Genetic profiling identifies risk of coronary artery disease long before onset of type 2 diabetes

Genetic profiling of type 2 diabetes subgroups has enabled researchers to predict coronary artery disease risk prior to clinical diagnosis with implications for possible earlier intervention

A growing body of research has established that type 2 diabetes (T2DM) is not a single disorder but a heterogeneous condition that can be stratified into five clinically and biologically distinct subgroups. A research team at Lund University, Sweden, has now extended this framework to examine whether genetic predisposition to these subgroups can help to assess the risk of coronary artery disease, one of the most common and consequential forms of cardiovascular disease.

The team has developed genetic risk scores based on subgroup-specific genetic signatures and has shown that these scores can predict not only the likelihood of developing T2DM, but also the risk of coronary artery disease before T2DM becomes clinically apparent. This finding has introduced a potential route to identify high-risk individuals at a stage when preventive strategies may still alter disease trajectory.

Coronary artery disease arises primarily from atherosclerosis, in which lipid-rich plaques accumulate within the arterial wall and restrict blood flow to the heart. The condition remains a leading cause of morbidity and mortality worldwide and often presents late, frequently after irreversible vascular damage has occurred. T2DM has long been recognised as a major risk factor for coronary artery disease, yet the biological relationship between different forms of T2DM and cardiovascular risk has remained insufficiently resolved.

Patients who present with coronary artery disease often receive a subsequent diagnosis of T2DM which suggests that metabolic dysfunction may remain undetected for years before overt disease emerges. Myocardial infarction represents one of the most severe clinical outcomes within this spectrum.

“T2DM is a silent disease which is often detected when the patient is seeking care for complications, such as coronary artery disease. We need to identify individuals with a high risk of developing T2DM and coronary artery disease at a much earlier stage, as this may allow us to improve prevention of complications, such as myocardial infarction.

“In our novel study, we have identified a group that we may be able to help at an earlier stage than we do today,” said Dr. Andreas Edsfeldt, associate professor in cardiology at Lund University Diabetes Centre and cardiologist at Skåne University Hospital in Malmö, Sweden.

The study has built on earlier work from the Lund University Diabetes Centre, which demonstrated that type 1 diabetes can be classified as a single subgroup, whereas T2DM comprises four distinct subtypes with differing clinical characteristics and disease trajectories. These classifications have previously emerged from the ANDIS (All New Diabetics in Skåne) study, which aims to register and characterise incident cases of T2DM in southern Sweden.

To extend these findings, the researchers analysed data from the Malmö Diet Cancer study, a large population-based cohort with long-term follow-up and randomly selected participants drawn from the general population. The analysis included 24,025 individuals, among whom 4,105 developed T2DM during the follow-up period.

Using data derived from genome-wide association studies, the team constructed genetic risk scores tailored to each of the five T2DM subgroups. These scores have enabled estimation of an individual’s inherited predisposition to develop specific forms of T2DM as well as associated cardiovascular complications.

The results have shown that the genetic risk scores reliably predicted the development of T2DM across subgroups. More notably, the score associated with the subgroup known as mild obesity-related T2DM – characterised by increased adiposity and earlier onset of T2DM – also predicted the risk of coronary artery disease before T2DM diagnosis. This observation suggests that genetic susceptibility linked to this subgroup may influence cardiovascular pathology independently of clinically manifest T2DM.

“Diabetes is a heterogeneous disease and the risk to develop coronary artery disease can differ greatly between individuals.

“Our DNA is inherited and largely stable across life, therefore genetic risk scores can help determine a person’s risk of developing T2DM and coronary artery disease early in life,” said Dr. Jiangming Sun, an associate professor at Lund University.

These findings have contributed to a growing recognition that precision medicine approaches may refine risk stratification beyond conventional clinical markers such as body mass index, blood glucose concentration and lipid profiles. By incorporating genetic information, clinicians may be able to identify individuals who require earlier monitoring or targeted preventive interventions.

“I hope that genetic risk scores can be used to identify individuals who are at risk of developing diabetes and coronary artery disease long before early signs of disease.

“This would give us a better opportunity to delay or prevent onset of the disease,” Edsfeldt said.

The study has also highlighted the importance of understanding the biological mechanisms that link specific T2DM subgroups to cardiovascular disease. The observed association between mild obesity-related T2DM and coronary artery disease has prompted plans for further investigation into the molecular and physiological pathways that drive atherosclerosis in this population.

“A limitation of our study is that it has been conducted on population studies where most participants are of European descent, which means that the findings may not be generalisable to other populations. Future studies in diverse populations are warranted to validate and extend these findings,” said Mengyu Pan, a doctoral candidate in bioinformatics at Lund University.

Pan’s work focuses on the relationship between T2DM and atherosclerosis. While the findings offer a promising step towards more individualised risk prediction, the authors have emphasised the need for caution in interpretation.

Taken together, the study has provided evidence that genetic profiling of T2DM subgroups may allow clinicians to anticipate cardiovascular risk earlier than previously possible.

For further reading please visit: 10.2337/dc25-1711