decreasing numbers of lipoprotein(a) KIV-2 repeats associated with elevated levels of lipoprotein(a)”.
They saw a consistent increase in MI risk linked to genetically elevated levels of lipoprotein (a) in all three studies, and noted that the KIV-2 genotype explained 21 per cent and 27 per cent of the total lipoprotein (a) concentrations in two of the three studies.
Kamstrup and colleagues wrote that:
“Instrumental variable analysis (in which the increase in lipoprotein (a) levels explained by the KIV-2 genotype was related to MI) directly demonstrated that genetically elevated lipoprotein (a) is associated with increased risk of MI, like elevations in plasma lipoprotein (a).”
They suggested that while the findings appear strong enough to show that the higher levels of lipoprotein (a) probably caused the increased risk of MI, final proof should still be sought using randomized clinical trials that show MI risk going down in response to therapies that lower lipoprotein (a).
In an accompanying editorial, Drs George Thanassoulis and Christopher J. O’Donnell of the National Heart, Lung and Blood Institute’s Framingham Heart Study, commented that although Kamstrup and colleagues revealed some “interesting mechanistic insights” into the biological link between lipoprotein (a) and MI, and put forward evidence that there might be potential benefit in reducing lipoprotein (a) early in life, the “clinical implications are quite limited”.
“These results do not provide the necessary evidence that genetic testing of the LPA locus or measurements of plasma lipoprotein(a) have a role in cardiovascular risk stratification or decisions regarding lipid-lowering therapy,” they wrote, agreeing with the authors in that “ultimately, despite nature’s best efforts to provide causal evidence for lipoprotein(a), only a true randomized controlled trial demonstrating reductions in MI with targeted lipoprotein(a)-lowering therapy can provide the evidence for benefits and risks of an lipoprotein(a)-lowering strategy”.
“Genetically Elevated Lipoprotein(a) and Increased Risk of Myocardial Infarction.”
Pia R. Kamstrup; Anne Tybjaerg-Hansen; Rolf Steffensen; Borge G. Nordestgaard.
Vol. 301 No. 22, June 10, 2009
Written by: Catharine Paddock, PhD