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Genetically Elevated Levels Of Lipoprotein Associated With Increased Risk Of Heart Attack

Date:
June 15, 2009
Source:
JAMA and Archives Journals
Summary:
A genetic analysis of data from three studies suggests that genetically elevated levels of lipoprotein(a) are associated with an increased risk of heart attack, according to a new study.
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A genetic analysis of data from three studies suggests that genetically elevated levels of lipoprotein(a) are associated with an increased risk of heart attack, according to a study in the June 10 issue of JAMA.

Myocardial infarction (MI; heart attack) remains a leading cause of illness and death despite targeting of low-density lipoprotein (LDL) cholesterol by statin therapy. "The need for identification of additional causal factors, and thus potential new targets for prophylactic treatment, is apparent. Elevated levels of lipoprotein(a) [a LDL particle bound to a plasminogen-like glycoprotein, apolipoprotein(a)] represent such a candidate; however, whether lipoprotein(a) causes MI is unclear. A randomized intervention trial showing that a reduction in lipoprotein(a) levels leads to a reduction in risk of MI would favor causality. Such a study has yet to be conducted," the authors write. They add that a mendelian (genetics) randomization study could also provide evidence of a causal relationship. "Simply put, association of elevated levels of lipoprotein(a), as well as association of genetic variation raising levels of lipoprotein(a), with risk of MI would suggest causality."

Levels of lipoprotein(a) may vary up to a thousand-fold among individuals, and levels are partly determined by variations in the LPA gene coding for the apolipoprotein(a) moiety (any equal part) of lipoprotein(a). The most influential LPA variation is the kringle IV type 2 (KIV-2) size variation. The number of KIV-2 repeats correlates inversely with levels of lipoprotein(a), according to background information in the article.

Pia R. Kamstrup, M.D., of Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark, and colleagues examined whether genetically elevated lipoprotein(a) levels are associated with increased risk of MI. Three studies of white individuals from Copenhagen, Denmark, were used: the Copenhagen City Heart Study (CCHS), a general population study with 16 years of follow-up (1991-2007, n = 8,637, 599 MI events); the Copenhagen General Population Study (CGPS), a general population study (2003-2006, n = 29 388, 994 MI events); and the Copenhagen Ischemic Heart Disease Study (CIHDS), a case-control study (1991-2004, n = 2,461, 1,231 MI events). For all participants, plasma lipoprotein(a) levels, lipoprotein(a) KIV-2 size variation genotype, and MIs were recorded from 1976 through July 2007.

The researchers found: "We observed an increase in risk of MI with increasing levels of lipoprotein(a), as well as with decreasing numbers of lipoprotein(a) KIV-2 repeats associated with elevated levels of lipoprotein(a). The increase in risk of MI associated with genetically elevated levels of lipoprotein(a) was consistently seen in 3 large independent studies…," they write. "The KIV-2 genotype explained 21 percent and 27 percent of the total lipoprotein(a) concentration variation in the CCHS and the CGPS. 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). These findings are consistent with a causal association of elevated lipoprotein(a) levels with increased MI risk."

"Nonetheless, final proof of causality still requires randomized clinical trials demonstrating reduced MI risk in response to lipoprotein(a)-lowering therapy."

Editorial: Mendelian Randomization - Nature's Randomized Trial in the Post-Genome Era

In an accompanying editorial, George Thanassoulis, M.D., and Christopher J. O'Donnell, M.D., M.P.H., of the National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Mass., comment on the findings of Kamstrup and colleagues.

"Although this study certainly provides interesting mechanistic insights into the biology of lipoprotein(a) in the context of MI and suggestive evidence regarding the potential benefit of decreasing lipoprotein(a) early in life, clinicians may ask: 'How will these results affect current approaches for prediction, prevention, and treatment of my patients?' At present, the clinical implications remain 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. 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."


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Materials provided by JAMA and Archives Journals. Note: Content may be edited for style and length.


Journal Reference:

  1. Pia R. Kamstrup; Anne Tybjaerg-Hansen; Rolf Steffensen; Borge G. Nordestgaard. Genetically Elevated Lipoprotein(a) and Increased Risk of Myocardial Infarction. JAMA, 2009;301(22):2331-2339 [link]

Cite This Page:

JAMA and Archives Journals. "Genetically Elevated Levels Of Lipoprotein Associated With Increased Risk Of Heart Attack." ScienceDaily. ScienceDaily, 15 June 2009. <www.sciencedaily.com/releases/2009/06/090609215933.htm>.
JAMA and Archives Journals. (2009, June 15). Genetically Elevated Levels Of Lipoprotein Associated With Increased Risk Of Heart Attack. ScienceDaily. Retrieved May 23, 2017 from www.sciencedaily.com/releases/2009/06/090609215933.htm
JAMA and Archives Journals. "Genetically Elevated Levels Of Lipoprotein Associated With Increased Risk Of Heart Attack." ScienceDaily. www.sciencedaily.com/releases/2009/06/090609215933.htm (accessed May 23, 2017).

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