medwireNews: Combining 10 weighted polygenic risk scores (10 PRS) of variants related to cardiovascular and renal complications in a joint model with traditional risk factors could optimize micro- and macrovascular risk prediction and treatment response in type 2 diabetes, say researchers.
The 10 PRS, developed by Johanne Tremblay (University of Montréal, Québec, Canada) and colleagues, comprises 598 single nucleotide polymorphisms associated with diabetes, obesity, blood pressure, albuminuria, glomerular filtration rate, biomarkers, lipids, stroke, cardiovascular disease, and low birthweight.
The researchers combined these with sex, ethnicity, age at diabetes onset, and diabetes duration into one logistic regression model (multiPRS) that they used to predict type 2 diabetes endpoints among 4098 participants of the ADVANCE study. They then validated the model in 17,604 individuals with type 2 diabetes in the UK Biobank study plus three smaller independent cohorts (post-MONICA, CLINPRADIA, CanPath).
As reported in Diabetologia, the model predicted that ADVANCE participants with a multiPRS in the top 30% were 3.1 times more likely to experience micro- or macrovascular complications than individuals with a lower multiPRS.
Among the individual outcomes, the increased likelihood associated with this high-risk multiPRS ranged from 2.2-fold for myocardial infarction to 4.4-fold for cardiovascular death and included a 2.5-fold increased probability of developing new or worsening nephropathy.
The area under the receiver operating characteristic curves (AUCs) for classification of combined micro- and macrovascular events, and microvascular and macrovascular events alone were 0.67, 0.67, and 0.68, respectively, with the AUC ranging from 0.64 to 0.72 for various specific micro- and macrovascular events .
These results indicate that the multiPRS model can predict individual as well as combined cardiovascular and renal complications of type 2 diabetes before these complications appear.
And the investigators note that similar AUCs were observed in each of the validation cohorts.
Tremblay and team also looked at whether multiPRS was associated with treatment response in ADVANCE. They found that individuals with a high-risk multiPRS had significant 20.3% and 32.3% lower risks for all-cause death and cardiovascular death, respectively, when given intensive blood pressure lowering treatment versus placebo.
Conversely, there was no significant risk reduction among the individuals with a low-risk multiPRS. There was also no significant reduction in either group with intensive versus standard glucose control, but intensive glucose control reduced the risk for end-stage renal disease by a significant 65.5% in the individuals with a high-risk multiPRS.
Moreover, when intensive blood pressure and glucose control were combined, the number needed to treat (NNT) to prevent one cardiovascular death over 5 years was 12 in the high-risk multiPRS group compared with 64 in the low-risk group.
Tremblay et al conclude that their “novel prediction model could be applied at the onset of diabetes to help identify high-risk individuals who could benefit from intensification of therapy or novel glucose-lowering treatments, without having to wait for outcomes to occur.”
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