{"title":"比较日本人群中通过全基因组关联研究发现的与 HbA1c 和血糖水平相关的基因位点。","authors":"Takuya Sakashita, Yasuyuki Nakamura, Yoichi Sutoh, Atsushi Shimizu, Tsuyoshi Hachiya, Yayoi Otsuka-Yamasaki, Naoyuki Takashima, Aya Kadota, Katsuyuki Miura, Yoshikuni Kita, Hiroaki Ikezaki, Jun Otonari, Keitaro Tanaka, Chisato Shimanoe, Teruhide Koyama, Isao Watanabe, Sadao Suzuki, Hiroko Nakagawa-Senda, Asahi Hishida, Takashi Tamura, Yasufumi Kato, Rieko Okada, Kiyonori Kuriki, Sakurako Katsuura-Kamano, Takeshi Watanabe, Shiroh Tanoue, Chihaya Koriyama, Isao Oze, Yuriko N Koyanagi, Yohko Nakamura, Miho Kusakabe, Masahiro Nakatochi, Yukihide Momozawa, Kenji Wakai, Keitaro Matsuo","doi":"10.1007/s13340-023-00618-0","DOIUrl":null,"url":null,"abstract":"<p><strong>Aims: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>Genetic variants associated with HbA1c levels were identified in <i>KCNQ1</i> and <i>TMC6</i>. None of the genetic variants associated with blood glucose levels in the discovery analysis were replicated. Association of rs2299620 in <i>KCNQ1</i> with HbA1c levels showed heterogeneity between individuals with BMI ≥ 25 kg/m<sup>2</sup> and BMI < 25 kg/m<sup>2</sup>.</p><p><strong>Conclusions: </strong>The variant rs2299620 in <i>KCNQ1</i> might affect HbA1c levels differentially based on BMI grouping in the Japanese population.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s13340-023-00618-0.</p>","PeriodicalId":11340,"journal":{"name":"Diabetology International","volume":null,"pages":null},"PeriodicalIF":1.3000,"publicationDate":"2023-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10113415/pdf/","citationCount":"0","resultStr":"{\"title\":\"Comparison of the loci associated with HbA1c and blood glucose levels identified by a genome-wide association study in the Japanese population.\",\"authors\":\"Takuya Sakashita, Yasuyuki Nakamura, Yoichi Sutoh, Atsushi Shimizu, Tsuyoshi Hachiya, Yayoi Otsuka-Yamasaki, Naoyuki Takashima, Aya Kadota, Katsuyuki Miura, Yoshikuni Kita, Hiroaki Ikezaki, Jun Otonari, Keitaro Tanaka, Chisato Shimanoe, Teruhide Koyama, Isao Watanabe, Sadao Suzuki, Hiroko Nakagawa-Senda, Asahi Hishida, Takashi Tamura, Yasufumi Kato, Rieko Okada, Kiyonori Kuriki, Sakurako Katsuura-Kamano, Takeshi Watanabe, Shiroh Tanoue, Chihaya Koriyama, Isao Oze, Yuriko N Koyanagi, Yohko Nakamura, Miho Kusakabe, Masahiro Nakatochi, Yukihide Momozawa, Kenji Wakai, Keitaro Matsuo\",\"doi\":\"10.1007/s13340-023-00618-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Aims: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>Genetic variants associated with HbA1c levels were identified in <i>KCNQ1</i> and <i>TMC6</i>. None of the genetic variants associated with blood glucose levels in the discovery analysis were replicated. Association of rs2299620 in <i>KCNQ1</i> with HbA1c levels showed heterogeneity between individuals with BMI ≥ 25 kg/m<sup>2</sup> and BMI < 25 kg/m<sup>2</sup>.</p><p><strong>Conclusions: </strong>The variant rs2299620 in <i>KCNQ1</i> might affect HbA1c levels differentially based on BMI grouping in the Japanese population.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s13340-023-00618-0.</p>\",\"PeriodicalId\":11340,\"journal\":{\"name\":\"Diabetology International\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.3000,\"publicationDate\":\"2023-01-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10113415/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Diabetology International\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1007/s13340-023-00618-0\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/4/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q4\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Diabetology International","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1007/s13340-023-00618-0","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/4/1 0:00:00","PubModel":"eCollection","JCR":"Q4","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Comparison of the loci associated with HbA1c and blood glucose levels identified by a genome-wide association study in the Japanese population.
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.
Supplementary information: The online version contains supplementary material available at 10.1007/s13340-023-00618-0.
期刊介绍：
Diabetology International, the official journal of the Japan Diabetes Society, publishes original research articles about experimental research and clinical studies in diabetes and related areas. The journal also presents editorials, reviews, commentaries, reports of expert committees, and case reports on any aspect of diabetes. Diabetology International welcomes submissions from researchers, clinicians, and health professionals throughout the world who are interested in research, treatment, and care of patients with diabetes. All manuscripts are peer-reviewed to assure that high-quality information in the field of diabetes is made available to readers. Manuscripts are reviewed with due respect for the author''s confidentiality. At the same time, reviewers also have rights to confidentiality, which are respected by the editors. The journal follows a single-blind review procedure, where the reviewers are aware of the names and affiliations of the authors, but the reviewer reports provided to authors are anonymous. Single-blind peer review is the traditional model of peer review that many reviewers are comfortable with, and it facilitates a dispassionate critique of a manuscript.
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