Dataset Information

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

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.

Supplementary information

The online version contains supplementary material available at 10.1007/s13340-023-00618-0.

SUBMITTER: Sakashita T

PROVIDER: S-EPMC10113415 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Sakashita Takuya T Nakamura Yasuyuki Y Sutoh Yoichi Y Shimizu Atsushi A Hachiya Tsuyoshi T Otsuka-Yamasaki Yayoi Y Takashima Naoyuki N Kadota Aya A Miura Katsuyuki K Kita Yoshikuni Y Ikezaki Hiroaki H Otonari Jun J Tanaka Keitaro K Shimanoe Chisato C Koyama Teruhide T Watanabe Isao I Suzuki Sadao S Nakagawa-Senda Hiroko H Hishida Asahi A Tamura Takashi T Kato Yasufumi Y Okada Rieko R Kuriki Kiyonori K Katsuura-Kamano Sakurako S Watanabe Takeshi T Tanoue Shiroh S Koriyama Chihaya C Oze Isao I Koyanagi Yuriko N YN Nakamura Yohko Y Kusakabe Miho M Nakatochi Masahiro M Momozawa Yukihide Y Wakai Kenji K Matsuo Keitaro K

Diabetology international 20230127 2

<h4>Aims</h4>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.<h4>Methods</h4>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-I ...[more]

PMID: 37090135

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Project description:Coronary artery disease (CAD) and cerebral infarction (CI) remain major causes of morbidity and mortality in humans. Recent genome-wide association studies have identified various genetic variants associated with these diseases. However, these studies were commonly conducted in a cross-sectional manner. Therefore, the present research performed longitudinal exome-wide association studies for CAD and CI using data on ~244,000 genotyped variants and the clinical data of 6,026 Japanese individuals who had attended annual health checkups for several years (mean followed-up period, 5±3 years). Following quality controls, the significance [false discovery rate (FDR) of <0.05] of association of the diseases with 24,651 single nucleotide polymorphisms (SNPs) in 5,989 individuals for three inheritance models was tested using the generalized estimating equation model. SNPs that reached statistical significance were further screened against a threshold of approxdf (a scale of small effective sample size) of >30. The longitudinal exome-wide association studies revealed that three SNPs [rs4606855 of ADGRE3 (P=2.5×10-6; FDR=0.031; approxdf=71), rs3746414 of ZFP64 (P=5.9×10-6; FDR=0.048; approxdf=93) and rs7132908 of FAIM2 (P<2.0×10-16; FDR<4.9×10-12; approxdf=65)] were significantly associated with the prevalence of CAD. A different set of three SNPs [rs6580741 of FAM186A (P<2.0×10-16; FDR<4.9×10-12; approxdf=48), rs1324015 of LINC00400 (P<2.0×10-16; FDR<4.9×10-12; approxdf=49) and rs884205 of TNFRSF11A (P<2.0×10-16; FDR<4.9×10-12; approxdf=32)] was significantly associated with CI. The comparison of disease incidence with these SNPs demonstrated that all the minor alleles were associated with decreased susceptibility to CAD or CI. In conclusion, six novel SNPs were identified as susceptibility loci for CAD (rs4606855 of ADGRE3, rs3746414 of ZFP64, and rs7132908 of FAIM2) or CI (rs6580741 of FAM186A, rs1324015 of LINC00400, and rs884205 of TNFRSF11A).

Dataset Information

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

Aims

Methods

Results

Conclusions

Supplementary information

Publications

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

Similar Datasets

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