John T. Wilkins, MD


Proteoforms in Cardiovascular Disease

The story of cardiovascular disease risk is often boiled down to the traditional risk factors: cholesterol, blood pressure, insulin resistance, body weight, tobacco use, diet, physical activity and genetics. These factors have an enormous impact on risk of cardiovascular disease, heart attack and stroke, but don’t explain all of the risk.

According to John T. Wilkins, MD, MS, associate professor of Medicine in the Division of Cardiology and of Preventive Medicine in the Division of Epidemiology, “there’s no question that these factors contribute greatly, but there are likely other factors we’re not measuring.”

One such factor could be modifications to apolipoproteins, a category of proteins found in the blood that mediate cholesterol metabolism and other processes involved in cardiovascular disease risk development.

Using participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study, Wilkins and Kelleher measured proteoforms of apolipoprotein A1 (apoA1) in 150 participants, comparing specific ratios of proteoforms to cardiovascular risk factors such as waist circumference (a marker of abdominal body fat) and HDL cholesterol. Publishing their findings in the Journal of the American Heart Association, the investigators reported a positive association between HDL — good cholesterol — and several proteoform variants of apoA1.

High levels of one specific apoA1 proteoform, characterized by the addition of a fatty acid to a specific region of the protein, was associated with lower waist circumference and higher HDL. Conversely, high levels of the unmodified apoA1 proteoform had the opposite pattern of association, associated with greater waist circumference and lower HDL.

It’s unclear if these modifications are a cause or consequence of abdominal body fat or HDL level; More work is required to map the biological pathways involved. Still, these findings present opportunities to enhance the understanding of metabolic health and potentially develop better biomarkers.

Wilkins believes that measuring the levels of these apolipoprotein proteoforms possibly could predict risk better than total apolipoprotein concentration alone. “This could be one way top-down proteomics could sharpen our ability to predict cardiovascular disease.”

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Selected Publications

Allen NB, Siddique J, Wilkins JT, Shay C, Lewis CE, Goff DC, Jacobs DR Jr, Liu K, Lloyd-Jones D “Blood pressure trajectories in early adulthood and subclinical atherosclerosis in middle age.” JAMA2014, 311(5) p. 490-7.  Summary |   Full Text (PMC) |   Full Text (DOI)

Wilkins JT, Ning H, Berry J, Zhao L, Dyer AR, Lloyd-Jones DM “Lifetime risk and years lived free of total cardiovascular disease.” JAMA2012, 308(17) p. 1795-801.  Summary |   Full Text (PMC) |   Full Text (DOI)

Rasmussen-Torvik LJ, Pacheco JA, Wilke RA, Thompson WK, Ritchie MD, Kho AN, Muthalagu A, Hayes MG, Armstrong LL, Scheftner DA, Wilkins JT, Zuvich RL, Crosslin D, Roden DM, Denny JC, Jarvik GP, Carlson CS, Kullo IJ, Bielinski SJ, McCarty CA, Li R, Manolio TA, Crawford DC, Chisholm RL “High density GWAS for LDL cholesterol in African Americans using electronic medical records reveals a strong protective variant in APOE.” Clin Transl Sci2012, 5(5) p. 394-9.  Summary |   Full Text (PMC) |   Full Text (DOI)


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