Cross-scale genetic, molecular, and cellular triangulation prioritizes ACSL5 as a T3-responsive candidate linking hypothyroidism liability to anemia
- 1Department of Hematology, The People’s Hospital of Jianyang City
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.
Results: Primary inverse-variance weighted (IVW) analysis associated hypothyroidism liability with higher anemia odds (OR = 1.0304; 95% CI, 1.0195–1.0414; p = 3.42 × 10 ⁻⁸ ). Both primary genome-wide association studies (GWASs) were UK Biobank-derived, and their exact participant overlap could not be determined from public summary-level information. A participant-independent FinnGen hypothyroidism-to-UK Biobank anemia validation reproduced the positive direction (28 instruments; IVW beta = 0.001448, p = 4.14 × 10 ⁻⁴ ); the complementary UK Biobank hypothyroidism-to-FinnGen anemia analysis was also positive. Strict original-ID reverse MR was not estimable; the exploratory eight-instrument analysis was null and heterogeneous. Six non-MHC CpGs passed Bonferroni correction, including two mapped to ACSL5 , while whole-blood ACSL5 expression showed an inverse SMR estimate. The public lookup returned no pairwise CpG-expression colocalization. In all three K562 experiments, hemin plus T3 increased HBA1 , HBA2 , GYPA , and ACSL5 expression. Triacsin C suppressed erythroid-marker expression, whereas oleic acid-BSA produced a partial increase without exogenous T3.
Conclusion: Cross-scale evidence prioritizes ACSL5 as a T3-responsive candidate linking hypothyroidism liability to anemia and implicates long-chain fatty-acid handling as a research direction. However, negative CpG-expression colocalization and nongene-specific pharmacological interventions preclude a mechanistic conclusion. Direct ACSL5 perturbation and primary erythroid-cell validation are required.
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BibTeX
@article{li2026crossscale,
title = {{Cross-scale genetic, molecular, and cellular triangulation prioritizes ACSL5 as a T3-responsive candidate linking hypothyroidism liability to anemia}},
author = {Hui Li and Tao Jiang and Huan Wang and Mei Wang and Sixi Xie},
journal = {Frontiers in Endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1943954},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1943954/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cross-scale genetic, molecular, and cellular triangulation prioritizes ACSL5 as a T3-responsive candidate linking hypothyroidism liability to anemia
AU - Hui Li
AU - Tao Jiang
AU - Huan Wang
AU - Mei Wang
AU - Sixi Xie
PY - 2026
DA - 2026/10/08
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1943954
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1943954/full
AB - 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. Results: Primary inverse-variance weighted (IVW) analysis associated hypothyroidism liability with higher anemia odds (OR = 1.0304; 95% CI, 1.0195–1.0414; p = 3.42 × 10 ⁻⁸ ). Both primary genome-wide association studies (GWASs) were UK Biobank-derived, and their exact participant overlap could not be determined from public summary-level information. A participant-independent FinnGen hypothyroidism-to-UK Biobank anemia validation reproduced the positive direction (28 instruments; IVW beta = 0.001448, p = 4.14 × 10 ⁻⁴ ); the complementary UK Biobank hypothyroidism-to-FinnGen anemia analysis was also positive. Strict original-ID reverse MR was not estimable; the exploratory eight-instrument analysis was null and heterogeneous. Six non-MHC CpGs passed Bonferroni correction, including two mapped to ACSL5 , while whole-blood ACSL5 expression showed an inverse SMR estimate. The public lookup returned no pairwise CpG-expression colocalization. In all three K562 experiments, hemin plus T3 increased HBA1 , HBA2 , GYPA , and ACSL5 expression. Triacsin C suppressed erythroid-marker expression, whereas oleic acid-BSA produced a partial increase without exogenous T3. Conclusion: Cross-scale evidence prioritizes ACSL5 as a T3-responsive candidate linking hypothyroidism liability to anemia and implicates long-chain fatty-acid handling as a research direction. However, negative CpG-expression colocalization and nongene-specific pharmacological interventions preclude a mechanistic conclusion. Direct ACSL5 perturbation and primary erythroid-cell validation are required.
SN - 1664-2392
ER -