Elevated Levels of Lipoprotein(a) Predict Increased Risk for Developing Cardiovascular Diseases

Measurement of the blood biomarker lipoprotein(a) predicts risk of developing cardiovascular disease as well as determination of such standard factors as cholesterol and triglycerides.

Lipoprotein(a) (LPA) is a plasma lipoprotein composed of a low-density lipoprotein (LDL) particle that is covalently linked to apolipoprotein(a) by a disulfide bond. On an equimolar basis, lipoprotein(a) is more atherogenic than LDL because the additional apolipoprotein(a) component may exacerbate atherothrombosis by promoting vascular inflammation and its potential antifibrinolytic activity is associated with inhibition of plasminogen. Lipoprotein(a) levels are 75% to 95% heritable and predominately determined by single-nucleotide variants at the LPA gene and copy number variants specifically in the kringle IV type II domain. Lipoprotein(a) levels greater than 50 milligrams per deciliter are associated with a 30 to 50% greater risk of ASCVD. Individuals with extremely high levels, greater than 200 milligrams per deciliter, may have a three to four times greater risk of ASCVD.

Investigators at Massachusetts General Hospital (Boston, USA) sought to determine if measurement of lipoprotein(a) and/or LPA genetic risk score (GRS) had clinical utility in risk prediction of incident atherosclerotic cardiovascular disease (ASCVD)

For this work, samples were obtained from The UK Biobank, which is a prospective observational study of approximately 500,000 volunteers aged 40 to 69 years who were recruited from 22 sites across the United Kingdom between 2006 and 2010. An LPA GRS was calculated for 374,099 unrelated individuals from this cohort with array-derived genotypes and lipoprotein(a) measures. The mean age of the overall study population was 57.6 years, and 204,355 individuals were female (54.6%). During a median follow-up of 11.1 years, 15, 444 individuals developed an incident ASCVD (peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, or cardiovascular mortality).

Result revealed that measured lipoprotein(a) and LPA GRS were associated with comparable risk of incident ASCVD events. The LPA GRS did not yield additional prognostic information beyond measured lipoprotein(a), and both measured lipoprotein(a) and LPA GRS yielded modest improvements in the discrimination of ASCVD risk as compared to measurement of traditional risk factors.

"Our work demonstrates that genetic risk scoring of lipoprotein(a) offers risk prediction of atherosclerotic cardiovascular disease that is comparable to directly measured lipoprotein(a)," said senior author Dr. Pradeep Natarajan, a researcher in the division of cardiology and cardiovascular research center at Massachusetts General Hospital. "We learned that genetic determinants of elevated lipoprotein(a) may help identify the most effective medication regimen for cardiovascular disease prevention. Using genetic factors enhances our ability to identify at-risk individuals for cardiovascular disease who could benefit from earlier preventive strategies. At the same time, genetic testing could help identify candidates for clinical trials who are critical to discovering innovative new therapies to address conditions like elevated lipoprotein(a) and related cardiovascular disease risks."

The study was published in the October 6, 2020, online edition of the journal JAMA Cardiology.

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