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Interaction between the GCKR rs1260326 variant and serum HDL cholesterol contributes to HOMA-β and ISIMatusda in the middle-aged T2D individuals

Journal of Human Genetics volume 68, pages 835–842 (2023)Cite this article

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Abstract

This study aims to investigate the correlations between islet function/ insulin resistance and serum lipid levels, as well as to assess whether the strength of such correlations is affected by the GCKR rs1260326 variant in healthy and T2D individuals. We performed an oral glucose tolerance test (OGTT) on 4889 middle-aged adults, including 3135 healthy and 1754 T2D individuals from the REACTION population study in the Nanjing region. We also measured their serum lipid levels and genotyped for rs1260326. We found that serum high-density lipoprotein (HDL) cholesterol and triglyceride (TG) levels were independently correlated with indexes of islet function (HOMA-β and IGI [insulinogenic index]) and insulin resistance (HOMO-IR and ISIMatsuda) in both healthy and T2D individuals. The correlations were significantly decreased in T2D individuals, with significant heterogeneities compared to healthy controls (I2 > 75%, Phet < 0.05). Although no correlation was observed between serum total cholesterol (TC) level and islet function/ insulin resistance in healthy controls, significant correlations were found in T2D individuals, with significant heterogeneity to healthy controls in the correlation with ISIMatsuda(I2 = 85.3%, Phet = 0.009). Furthermore, we found significant interactions of the GCKR rs1260326 variant for the correlations between serum HDL cholesterol and HOMA-β/ISIMatsuda in T2D subjects (P = 0.015 and 0.038, respectively). These findings illustrate that distinct correlations between serum lipid levels and islet function/ insulin resistance occurred in T2D subjects compared to healthy individuals. Common gene variants, such as rs1260326, might interact substantially when studied in specific populations, especially T2D disease status.

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Fig. 1: Flowchart of this study.
Fig. 2: The correlation between serum HDL level and log(HOMA-β) and log(ISImatsuda) in T2D individuals, stratified by rs1260326.

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Data availability

The data from this study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank all study participants and the research staff who participated in this work.

Funding

This work was supported by the National Natural Science Foundation of China (81670715, 81830023, 82070803 and 82200888), Jiangsu Province Youth Medical Talents Project (QNRC2016584), the Natural Science Foundation of Jiangsu Province (BK20220714 and BK20220708), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Author notes

  1. These authors contributed equally: Min Shen, Liying Jiang, Hechun Liu.

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Min Shen, Liying Jiang, Hechun Liu, Hao Dai, Hemin Jiang, Yu Qian, Zhixiao Wang, Shuai Zheng, Heng Chen, Tao Yang, Qi Fu & Kuanfeng Xu

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  1. Min Shen
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Contributions

KX directed the study design, performed statistical analyses and overall project management, and revised the manuscript. MS and LJ performed statistical analyses and drafted the initial manuscript. HL performed part of the statistical analyses and revised the manuscript. QF participated in the study design, and revised the manuscript. HD, ZW and SZ performed project management and sample processing. HJ, YQ and HC carried out the laboratory measurements. TY contributed to the study design and edited the manuscript. All the authors approved the final manuscript.

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Correspondence to Qi Fu or Kuanfeng Xu.

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Shen, M., Jiang, L., Liu, H. et al. Interaction between the GCKR rs1260326 variant and serum HDL cholesterol contributes to HOMA-β and ISIMatusda in the middle-aged T2D individuals. J Hum Genet 68, 835–842 (2023). https://doi.org/10.1038/s10038-023-01191-9

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