Evidence of Epistatic Interactive Effects of HK1 and GCK Genes on Circulating Hemoglobin A1c Levels in Humans
7 affiliations
- 1Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, 4444 Forest Park Ave, St. Louis, MO 63108, USA
- 2G. H. Sergievsky Center, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Departments of Neurology and Epidemiology, Columbia University Irving Medical Center, New York, NY 10032, USA
- 3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
- 4Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, USA
- 5Department of Medicine, Section of Geriatrics, Boston Medical Center, Boston University School of Medicine, Boston, MA 02118, USA
- 6Unit of Epidemiology, Biostatistics and Biodemography, Department of Public Health, Southern Denmark University, 5230 Odense, Denmark
- 7Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15260, USA
Abstract
Hemoglobin A1c (HbA1c), an important diagnostic biomarker for type 2 diabetes (T2D), is also associated with aging, cognitive performance, and mortality. To identify epistatic interactions, we assessed 133 known gene variants associated with HbA1c among 3778 non-diabetic subjects of European ancestry in the Long Life Family Study (LLFS). We applied Bayesian imputation based association mapping (BIMBAM) to identify significant pairwise epistatic interactions among 133 genetic variants. To take into account confounding effects, we adjusted age, sex, field centers, body mass index (BMI), and genetic principal components (PCs). This analysis yielded seven pairs with log10(BF) > 10; of those, six pairs were confirmed using a full-term mixed regression model. Specifically, these included significant interactions of HK1-rs17476364 with variants in GCK (rs2971670, rs4607517) or G6PC2 (rs560887), as well as between HK1-rs16926246 and the same variants (p values for each term ≤ 7.14 × 10−3). All epistatic interactions between HK1 and GCK, and between HK1 and G6PC2 were replicated at p < 0.05 in at least one of two large independent studies (namely, Framingham Offspring Study; Health and Retirement Study). The present study revealed that HK1 and GCK interact to contribute to regulating levels of HbA1c and are likely to be involved in molecular mechanisms underlying healthy aging processes.
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BibTeX
@article{wang2026evidence,
title = {{Evidence of Epistatic Interactive Effects of HK1 and GCK Genes on Circulating Hemoglobin A1c Levels in Humans}},
author = {Lihua Wang and Joseph H. Lee and Bharat Thyagarajan and Anatoliy I. Yashin and E. Warwick Daw and Thomas T. Perls and Kaare Christensen and Joseph M. Zmuda and Michael A. Province and Ping An},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219797},
url = {https://www.mdpi.com/1422-0067/27/21/9797},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Evidence of Epistatic Interactive Effects of HK1 and GCK Genes on Circulating Hemoglobin A1c Levels in Humans
AU - Lihua Wang
AU - Joseph H. Lee
AU - Bharat Thyagarajan
AU - Anatoliy I. Yashin
AU - E. Warwick Daw
AU - Thomas T. Perls
AU - Kaare Christensen
AU - Joseph M. Zmuda
AU - Michael A. Province
AU - Ping An
PY - 2026
DA - 2026/10/31
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219797
UR - https://www.mdpi.com/1422-0067/27/21/9797
AB - Hemoglobin A1c (HbA1c), an important diagnostic biomarker for type 2 diabetes (T2D), is also associated with aging, cognitive performance, and mortality. To identify epistatic interactions, we assessed 133 known gene variants associated with HbA1c among 3778 non-diabetic subjects of European ancestry in the Long Life Family Study (LLFS). We applied Bayesian imputation based association mapping (BIMBAM) to identify significant pairwise epistatic interactions among 133 genetic variants. To take into account confounding effects, we adjusted age, sex, field centers, body mass index (BMI), and genetic principal components (PCs). This analysis yielded seven pairs with log10(BF) > 10; of those, six pairs were confirmed using a full-term mixed regression model. Specifically, these included significant interactions of HK1-rs17476364 with variants in GCK (rs2971670, rs4607517) or G6PC2 (rs560887), as well as between HK1-rs16926246 and the same variants (p values for each term ≤ 7.14 × 10−3). All epistatic interactions between HK1 and GCK, and between HK1 and G6PC2 were replicated at p < 0.05 in at least one of two large independent studies (namely, Framingham Offspring Study; Health and Retirement Study). The present study revealed that HK1 and GCK interact to contribute to regulating levels of HbA1c and are likely to be involved in molecular mechanisms underlying healthy aging processes.
SN - 1422-0067
ER -