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Comparison of the loci associated with HbA1c and blood glucose levels identified by a genome-wide association study in the Japanese population

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Abstract

Aims

Hemoglobin A1c (HbA1c) levels are widely employed to diagnose diabetes. However, estimates of the heritability of HbA1c and glucose levels are different. Therefore, we explored HbA1c- and blood glucose-associated loci in a non-diabetic Japanese population.

Methods

We conducted a two-stage genome-wide association study (GWAS) on variants associated with HbA1c and blood glucose levels in a Japanese population. In the initial stage, data of 4911 participants of the Japan Multi-Institutional Collaborative Cohort (J-MICC) were subjected to discovery analysis. In the second stage, two datasets from the Tohoku Medical Megabank project, with 8175 and 40,519 participants, were used for the replication study. Association of the imputed variants with HbA1c and blood glucose levels was determined via linear regression analyses adjusted for age, sex, body mass index (BMI), smoking, and genetic principal components (PC1–PC10). Moreover, we performed a BMI-stratified GWAS on HbA1c levels in the J-MICC. The discovery analysis and BMI-stratified GWAS results were validated with re-analyses of normalized HbA1c levels adjusted for site in addition to the above, and blood glucose adjusted for fasting time as an additional covariate.

Results

Genetic variants associated with HbA1c levels were identified in KCNQ1 and TMC6. None of the genetic variants associated with blood glucose levels in the discovery analysis were replicated. Association of rs2299620 in KCNQ1 with HbA1c levels showed heterogeneity between individuals with BMI ≥ 25 kg/m2 and BMI < 25 kg/m2.

Conclusions

The variant rs2299620 in KCNQ1 might affect HbA1c levels differentially based on BMI grouping in the Japanese population.

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Data availability

Data are available upon reasonable request. Details can be found on the J-MICC Study website (http://www.jmicc.com/).

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Acknowledgements

The authors thank the staff of the Laboratory for Genotyping Development, Center for Integrative Medical Sciences at RIKEN, and the staff of the BioBank Japan project. We also thank Dr. Nobuyuki Hamajima and Dr. Hideo Tanaka, the previous principal investigators of the J-MICC study, for their continued support of the current study. This work was supported by Grants-in-Aid for Scientific Research for Priority Areas of Cancer [grant number 17015018], Innovative Areas [grant number 221S0001], and JSPS KAKENHI [grant numbers 17390186, 20390184, 24390165, 16H06277, and 19H03902] from the Japanese Ministry of Education, Culture, Sports, Science, and Technology. This study was also supported, in part, by the BioBank Japan Project of the Japan Agency for Medical Research and Development since April 2015 and the Ministry of Education, Culture, Sports, Science and Technology from April 2003 to March 2015.

Author information

Authors and Affiliations

  1. Department of Public Health, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan

    Takuya Sakashita, Yasuyuki Nakamura, Naoyuki Takashima, Aya Kadota, Katsuyuki Miura & Yoshikuni Kita

  2. TAKARA BIO INC., 7-4-38 Nojihigashi, Kusatsu, Shiga, 525-0058, Japan

    Takuya Sakashita

  3. Takeda Hospital Medical Examination Center, Kyoto, Japan

    Yasuyuki Nakamura

  4. Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan

    Yoichi Sutoh, Atsushi Shimizu, Tsuyoshi Hachiya & Yayoi Otsuka-Yamasaki

  5. Department of Public Health, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osaka-Sayama, Osaka, 589-8511, Japan

    Naoyuki Takashima

  6. NCD Epidemiology Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan

    Aya Kadota & Katsuyuki Miura

  7. Faculty of Nursing Science, Tsuruga Nursing University, 78-2-1 Kizaki, Tsuruga, Fukui, 914-0814, Japan

    Yoshikuni Kita

  8. Department of Comprehensive General Internal Medicine, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Hiroaki Ikezaki

  9. Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Hiroaki Ikezaki

  10. Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Jun Otonari

  11. Department of Preventive Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan

    Keitaro Tanaka

  12. Department of Pharmacy, Saga University Hospital, 5-1-1 Nabeshima, Saga, 849-8501, Japan

    Chisato Shimanoe

  13. Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo- ku, Kyoto, 602-8566, Japan

    Naoyuki Takashima, Teruhide Koyama & Isao Watanabe

  14. Department of Public Health, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan

    Sadao Suzuki & Hiroko Nakagawa-Senda

  15. Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Asahi Hishida, Takashi Tamura, Yasufumi Kato, Rieko Okada & Kenji Wakai

  16. Laboratory of Public Health, Division of Nutritional Sciences, School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan

    Kiyonori Kuriki

  17. Department of Preventive Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan

    Sakurako Katsuura-Kamano & Takeshi Watanabe

  18. Department of Epidemiology and Preventive Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan

    Shiroh Tanoue & Chihaya Koriyama

  19. Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan

    Isao Oze & Keitaro Matsuo

  20. Division of Cancer Information and Control, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan

    Yuriko N. Koyanagi

  21. Cancer Prevention Center, Chiba Cancer Center Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba, 260-8717, Japan

    Yohko Nakamura & Miho Kusakabe

  22. Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-Minami, Higashi-ku, Nagoya, 461-8673, Japan

    Masahiro Nakatochi

  23. Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan

    Yukihide Momozawa

  24. Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Keitaro Matsuo

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  1. Takuya Sakashita
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  2. Yasuyuki Nakamura
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Contributions

Conceptualization, TS and YN; methodology, TS and YN; validation, YS, AS, TH and YO-Y; formal analysis, TS, YN, YS, YO-Y and MN; writing—original draft, TS and YN; writing—review and editing; YN and YS; visualization, YN and MN; supervision, YN; investigation and resources, YN, YS, AS, TH, YO-Y, NT, AK, KM, YK, HI, JO, KT, CS, TK, IW, SS, HN-S, AH, TT, YK, RO, KK, SK-K, TW, ST, CK, IO, YNK, YN, MK, MN, YM, KW and KM. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Takuya Sakashita.

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Conflict of interest

Takuya Sakashita is an employee of Takara Bio, Inc., Japan. Dr. Hachiya is a board member of Genome Analytics Japan Inc. Dr. Nakatochi reports receiving grants from Boehringer Ingelheim outside the submitted work. All other authors declare that they have no conflicts of interest associated with this study.

Human rights statement and informed consent

All procedures were in accordance with the technical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later revisions. Informed consent was obtained from all participants before inclusion into the J-MICC study. The main study protocol of the J-MICC study was approved on July 20, 2005 by the Ethics Committee at Nagoya University School of Medicine (approval number 253).

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Sakashita, T., Nakamura, Y., Sutoh, Y. et al. Comparison of the loci associated with HbA1c and blood glucose levels identified by a genome-wide association study in the Japanese population. Diabetol Int 14, 188–198 (2023). https://doi.org/10.1007/s13340-023-00618-0

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