Genetics Can Predict Diabetes Even Without Clinical Risk Factors

Diabetes has become one of the most common chronic diseases worldwide in recent years. Although it is generally thought to be recognized through elevated blood glucose levels, a new study shows that genetic factors may play a much deeper role in determining disease risk. The research was led by Dr. Filipe A. Moura of Yale School of Medicine. On 18 December 2024, Diabetes, Obesity and Metabolism published its findings. Going beyond traditional screening approaches, this study reassessed diabetes risk from a genetic perspective.

Study Methods and Participant Characteristics

The research involved a large cohort of 9,388 participants. They were part of a clinical trial evaluating evolocumab, a drug that lowers LDL (bad cholesterol), and had not been diagnosed with diabetes at baseline. Their mean age was 63; 22.7% were women and 97.3% were white.

The participants' mean body mass index (BMI) was 28.7, and their median HbA1c level was 5.7%. Genetic screening used a multiethnic score incorporating 1.2 million genetic variants, known as a polygenic risk score (PRS). Participants were divided into high-risk (the top 20%) and low-to-intermediate-risk groups based on this genetic score.

Results: The Predictive Power of Genetic Risk Scores

During the study, 7.3% of participants developed diabetes. However, this risk varied substantially with the genetic risk score.

• Diabetes occurred in 12.1% of people with high genetic risk scores, compared with 6.8% in the low-to-intermediate-risk group.

• In the high genetic risk group, the adjusted relative risk of diabetes per standard deviation was calculated as 1.22 (P < 0.001).

• Among normal-weight people (BMI 18.5-25), those with high genetic risk scores had a 2.45-fold higher diabetes risk than those in the low-to-intermediate-risk group.

These findings show that genetic factors can predict diabetes risk independently of clinical risk factors such as obesity or elevated HbA1c.

The Effect of Evolocumab on Diabetes Risk

Evolocumab was not found to increase diabetes risk, and genetic risk factors were similar in the treatment and control groups. This suggests that LDL-lowering treatments do not directly affect diabetes risk.

What Does This Mean?

This study shows the need to go beyond traditional approaches based solely on weight or blood glucose when assessing diabetes risk. In particular, the finding that even normal-weight people can have a diabetes risk comparable to that of people with obesity because of genetic risk suggests that they represent a distinct phenotypic group.

Genetic information has considerable potential for early identification and prevention of diabetes risk. It could guide the development of individualized treatment and risk-reduction strategies.

Limitations

Caution is needed when generalizing these findings. The participant population may have had a higher genetic risk than the general population, and most participants were white. Similar research in larger and more diverse populations is needed.

Final Thoughts

By uncovering the hidden genetic story of diabetes, this study challenges conventional medical approaches. Identifying people at risk earlier may make it possible to take measures that improve quality of life. Genetic screening and individualized healthcare could bring major advances in this field.