Lipoprotein(a)—An Independent Risk Factor for Cardiovascular Disease?

From PROMIS, genetic variants that were exclusively associated with apoprotein(a) size and concentration provide further indication that lowering the lipoprotein(a) concentration may be a strategy to reduce cardiovascular disease risk.

Written by Alexandra S. Kadner PhD

With Danish Saleheen, MD, and Mary Ellen Sweeney, MD

An estimated 20% of adults, some 63 million people in the United States, will have elevated levels of inherited lipoprotein(a) [Lp(a)] greater than 50 mg/dL, which is easy to test for but isn’t usually included in standard lipid panels.1 An elevated Lp(a) raises the risk of coronary heart disease  (CHD)
2- to 4-fold but is rarely identified.

“Our findings advance understanding of the causal relevance of the Lp(a) pathway to CHD and suggest that interventions that lower Lp(a) concentration could be more effective in reducing CHD risk in individuals who have smaller apolipoprotein A (Apo A) isoforms than individuals with larger isoforms,”2 reported Danish Saleheen, MBBS, PhD, lead author and assistant professor of biostatistics and epidemiology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, in a study published in Lancet Diabetes Endocrinology.

The distinctive finding from this study was the concurrent analysis of Lp(a) concentration and Apo A isoform size as independent risk factors for myocardial infarction (MI) supported by a highly powered cohort,2 according to the authors.

The role of elevated serum levels of Lp(a) was notable given the increased risk of cardiovascular disease confirmed in White Americans; and, while Lp(a) may be higher in African Americans, their risk for CVD does not appear to rise proportionally with this protein level.3

Both human genetic analyses and epidemiological studies have indicated a relationship between the Lp(a) pathway and CHD and aortic stenosis.4-9 Apo A occurs in a variety of isoforms, that can vary in size up to 10-fold and this variation in Apo size is thought to be due, at least in part, to a number variation in the Lp(a) gene.5

“Moreover, we found that the Apo A isoform size and lipoprotein(a) concentration are inversely correlated with each other, and with CHD risk,” Dr. Saleheen said. Individuals with larger Apo A isoform size appear to have lower relative risk of CHD, whereas people with higher lipoprotein(a) concentrations will have higher relative risk.2

Genetic Determinants of Cardiovascular Disease

“Our study aimed to identify genetic variants in the human genome that were exclusively associated with Apo A isoform size or the logarithm of the lipoprotein(a) concentration, but not with both”, Dr. Saleheen told EndocrineWeb.

"The analysis found 232 SNPs associated with Apo A protein isoform size (p < 5 ×10) and only 1 of these, rs2457564, was not related to Lp(a) concentration or the other traits we measured,"2 said Dr. Saleheen. "For each copy of the minor allele at rs2457564 (minor allele frequency: 0.41) the Apo A protein isoform size decreased by 0.24 SD units (p = 5.20 ×10), and allelic variation at rs2457564 was associated with LPA KIV2 repeat number (β=0.15 SD units, p = 2.3 ×10)."2

Similarly, 324 SNPs were found to be associated with the logarithm of Lp(a) concentration. Out of these, only rs3777392 was exclusively associated with Lp(a) concentration, but not with apolipoprotein isoform size or any other traits measured.2

Independent Risk Factors for MI: Apo A Size and Lp(a) Concentration 

Apo A isoform size and Lp(a) concentration had opposite effects on the odds of myocardial infarction (MI), said Dr. Salaheen. After adjusting for Lp(a) concentration and other cardiovascular risk factors, the odds ratio (OR) for MI was 0·93 (95% CI 0.90–0.97; p < 0.0001) for each 1-SD increment of LPA KIV2 repeats. Conversely, after adjusting for LPA KIV2 repeats and other factors, the OR for MI was 1.10 (95% CI 1.05–1.14; p < 0.0001) for each 1-SD increment in Lp(a) concentration.2

“The findings confirmed that small Apo A isoform size and high Lp(a) concentration are independent risk factors for CHD, and any interventions that lower Lp(a) levels would lower CHD risk in individuals with small Apo A isoforms,” Dr. Salaheen told EndocrineWeb.

