Frontiers in endocrinology
Cross-scale genetic, molecular, and cellular triangulation prioritizes ACSL5 as a T3-responsive candidate linking hypothyroidism liability to anemia
By Li H, Jiang T, Wang H and 2 others.
Abstract
Purpose
Anemia is a recognized complication of hypothyroidism, but disease-level genetic studies have not identified a clear erythroid cell-intrinsic target. We integrated genetic validation, molecular-QTL prioritization, and replicated triiodothyronine (T3)-responsive erythroid experiments to identify candidates linking hypothyroidism liability to anemia.
Materials and methods
Two-sample Mendelian randomization (MR) assessed genetically predicted hypothyroidism and anemia. Source metadata were reviewed for possible sample overlap, and two cross-biobank forward validations were performed. Strict reverse MR used the original OpenGWAS identifiers; because anemia provided no genome-wide-significant instruments, a post hoc analysis used p < 5 × 10-6. Non-major histocompatibility complex (MHC) methylation summary-based Mendelian randomization (SMR) and whole-blood expression SMR were integrated, followed by a public fine-mapping/colocalization lookup for two acyl-CoA synthetase long-chain family member 5 (ACSL5) cytosine-phosphate-guanine (CpG) sites and the ACSL5 eQTL. ACSL5 was examined in three independent hemin-induced K562, a human chronic myelogenous leukemia cell line experiments with or without T3; Triacsin C and oleic acid-bovine serum albumin (BSA) served as pathway-level perturbations.