Clinical Applications of YKL-40 (Chitinase-3-Like Protein 1)

YKL‑40 is a blood‑based inflammatory biomarker associated with a wide range of inflammatory, metabolic, neurodegenerative, and malignant conditions.^1-4 Due to the lack of disease specificity, clinical applicability is reliant on contextual interpretation of the laboratory findings. A highly conserved protein product of the chitinase-3-like protein 1 (CHI3L1) gene, YKL-40 is named for its three N-terminal amino acids (tyrosine [Y], lysine [K], and leucine [L]) and its molecular weight (40 kDa).^1-2 It can be secreted by various types of cells, including macrophages, neutrophils, chondrocytes, synoviocytes, smooth muscle cells, fibroblast-like cells, and tumor cells, and may serve a role in apoptosis and remodeling or degradation of the extracellular matrix.^2-3 Elevated levels of YKL-40 positively correlate with inflammation occurring in the setting of diabetes mellitus, inflammatory bowel disease, acute kidney injury, chronic kidney disease, rheumatoid arthritis (RA), Alzheimer’s disease (AD), multiple sclerosis, coronary artery disease, and colorectal cancer.^1-4

Given the broad range of diseases triggering a YKL-40 inflammatory signal, its clinical applicability necessitates a clinical context and symptomology for it to be understood and interpreted. This means that, like CRP or sedimentation rate, YKL-40 is unlikely to be diagnostic for any particular disease. Rather, within a given clinical context, YKL-40 levels can lend evidence toward a diagnosis or facilitate monitoring of disease status and therapeutic efficacy.

Clinical information

YKL-40 levels have been studied in both cerebral spinal fluid and blood for a variety of conditions and purposes. Blood testing offers greater convenience for both the physician and patient. Measurements of YKL-40 levels from a blood draw have been reported for the following clinical uses:

• RA disease and therapeutic monitoring: A meta-analysis5 of 11 studies of circulating YKL-40 levels concluded that measurements of YKL-40 are significantly higher in RA patients relative to healthy controls and that YKL-40 levels positively correlated with both RA disease activity and rheumatoid factor level. Another metanalysis by Tizaoui et al1 reported that YKL-40 can be used to monitor therapeutic efficacy as measured levels decreased in patients on treatment.
• Kidney transplant: In patients undergoing deceased donor kidney transplantation, lower levels of YKL-40 correlated with immediate graft function.⁶ Additionally, YKL-40 levels assessed within hours of transplant predict need for dialysis. In the event of delayed graft function, elevated donor YKL-40 concentration was associated with a lower risk of graft failure.⁷
• Type 2 diabetes (T2D): Blood-based YKL-40 has been studied in T2D patients for multiple decades. A 2006 study showed that YKL-40 and hsCRP are related to insulin resistance, with no correlation found between YKL-40 and hsCRP, meaning that elevated YKL-40 is an independent predictor of insulin resistance.⁸ Further, YKL-40 was also shown to be an independent indicator of albuminuria associated with early-stage nephropathy in T2D patients.⁹
• Colorectal cancer: A 2022 meta-analysis¹⁰ of nine studies employing blood YKL-40 measurements concluded that, collectively, the published literature shows that elevated YKL-40 levels are related to worse prognosis for patients and therefore might be useful as a reliable indicator throughout treatment and disease course.
• AD and dementia: In preclinical AD subjects, YKL-40, along with glial fibrillary acid protein (GFAP), were shown to be significantly elevated relative to healthy controls.¹¹ More generally, in a study with groups of patients diagnosed with AD, frontotemporal dementia, Lewy body dementia, or vascular dementia, YKL-40 was significantly elevated in all groups relative to healthy controls¹² and elevated plasma YKL-40 levels are associated with poorer cognition and lower brain volume.¹³

Test Name	Test No.
YKL-40 (Chitinase-3-Like Protein 1; CHI3L1), Plasma	140600