Statin signature: using proteomics to detect pharmacological fingerprints

Background

Lowering low-density lipoprotein cholesterol with statin therapy is a primary strategy for reducing cardiovascular morbidity and mortality. Yet, adherence to and persistence with statin medication is generally low, complicating the ability to evaluate whether treatment is effective.

Methods

Using modified-aptamer proteomics technology, SomaScan® assay v4.0, we assessed ∼5,000 proteins in 8,395 EDTA plasma samples from individuals aged 29-64 at visit 1 of the Fenland study, totaling ∼42 million protein measurements. A total of 305 individuals (3.6%) reported active statin medication use at this study visit. Predicted statin use was modeled with protein measurements using machine learning methods in 70% of Fenland as a training dataset. A hold-out dataset was used to assess model performance. A predictive model using elastic net logistic regression was optimized based on AUC and robustness to assay noise and sample handling conditions to detect a signature of statin usage.

Results

A total of 839 proteins differed significantly between the ‘active statin’ and ‘no statin’ use groups in univariate analysis (FDR <0.01). Eight of the top 50 significant proteins have known mechanistic associations with statin pharmacology, including HMGCS1, PCSK9, and APOB. A six-protein model was developed with an AUC of 0.91 (sensitivity=0.82, specificity=0.88) and 0.90 (sensitivity=0.80, specificity=0.87) on the training and hold-out datasets, respectively, to predict whether a statin signature is present or not.

Conclusions

We successfully developed a blood-based protein-only model that detects mechanistically-relevant protein changes to predict active statin use in adults. The protein model could compliment self-reported medication status in clinical trials and in healthcare.

Authors

Jessica Kuzma
Sama Shrestha
Clare Paterson
Hannah Biegel
Lori K. Bogren
Michael A. Hinterberg
Yolanda Hagar
Stephen A. Williams

SomaLogic Operating Company, Inc, Boulder CO, USA