Circulating SCGB3A2 Is Associated With Impaired Coronary Collateralization in Patients With Chronic Total Occlusion and Type 2 Diabetes: A Proteomic Discovery and Validation Study.
Chen J, Chen S, et al. • Journal of diabetes • 2026
Circulating SCGB3A2 is independently associated with impaired coronary collateralization in CTO patients, and its addition to clinical models improves risk stratification, particularly in patients with T2DM.
Key Findings
Results
Among 265 proteins profiled by Olink proteomics, SCGB3A2 showed the strongest differential expression signal and highest variable importance in distinguishing CTO patients with poor versus good coronary collateralization.
Olink proteomic profiling was performed in a discovery cohort of 88 CTO patients with T2DM stratified by collateral status.
Eight proteins showed nominal differential expression among 265 total proteins profiled.
SCGB3A2 was selected based on exhibiting the strongest signal in nominal differential expression analysis and highest variable importance in partial least squares-discriminant analysis.
SCGB3A2 was subsequently validated by ELISA in an independent cohort of 832 CTO patients (425 with T2DM and 407 without diabetes).
Results
In the T2DM validation cohort, serum SCGB3A2 levels were significantly higher in patients with poor coronary collateralization and inversely correlated with Rentrop grades.
Both the association with poor collateralization and the inverse correlation with Rentrop grades were statistically significant (both p < 0.001).
The validation cohort included 425 patients with T2DM.
Collateral status was assessed using Rentrop grading.
Results
SCGB3A2 remained independently associated with poor coronary collateralization after multivariable adjustment in the T2DM cohort.
The odds ratio per 10 ng/mL increase in SCGB3A2 was 1.63 (95% CI, 1.39–1.94; p < 0.001).
This association persisted after adjustment for clinical risk factors.
The effect size indicates that each 10 ng/mL increment in SCGB3A2 was associated with a 63% higher odds of poor collateralization.
Results
Addition of SCGB3A2 to a clinical risk model improved discrimination and reclassification for poor coronary collateralization in T2DM patients.
The C-statistic increased from 0.73 to 0.78 with the addition of SCGB3A2 to the clinical model.
Net Reclassification Improvement (NRI) was 0.62.
Integrated Discrimination Improvement (IDI) was 0.08.
These metrics indicate both improved classification and incremental predictive value beyond established clinical risk factors.
Results
Similar associations between SCGB3A2 and impaired coronary collateralization were observed in CTO patients without diabetes.
The non-diabetic subgroup comprised 407 patients in the validation cohort.
The association between SCGB3A2 and poor collateralization was not exclusive to T2DM patients.
The paper notes that similar associations were observed in patients without diabetes, suggesting a broader relevance of SCGB3A2 in coronary collateral remodeling.
What This Means
This research suggests that a protein called SCGB3A2, which circulates in the blood, is linked to poor development of natural bypass vessels (called coronary collaterals) in patients who have a completely blocked coronary artery (chronic total occlusion, or CTO). The study first used a broad protein-scanning technology (Olink proteomics) in a small group of 88 diabetic CTO patients to identify candidate proteins, then confirmed the findings using a standard blood test (ELISA) in a much larger group of 832 CTO patients, about half of whom had type 2 diabetes. Patients with poorly developed collateral vessels had significantly higher blood levels of SCGB3A2, and this relationship held up even after accounting for other known risk factors.
The practical implication is that measuring SCGB3A2 in blood could help doctors better identify which CTO patients—especially those with type 2 diabetes—are unlikely to have developed adequate natural bypass vessels around their blockage. Adding SCGB3A2 to existing clinical information improved the ability to correctly classify patients, raising the predictive accuracy (C-statistic) from 0.73 to 0.78. This research suggests SCGB3A2 may reflect underlying biological processes that cause collateral vessel formation to fail, and could potentially serve as a biomarker for risk stratification in this patient population. Similar associations were also found in CTO patients without diabetes, suggesting the protein's relevance may extend beyond diabetic patients.
Chen J, Chen S, Wang J, Huang K, Wang A, Lu L, et al.. (2026). Circulating SCGB3A2 Is Associated With Impaired Coronary Collateralization in Patients With Chronic Total Occlusion and Type 2 Diabetes: A Proteomic Discovery and Validation Study.. Journal of diabetes. https://doi.org/10.1111/1753-0407.70281