Biomarkers of Inflammation: GlycA

GlycA is a robust marker of systemic inflammation and an increasingly valuable biomarker for assessing cardiovascular, metabolic, and autoimmune disorders. Elevated levels are associated with obesity, insulin resistance, metabolic syndrome, type 2 diabetes, cardiovascular disease, hypertension, lupus, psoriasis, arthritis, infection, immune activation, and other inflammatory conditions.

Low levels of GlycA suggest low levels of systemic inflammation. However, this does not hold true in sickle cell anemia, where levels can be falsely decreased due to the hemolytic destruction of red blood cells

Increasing levels reflect increasing disease severity and warrant further investigation of the underlying causes of inflammation. Healthy lifestyle changes and a nutrient-rich diet can help reduce elevated GlycA. Regular exercise can significantly reduce GlycA, especially when combined with weight loss and favorable dietary changes.

Standard Range: 0.00 – 400.00 umol/L

The ODX Range: 100.00 – 300.00 umol/L

Low levels of GlycA may be seen in sickle cell anemia despite the presence of inflammation, apparently due to hemolysis (Fuertes-Martin 2020). Otherwise, in general, low GlycA suggests reduced inflammation and glycation.

High levels of GlycA are associated with systemic inflammation, cardiovascular disease and mortality, all-cause mortality, Kawasaki’s disease, inflammatory bowel disease (Dierckx 2019), atherosclerotic plaque, major adverse cardiac events (An 2018), hypertension, renal disease, polyarthritis, alcoholic liver disease, COPD, cognitive changes, decreased gut microbiota diversity (Fuertes-Martín 2020), coronary artery calcium (Tibuakuu 2019), subclinical vascular inflammation, acute febrile illness, insulin resistance, metabolic syndrome, type 2 diabetes, adiposity, colorectal cancer, and autoimmune disorders including psoriasis, lupus (Connelly 2017), rheumatoid arthritis (Rodriguez-Carrio 2020), severe systemic and respiratory infections, septicemia, pneumonia, and increased inflammatory cytokines (Ritchie 2015).

Overview

Serum glycoprotein acetylation (GlycA), measured by NMR, is a robust marker of systemic inflammation that reflects the glycosylation of acute phase proteins (Dierckx 2019). Elevations in GlycA are associated with elevations in other inflammatory biomarkers, including TNF-alpha, fibrinogen, hs-CRP, serum amyloid A (SAA), Lp-PLA2, IL-6, microbial peptides, and circulating white blood cells, especially neutrophils. Neutrophils produce two of the major proteins that contribute to GlycA concentrations in the blood, i.e., alpha-1-acid glycoprotein and haptoglobin. Major research studies demonstrate an association between elevated GlycA and CVD, including CATHGEN, PREVEND, Women’s Health Study, MESA, and JUPITER. Besides being a more sensitive marker of inflammation than hs-CRP, GlycA is more convenient as it only requires a single measurement. In contrast, hs-CRP should be assessed using two serial measurements at least two weeks apart. Also, hs-CRP arises early in the acute phase response, whereas most proteins that generate GlycA occur later in the acute phase response (Connelly 2017).

GlycA reflects multiple inflammatory pathways, and elevated levels can be seen in both acute and chronic inflammation. It is likely a more sensitive marker than C-reactive protein for assessing cardiometabolic risk. Interestingly while statins may reduce CRP by up to 30%, they don’t reduce GlycA, suggesting that systemic inflammation and cardiac risk may persist despite statin use (Lawler 2020).

A strong independent inverse association is observed between GlycA levels and cardiovascular health indicators. Data from 6,479 subjects in the cross-sectional Multi-Ethnic Study of Atherosclerosis (MESA) found that GlycA decreased relative to improvements in LS7 scores, i.e., Life’s Simple 7 health and behavioral indicators. These include diet, physical activity, BMI, blood pressure, smoking status, and levels of total cholesterol and fasting blood glucose. Participants with optimal LS7 scores of 12-14 maintained a mean GlycA level of 282 umol/L versus 312 umol/L in those with poor cardiovascular health scores. For each one-unit increment in LS7 scores, GlycA levels decreased by 5 umol/L (Benson 2018).

