Missense variants in SORT1 are associated with LDL-C in an Amish population

• DOI: 10.1016/j.jlr.2023.100468
• Publication Date: 2023-10-31T22:57:39Z
• Authors: Kelly A. Mitok; Kathryn L. Schueler; Sarah M. King; Joseph Orr; Kathleen A. Ryan; Mark P. Keller; Ronald M. Krauss; Braxton D. Mitchell; Alan R. Shuldiner; Alan D. Attie
• Keywords: Exome

Common noncoding variants at the human 1p13.3 locus associated with SORT1 expression are among those most strongly low-density lipoprotein cholesterol (LDL-C) in genome-wide association studies. However, validation studies mice and cell lines have produced variable results regarding directionality of effect on LDL-C. This, together fact that several genes, has raised question whether is causal gene this locus. Using whole exome sequencing members an Amish population, we identified coding increased (rs141749679, K302E) decreased (rs149456022, Q225H) Further, analysis plasma particle subclasses by ion mobility a subset rs141749679 (K302E) carriers revealed higher levels large LDL particles compared to noncarriers. In contrast these Amish, sortilin K302E mutation introduced into C57BL/6J mouse via CRISPR/Cas9 resulted non-high-density cholesterol, Q225H did not alter mice. This indicative different effects mutations metabolism two species. To our knowledge, first evidence naturally occurring LDL-C, thus supporting as responsible for