# A Novel 10‐Protein Score for Liver Fat Content Predicts Cardiovascular‐Kidney‐Metabolic Disease Risk

## TL;DR

A new blood test using 10 proteins accurately measures liver fat and predicts heart, kidney, and metabolic disease risks better than existing methods.

## Contribution

A novel 10-protein plasma score for liver fat content that outperforms existing methods and integrates with genetic risk scores.

## Key findings

- The 10-protein score showed superior diagnostic accuracy for hepatic steatosis compared to the fatty liver index (AUC = 0.850 vs. 0.794).
- The score significantly enhanced risk prediction for 8–10 CKM outcomes beyond standard risk factors and FLI.
- The score showed significant interactions with polygenic risk scores for type 2 diabetes (P-interaction < 0.001).

## Abstract

Liver fat content (LFC) is a key biomarker for cardiovascular‐kidney‐metabolic (CKM), yet noninvasive assessment remains challenging. It aims to develop a plasma proteomic‐based LFC score to predict MRI‐derived proton density fat fraction (MRI‐PDFF), evaluate its association with 14 CKM diseases, and explore interactions with polygenic risk scores (PRS). Both the comprehensive 62‐protein and simplified 10‐protein LFC scores are developed and validated in 5,320 UK Biobank participants (96.8% White). The 10‐protein LFC score, comprising proteins involved in adipogenesis, lipid metabolism, and insulin signaling (IGFBP2, FABP4, MET, CPM, CES1, IGFBP1, CDHR2, RBP5, ERBB2, SSC5D), showed superior diagnostic accuracy for hepatic steatosis compared to fatty liver index(FLI) (AUC = 0.850 vs. 0.794). Among 45,444 participants, it exhibited significant associations with 16 cardiometabolic risk markers and 13 incident CKM outcomes, particularly metabolic dysfunction‐associated steatotic liver disease (MASLD), type 2 diabetes (T2D), chronic kidney disease, and coronary heart disease. The score significantly enhanced risk prediction for 8–10 CKM outcomes beyond standard risk factors and FLI (e.g., MASLD,C‐index improved from 0.743 to 0.774; T2D, from 0.773 to 0.806). The score showed significant interactions with PRS for T2D (P‐interaction<0.001). The 62‐protein model yielded similar results. A 10‐protein score accurately quantifies liver fat, predicts cardiometabolic risk, and integrates with genetic risk for precision prevention, providing a practical MRI alternative.

A novel 10‐protein plasma score precisely quantifies liver fat, outperforming the fatty liver index. It robustly predicts the risk of numerous cardiovascular‐kidney‐metabolic diseases and integrates with genetic data for precision prevention, offering a practical alternative to magnetic resonance imaging (MRI).