Quantifying Systemic Inflammation using the biomarker GlycA
—Dr. William Cromwell, MD, FAHA, FNLA
What is Chronic Inflammation?
Chronic, low grade inflammation is present in many metabolic conditions and has been shown to be significantly predictive of risk for cardiovascular events and diabetes. Beyond being part of high-risk conditions like metabolic syndrome and insulin resistance, inflammation is also directly involved in multiple steps leading to cardiovascular events and diabetes.
Chronic inflammation doesn’t produce symptoms and therefore requires bioanalysis to detect. The only way to measure it is with blood tests such as high sensitivity C reactive protein (hs-CRP) or GlycA. When compared to hs-CRP, GlycA shows less variability and is a stronger predictor of cardiovascular events, diabetes and death.
GlycA is a nuclear magnetic resonance (NMR) signal that reflects the level of inflammatory proteins in the blood. Because multiple proteins are included in this test, GlycA levels are very stable when measured multiple times in the same individual. Multiple studies show that increased GlycA is significantly predictive of risk for future cardiovascular events, developing diabetes and death. This relationship remains significantly predictive even after adjusting for major risk factors including hypertension, smoking, diabetes, cholesterol or triglyceride levels, and treatment with statin medications.
Check out this short video from Sutter Health about the impact of chronic inflammation on your body.
Overview of Systemic Inflammation
In settings of acute or chronic inflammation, a type of large white blood cells called “monocytes” are recruited to sites of inflammation. Once monocytes enter tissues, they are call macrophages. Macrophages secrete a variety of proinflammatory cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha). In addition to causing local inflammation, inflammatory cytokines enter the circulation triggering liver production and secretion of a wide range of "acute-phase proteins."1
- Acute-phase proteins are N-linked glycoproteins. That means they contain a diverse combination of glycan (sugar) chains attached to the nitrogen group of asparagine residues).
- Examples of acute-phase proteins include alpha-1-antitrypsin, alpha-1-antichymotrypsin, alpha-1-acid glycoprotein, haptoglobin, transferrin, and C-reactive protein.
Acute and chronic inflammation influence the quantity and structure of acute-phase proteins.
- Circulating levels of acute-phase proteins reflect increasing or decreasing states of acute and chronic inflammation. As inflammation increases, acute-phase protein values rise. As inflammation decreases, acute-phase protein levels decline.
- Additionally, inflammation modifies the structure and composition of acute-phase proteins. As inflammation increases, the extent and complexity of N-glycosylation of various acute-phase proteins increase. 2,3 These modifications impact acute-phase proteins' function and may strengthen their association with atherosclerosis, insulin resistance, and risk for heart attack, stroke, type 2 diabetes, and death. 4
Options for Measuring Systemic Inflammation
Historically, systemic inflammation has been assessed by quantifying individual acute phase proteins (e.g., C-reactive protein, fibrinogen, haptoglobin, transferrin) or proinflammatory cytokines (e.g., IL-1, IL-6, TNF-alpha).
- Of these, high sensitivity C-reactive protein (hs-CRP) demonstrates the most robust associations with incident CVD risk and all-cause mortality, including CVD-related mortality, independent of other CVD risk factors, such as non-HDL cholesterol, smoking, or hypertension. 4,5
- From a laboratory perspective, hsCRP is stable in fresh and frozen samples, shows a wide dynamic range, and can be quantified by relatively inexpensive, standardized, and precise high-sensitivity immunoassays. 6,7
- As a result, multiple guidelines advocate testing hsCRP in patients with intermediate CVD risk, as assessed by conventional CVD risk biomarkers, to aid decision-making regarding how aggressively to treat such patients. 8,9
More recently, acute phase proteins can be measured in aggregate by a nuclear magnetic resonance (NMR) signal called GlycA.
- The GlycA signal comes from the methyl groups found on N-acetylglucosamine residues attached to circulating plasma proteins.3
- Because most circulating N-glycosylated proteins are acute-phase proteins, the GlycA test reflects changes in the overall quantity of various acute-phase proteins and the glycan chain complexity of these proteins (see Figure 1 below).3,4
- Acute-phase proteins contributing to the GlycA signal include alpha-1-antitrypsin, alpha-1-antichymotrypsin, alpha-1-acid glycoprotein, haptoglobin, and transferrin.3
A simplified illustration showing how the GlycA ‘peak’ on 1H-NMR relates to systemic inflammation. In the setting of inflammation, irrespective of the trigger, macrophages are recruited to the site of inflammation where they secrete a variety of cytokines, namely IL-1, IL-6, and TNF-alpha. These cytokines act locally to induce an inflammatory response aimed at removing the insulting trigger and promoting subsequent tissue recovery. However, some of these cytokines also enter the systemic circulation and reach the liver, where they induce an increased production and secretion of several so-called acute phase reactants, as well as various glycosylation-mediating enzymes, known as glycosyltransferases, which alter the glycosylation patterns of the latter acute phase reactants. The acute phase reactants themselves, and their glycosyltransferase-modified derivatives (denoted by * in the figure) contribute to the GlycA peak seen on the 1H-NMR analyzer. AAT, alpha-1-antitrypsin; AGP, alpha-1-acid glycoprotein; CRP, C-reactive peptide.
Source: (Ballout RA, Remaley AT. GlycA: A New Biomarker for Systemic Inflammation and Cardiovascular Disease (CVD) Risk Assessment. J Lab Precis Med 2020;5)
Clinical Comparison of GlycA versus hsCRP
Dr. William Cromwell, MD, is the Chief Medical Officer for Precision Health Reports. He is a leading expert in the management of metabolic disorders and lipoprotein disorders including diabetes management. Through our products, he extends his three decades of research and in-clinic experience to enable practicing healthcare providers across the U.S. to better deliver personalized care to their patients. Our analyses change the conversation from trying to explain data to instead having a meaningful conversation about a person’s individual risks of developing serious and costly cardiometabolic diseases.
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