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[Preprint]. 2024 May 21:2024.05.16.594575.

doi: 10.1101/2024.05.16.594575.

A Novel Gene ARHGAP44 for Longitudinal Changes in Glycated Hemoglobin (HbA1c) in Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Offspring Study (FOS)

Affiliations

¹ Department of Genetics Division of Statistical Genomics, Washington University School of Medicine. St. Louis, MO, USA.
² Department of Radiology, Washington University School of Medicine. St. Louis, MO, USA.
³ Departments of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
⁴ Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Departments of Neurology and Epidemiology, Columbia University, New York City, NY, USA.
⁵ Social Science Research Institute, Duke University, Durham, NC, USA.
⁶ Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Department of Chemistry, Washington University School of Art and Sciences, St. Louis, MO, USA.
⁸ Deptartment of Computer Science and Center for Genome Sciences, Washington University, St. Louis, MO, USA.
⁹ Departments of Medicine and Geriatrics, Boston University School of Medicine, Boston, MA, USA.
¹⁰ Danish Aging Research Center, Epidemiology, University of Southern Denmark, Odense, Denmark.

PMID: 38826208
PMCID: PMC11142083
DOI: 10.1101/2024.05.16.594575

A Novel Gene ARHGAP44 for Longitudinal Changes in Glycated Hemoglobin (HbA1c) in Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Offspring Study (FOS)

Siyu Wang et al. bioRxiv. 2024.

[Preprint]. 2024 May 21:2024.05.16.594575.

doi: 10.1101/2024.05.16.594575.

Authors

Affiliations

¹ Department of Genetics Division of Statistical Genomics, Washington University School of Medicine. St. Louis, MO, USA.
² Department of Radiology, Washington University School of Medicine. St. Louis, MO, USA.
³ Departments of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
⁴ Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Departments of Neurology and Epidemiology, Columbia University, New York City, NY, USA.
⁵ Social Science Research Institute, Duke University, Durham, NC, USA.
⁶ Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Department of Chemistry, Washington University School of Art and Sciences, St. Louis, MO, USA.
⁸ Deptartment of Computer Science and Center for Genome Sciences, Washington University, St. Louis, MO, USA.
⁹ Departments of Medicine and Geriatrics, Boston University School of Medicine, Boston, MA, USA.
¹⁰ Danish Aging Research Center, Epidemiology, University of Southern Denmark, Odense, Denmark.

PMID: 38826208
PMCID: PMC11142083
DOI: 10.1101/2024.05.16.594575

Abstract

Glycated hemoglobin (HbA1c) indicates average glucose levels over three months and is associated with insulin resistance and type 2 diabetes (T2D). Longitudinal changes in HbA1c (ΔHbA1c) are also associated with aging processes, cognitive performance, and mortality. We analyzed ΔHbA1c in 1,886 non-diabetic Europeans from the Long Life Family Study to uncover gene variants influencing ΔHbA1c. Using growth curve modeling adjusted for multiple covariates, we derived ΔHbA1c and conducted linkage-guided sequence analysis. Our genome-wide linkage scan identified a significant locus on 17p12. In-depth analysis of this locus revealed a variant rs56340929 (explaining 27% of the linkage peak) in the ARHGAP44 gene that was significantly associated with ΔHbA1c. RNA transcription of ARHGAP44 was associated with ΔHbA1c. The Framingham Offspring Study data further supported these findings on the gene level. Together, we found a novel gene ARHGAP44 for ΔHbA1c in family members without T2D. Follow-up studies using longitudinal omics data in large independent cohorts are warranted.

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Figures

**Figure 1**
A. An overlay of Manhattan plot from the GWAS and GWLS results. The illustration synthesizes our findings in the overall data. The horizonal black reference line denotes the established criteria for genome-wide significance (p < 5e-8), and linkage scan significance (LODs > 3.0). B. Highlights of the identified lead SNP rs56340929 under the right linkage peak (*17p12*) in the linkage-enriched families. The black line denotes a threshold at LODs > 3.0, while vertical gray lines represent the 1-LOD support interval. SNP rs56340929 is located within this interval.

See this image and copyright information in PMC

References

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This is a preprint.

A Novel Gene ARHGAP44 for Longitudinal Changes in Glycated Hemoglobin (HbA1c) in Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Offspring Study (FOS)

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A Novel Gene ARHGAP44 for Longitudinal Changes in Glycated Hemoglobin (HbA1c) in Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Offspring Study (FOS)

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Abstract

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