Kv11.1 (hERG) Protein Interaction Networks Connect Endocytic Trafficking to Polygenic Influences on Cardiac Repolarization

ABSTRACT: Polygenic scores (PGS) capture the combined effect of many common genetic variants on quantitative traits and disease risk, yet their functional consequences at the protein level remain poorly defined. Here, we integrated quantitative and interaction proteomics to resolve how polygenic liability for cardiac repolarization manifests in human cells. We studied human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) from donors with extreme PGS for QT interval duration, a clinically relevant electrophysiologic trait associated with arrhythmia risk. Global quantitative proteomics revealed increased abundance of mitochondrial proteins in high-PGS cardiomyocytes. To define protein network–level effects on a key repolarizing ion channel, we performed multiplexed affinity purification–mass spectrometry (AP-MS) of Kv11.1 (hERG). While mitochondrial changes did not directly explain Kv11.1-associated complexes, interactome analysis revealed increased association of Kv11.1 with myosin motor proteins and endosomal recycling machinery in high-PGS cells. These findings are consistent with altered channel trafficking dynamics of Kv11.1, distinct from the trafficking defects observed in monogenic Kv11.1 variants. Together, these data show that integrating global and interaction proteomics can resolve how polygenic variation reshapes protein networks. This approach connects genomic risk to subcellular remodeling and provides a generalizable framework to probe the proteomic basis of complex traits.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pluripotent Stem Cell, Cell Culture, Cardiac Muscle Cell

DISEASE(S): Arrhythmia

SUBMITTER: Christian Egly  

LAB HEAD: Christian Lawrence Egly

PROVIDER: PXD077616 | Pride | 2026-10-26

REPOSITORIES: Pride