GlycA is a valuable biomarker for evaluating the underlying low-grade inflammation associated with insulin resistance, metabolic syndrome, loss of beta cell function, and type 2 diabetes. Data from the large PREVEND cohort study found that T2DM incidence was significantly associated with increased GlycA but not hs-CRP. Researchers note that after multiple variable adjustments, the group with a significantly increased risk of T2DM had the highest GlycA and the lowest hs-CRP (Connelly 2016). A study of 169 sedentary individuals with “pre-diabetes” suggested that a six-month structured diet, exercise, and lifestyle program can reduce GlycA, visceral adiposity, and associated risk of developing T2DM (Bartlett 2017).

GlycA may be a useful marker to identify active inflammatory bowel disease (IBD). One prospective observational study of 58 subjects with IBD found that GlycA was significantly higher in active IBD and returned to the levels of healthy controls once mucosal healing occurred. GlycA was able to identify inflammation in ulcerative colitis even when CRP was not elevated. Researchers suggest that GlycA may be preferred over fecal calprotectin as a prognostic indicator (Dierckx 2019).

GlycA may not be of significant clinical value in cancer or sickle cell anemia. The relationship between glycoproteins and cancer, however, is complex. In some cancers, GlycA will be elevated, while in others, there can be a downward trend (Fuertes-Martin 2020).

Sickle cell anemia may be associated with low GlycA despite the presence of inflammation, apparently due to hemolysis associated with the disease. Otherwise, in general, low GlycA suggests reduced inflammation and glycation (Fuertes-Martin 2020).

References  

An, Lihua et al. “Increased glycoprotein acetylation is associated with high cardiac event rates: Analysis using coronary computed tomography angiography.” Anatolian journal of cardiology vol. 20,3 (2018): 152-158. doi:10.14744/AnatolJCardiol.2018.01058

Bartlett, David B et al. “Association of the Composite Inflammatory Biomarker GlycA, with Exercise-Induced Changes in Body Habitus in Men and Women with Prediabetes.” Oxidative medicine and cellular longevity vol. 2017 (2017): 5608287. doi:10.1155/2017/5608287

Benson, Eve-Marie A et al. “Associations of ideal cardiovascular health with GlycA, a novel inflammatory marker: The Multi-Ethnic Study of Atherosclerosis.” Clinical cardiology vol. 41,11 (2018): 1439-1445. doi:10.1002/clc.23069

Connelly, Margery A et al. “GlycA, a marker of acute phase glycoproteins, and the risk of incident type 2 diabetes mellitus: PREVEND study.” Clinica chimica acta; international journal of clinical chemistry vol. 452 (2016): 10-7. doi:10.1016/j.cca.2015.11.001

Connelly, Margery A et al. “GlycA, a novel biomarker of systemic inflammation and cardiovascular disease risk.” Journal of translational medicine vol. 15,1 219. 27 Oct. 2017, doi:10.1186/s12967-017-1321-6                    

Dierckx, Tim et al. “GlycA, a Nuclear Magnetic Resonance Spectroscopy Measure for Protein Glycosylation, is a Viable Biomarker for Disease Activity in IBD.” Journal of Crohn's & colitis vol. 13,3 (2019): 389-394. doi:10.1093/ecco-jcc/jjy162

Fuertes-Martín, Rocío et al. “Title: Human Serum/Plasma Glycoprotein Analysis by 1H-NMR, an Emerging Method of Inflammatory Assessment.” Journal of clinical medicine vol. 9,2 354. 27 Jan. 2020, doi:10.3390/jcm9020354

Lawler, Patrick R, and Samia Mora. “Glycosylation Signatures of Inflammation Identify Cardiovascular Risk: Some Glyc It Hot.” Circulation research vol. 119,11 (2016): 1154-1156. doi:10.1161/CIRCRESAHA.116.310005

Ritchie, Scott C et al. “The Biomarker GlycA Is Associated with Chronic Inflammation and Predicts Long-Term Risk of Severe Infection.” Cell systems vol. 1,4 (2015): 293-301. doi:10.1016/j.cels.2015.09.007

Rodriguez-Carrio, Javier et al. “GlycA Levels during the Earliest Stages of Rheumatoid Arthritis: Potential Use as a Biomarker of Subclinical Cardiovascular Disease.” Journal of clinical medicine vol. 9,8 2472. 1 Aug. 2020, doi:10.3390/jcm9082472

Tibuakuu, Martin et al. “GlycA, a novel inflammatory marker, is associated with subclinical coronary disease.” AIDS (London, England) vol. 33,3 (2019): 547-557. doi:10.1097/QAD.0000000000002079