Could 'Liquid Biopsy' Detect Vascular Complications in Diabetes?

Roxanne Nelson, RN, BSN

October 01, 2019

A novel test requiring just a few drops of blood may one day improve the diagnosis of life-threatening vascular complications in patients with diabetes, according to new findings.

This "liquid biopsy" has the potential to be a noninvasive, clinically convenient test that can analyze DNA by using highly sensitive blood biomarkers and be predictive of vascular complications, said study coauthor Chuan He, PhD, John T. Wilson Distinguished Service Professor at the University of Chicago, Illinois.

Although clinical variables for detecting vascular complications of diabetes, such as urinary albumin, serum ALT, AST, creatinine, gamma-glutamyl transpeptidase, and lipoprotein A, appear to have a high clinical sensitivity or specificity, the overall accuracy when considering both sensitivity and specificity is not thought to be satisfactory, the researchers explain in their article, published October 1 in Clinical Chemistry by Ying Yang of Zhongnan Hospital of Wuhan University, Hubei, China, and colleagues from the United States.

"We see this novel test as being more accurate than existing clinical factors, or risk factors, for these complications and has the capacity to diagnose these complications earlier," added co-corresponding author Wei Zhang, PhD, associate professor of cancer epidemiology and prevention at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

"If we can accurately identify which patients are developing complications, we may have more intervention approaches to improve clinical outcomes," he added.

Asked to comment, Anne Peters, MD, director, USC Clinical Diabetes Program and professor of clinical medicine, Keck School of Medicine at the University of Southern California, Los Angeles, explained that developing reliable blood tests for serious illnesses such as cancer or cardiovascular disease "is the holy grail for clinicians, since it avoids the need for complex and potentially harmful tests like angiograms and biopsies."

If this test pans out for diabetes complications, it would help "pick up people at risk for these conditions, which could help with prevention," she told Medscape Medical News. 

"Anything that reliably and simply helps me individualize the need for therapies," would be a big step forward, she added.

Borrowing Liquid Biopsies From Cancer Diagnosis

There has been extensive investigation of circulating cell-free DNA (cfDNA) in the blood as a potential noninvasive strategy for diagnosing certain cancers and some cardiovascular conditions. 

Tissue biopsy is currently the gold standard for diagnosing liver cancer, but it is comparatively expensive, difficult, invasive, and time-consuming. Although blood-based tests currently exist, they perform poorly in detecting early stage cancers, which is a particular problem in liver cancer.

The scientists used this same test, which requires just 3 to 5 mL of blood, in a prior study to analyze blood samples of more than 3000 people to accurately identify liver cancer in patients without mistakenly flagging those just at risk. It outperformed current blood tests by detecting about 88% of tumors.

The novel approach, developed by He and Zhang, looks for markers called 5-hydroxymethylcytosines (5hmC) in circulating cell-free DNA, which can be detected in just a few drops of plasma.

Reduction of global levels of 5hmCs has been reported in various cancers and nervous system disorders, and more recently, studies have suggested correlation between alterations in 5hmCs and diabetic complications, the researchers explain.

Promising but Validation Needed

The current study involved 62 Chinese patients with diabetes (12 patients without vascular complications, 34 patients with a singular vascular complication, and 16 with multiple vascular complications).

Within this cohort, 36 patients required insulin, 34 used oral glucose-lowering medications, 25 were on blood pressure-lowering medications, and seven patients used drugs to reduce lipids.

The mean age of participants was 59 years (range, 34 to 86 years) and more than half (61.3%, n = 38) were men. Baseline characteristics including age, gender distribution, body mass index (BMI), and smoking were not significantly different between patients with or without complications, or between patients with single or multiple complications (P > .05).

The cohort was randomized to a training set (n = 31) and a testing set (n = 31). A 16-gene panel of 5hmC markers was identified for differentiating patients with and without complications.

A weighted score for identifying complications was computed based on the 16-gene panel and the final multivariable model drawn from the training set.

The researchers found that there were significant changes in 5hmC markers associated with macrovascular/microvascular complications — the 16-gene 5hmC marker panel was able to accurately differentiate patients experiencing vascular complications from those without them.

In both the training and testing set, patients without complications had significantly lower scores versus those with complications.

Next, 50 patients with single or multiple complications who had diagnostic information available were also randomized to a training set (n = 25) and a testing set (n = 25), and 159 further candidate marker genes were selected.

The authors were able to identify a 13-gene panel of 5hmC marker genes that could differentiate patients with single versus multiple complications, with the weighted scores of those with single complications significantly differing from patients with multiple complications in both the training and testing sets.

The panel outperformed standard clinical variables including urinary albumin.

"The currently available clinical predictors or risk factors such as the albumin level, a patient's BMI, the length of time they've had diabetes, or a blood test analyzing how much waste product is present — are prone to error and don't identify complications early enough to intervene with treatment," Zhang explained.

"The next step is to further refine the biomarker panel and validate the panel in larger and independent cohorts," added Zhang.

"Collaborators in the United States and China are working together to complete a major validation study and we plan to bring this blood test to a multicenter clinical trial in the near future."

The research was supported by grants from the National Natural Science Foundation of China and Health Commission of Hubei Province Scientific Research Project. Wei Zhang was partially supported by the Career Development Fund of the National Institutes of Health. The 5hmC-Seal technology was invented by He and licensed by Shanghai Epican Genetech for clinical diagnosis and prognosis from the University of Chicago. Coauthors Xingyu Lu and Yanqun Song are employees and shareholders of Shanghai Epican Genetech. He and Zhang are shareholders of Shanghai Epican Genetech. He is a scientific founder of Accent Therapeutics and a member of its scientific advisory board. Other authors have reported no relevant financial relationships.

Clin Chem. Published October 1, 2019. Abstract

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