This study is the first to distinguish the effects of Apo A isoform size from those of lp(a) concentration, and to distinguish the causes of Apo A isoform size and Lp (a) concentration by identifying genetic variants that are uniquely associated with one of these traits, but not with both, which will have relevance for emerging therapies targeting lipoprotein(a), according to Dr. Saleheen.

Are the Findings Ready for Clinical Practice?

The clinical impact of the study will be indirect, by “taking drugs in the right direction, although Lp(a) is not quite there yet as a disease marker,” Mary Ellen Sweeney, MD, associate professor of endocrinology, diabetes and lipid metabolism at the Emory School of Medicine in Atlanta, told EndocrineWeb. The main benefit of these findings is to prepare the way for a systematic study of genetic risk factors for CHD, as well as to lay the groundwork to develop agents that lower Lp(a) levels, she said.

“However, while agents that lower lipoprotein(a) concentrations are available, some like niacin, are not associated with a reduction in CHD risk,” Dr. Sweeney said. “Moreover, other therapeutics, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower Lp(a) concentrations as well as LDL-cholesterol.”

‘In clinical trials, differentiation of the specific effects lipoprotein(a) reduction from LDL reduction will be difficult,” said Dr. Sweeney. “At present Apo A isoform size and Lp(a) concentrations are advanced disease markers for those with premature or familial CHD, or for patients with unexpected lack of response to treatment.”

 “Elevated Lp(a) is a difficult problem, and we have very little to offer these patients,” so any avenue for improvement therapeutics will be advantageous,” she said.

As such, PCSK9-inhibitors present the best potential to lower cholesterol even further, with early reports of cardiovascular benefit with evolocumab in the FOURIER trial.10Accordingly, there is considerable hope in the clinical community that CHD risk may be more effectively managed in a greater proportion of patients than with current standard of care.

Background on the Study Protocol 

The study was designed as a genetic and biomarker analysis of the causal effects of Apo A isoform size and Lp(a) concentration on the risk for coronary heart disease, using the principle of Mendelian randomization.2

Lp(a) concentration and lipid-related markers were assayed in 9015 patients with MI and 8629 sex- and age-matched controls. LPA KIV2 repeats were assayed in 6277 patients with MI and 6387 controls.

"The study was based on an independent protocol, using randomly selecting patients and controls from the ongoing Pakistan Risk of Myocardial Infarction Study that has to date enrolled more than 42,000 participants,"2,11 Dr. Saleheen told EndocrineWeb,

Sources

  1.  Lipoprotein Foundation. Understand inherited Lipoprotein(a). Available at: http://www.lipoproteinafoundation.org/?page=understandlpa. Accessed April 19, 2017.
  2. Saleheen D,  Haycock PC, Zhao W, et al. Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis. Lancet Diabetes Endocrinol. 2017. Published online at: http://dx.doi.org/10.1016/ S2213-8587(17)30088-8.
  3. Enkhmaa B, Anuurad E, Zhang W, Berglunda L. Significant associations between lipoprotein(a) and corrected apolipoprotein B-100 levels in African-Americans. Atherosclerosis. 2014; 235(1): 223–229.2.  
  4. Anuurad E, Boffa MB, Koschinsky ML, Berglund L. Lipoprotein(a): a unique risk factor for cardiovascular disease. Clin Lab Med. 2006;26(4):751-772. doi:10.1016/j.cll.2006.07.002.            
  5. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med. 2013;273(1):6-30. doi:10.1111/j.1365-2796.2012.02592.x.
  6. Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361(26):2518-2528. doi:10.1056/NEJMoa0902604.
  7. Erqou S, Kaptoge S, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302(4):412-423. doi:10.1001/jama.2009.1063.
  8. Erqou S, Thompson A, Di Angelantonio E, et al, for theEmerging Risk Factors Collaboration. Apolipoprotein (a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J Am Coll Cardiol. 2010;55(19):2160-2167.
  9. Thanassoulis G, Campbell CY, Owens DS, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013;368(6):503-512.
  10. Sabatine MS, Giugliano RP, Keech AC, et al, for the FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017. Published online ahead of print. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1615664#t=abstract.
  11. Saleheen D, Zaidi M, Rasheed A, et al. The Pakistan Risk of Myocardial Infarction Study: a resource for the study of genetic, lifestyle and other determinants of myocardial infarction in South Asia. Eur J Epidemiol. 2009;24(6):329-338.

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