Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians

Peng Chen, Fumihiko Takeuchi, Jong Young Lee, Huaixing Li, Jer Yuarn Wu, Jun Liang, Jirong Long, Yasuharu Tabara, Mark O. Goodarzi, Mark A. Pereira, Young Jin Kim, Min Jin Go, Daniel O. Stram, Eranga Vithana, Chiea Chuen Khor, Jianjun Liu, Jiemin Liao, Xingwang Ye, Yiqin Wang, Ling LuTerri L. Young, Jeannette Lee, Ah Chuan Thai, Ching Yu Cheng, Rob M. Van Dam, Yechiel Friedlander, Chew Kiat Heng, Woon Puay Koh, Chien Hsiun Chen, Li Ching Chang, Wen Harn Pan, Bin Qi, Masato Isono, Wei Zheng, Qiuyin Cai, Yutang Gao, Ken Yamamoto, Keizo Ohnaka, Ryoichi Takayanagi, Yoshikuni Kita, Hirotsugu Ueshima, Chao A. Hsiung, Jinrui Cui, Wayne H.H. Sheu, Jerome I. Rotter, Yii Der I. Chen, Chris Hsu, Yukinori Okada, Michiaki Kubo, Atsushi Takahashi, Toshihiro Tanaka, Frank J.A. Van Rooij, Santhi K. Ganesh, Jinyan Huang, Tao Huang, Jianmin Yuan, Joo Yeon Hwang, Myron D. Gross, Themistocles L. Assimes, Tetsuro Miki, Xiao Ou Shu, Lu Qi, Yuan Tson Chen, Xu Lin, Tin Aung, Tien Yin Wong, Yik Ying Teo, Bong Jo Kim, Norihiro Kato, E. Shyong Tai

Research output: Contribution to journalArticle

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Abstract

Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [ P value = 1.3 × 10 -23], HBS1L/MYB [8.5 × 10-15], MYO9B [9.0 × 10-12], and CYBA [1.1 × 10-8] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (<7.0 mmol/L) but elevated HbA1c (≥6.5%), 36.1% had HbA1c <6.5% after adjustment for these six variants. Our East Asian GWAS meta-analysis has identified novel variants associated with HbA1c as well as demonstrated that the effects of known variants are largely transferable across ethnic groups. Variants affecting erythrocyte parameters rather than glucose metabolism may be relevant to the use of HbA1c for diagnosing diabetes in these populations.

Original languageEnglish
Pages (from-to)2551-2562
Number of pages12
JournalDiabetes
Volume63
Issue number7
DOIs
Publication statusPublished - 01-01-2014

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Glycosylated Hemoglobin A
Hemoglobins
Genome-Wide Association Study
Meta-Analysis
Glucose
Ethnic Groups
Type 2 Diabetes Mellitus
Blood Glucose
Fasting
Erythrocytes
Genome
Population

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Chen, P., Takeuchi, F., Lee, J. Y., Li, H., Wu, J. Y., Liang, J., ... Tai, E. S. (2014). Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians. Diabetes, 63(7), 2551-2562. https://doi.org/10.2337/db13-1815
Chen, Peng ; Takeuchi, Fumihiko ; Lee, Jong Young ; Li, Huaixing ; Wu, Jer Yuarn ; Liang, Jun ; Long, Jirong ; Tabara, Yasuharu ; Goodarzi, Mark O. ; Pereira, Mark A. ; Kim, Young Jin ; Go, Min Jin ; Stram, Daniel O. ; Vithana, Eranga ; Khor, Chiea Chuen ; Liu, Jianjun ; Liao, Jiemin ; Ye, Xingwang ; Wang, Yiqin ; Lu, Ling ; Young, Terri L. ; Lee, Jeannette ; Thai, Ah Chuan ; Cheng, Ching Yu ; Van Dam, Rob M. ; Friedlander, Yechiel ; Heng, Chew Kiat ; Koh, Woon Puay ; Chen, Chien Hsiun ; Chang, Li Ching ; Pan, Wen Harn ; Qi, Bin ; Isono, Masato ; Zheng, Wei ; Cai, Qiuyin ; Gao, Yutang ; Yamamoto, Ken ; Ohnaka, Keizo ; Takayanagi, Ryoichi ; Kita, Yoshikuni ; Ueshima, Hirotsugu ; Hsiung, Chao A. ; Cui, Jinrui ; Sheu, Wayne H.H. ; Rotter, Jerome I. ; Chen, Yii Der I. ; Hsu, Chris ; Okada, Yukinori ; Kubo, Michiaki ; Takahashi, Atsushi ; Tanaka, Toshihiro ; Van Rooij, Frank J.A. ; Ganesh, Santhi K. ; Huang, Jinyan ; Huang, Tao ; Yuan, Jianmin ; Hwang, Joo Yeon ; Gross, Myron D. ; Assimes, Themistocles L. ; Miki, Tetsuro ; Shu, Xiao Ou ; Qi, Lu ; Chen, Yuan Tson ; Lin, Xu ; Aung, Tin ; Wong, Tien Yin ; Teo, Yik Ying ; Kim, Bong Jo ; Kato, Norihiro ; Tai, E. Shyong. / Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians. In: Diabetes. 2014 ; Vol. 63, No. 7. pp. 2551-2562.
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abstract = "Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [ P value = 1.3 × 10 -23], HBS1L/MYB [8.5 × 10-15], MYO9B [9.0 × 10-12], and CYBA [1.1 × 10-8] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76{\%} of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (<7.0 mmol/L) but elevated HbA1c (≥6.5{\%}), 36.1{\%} had HbA1c <6.5{\%} after adjustment for these six variants. Our East Asian GWAS meta-analysis has identified novel variants associated with HbA1c as well as demonstrated that the effects of known variants are largely transferable across ethnic groups. Variants affecting erythrocyte parameters rather than glucose metabolism may be relevant to the use of HbA1c for diagnosing diabetes in these populations.",
author = "Peng Chen and Fumihiko Takeuchi and Lee, {Jong Young} and Huaixing Li and Wu, {Jer Yuarn} and Jun Liang and Jirong Long and Yasuharu Tabara and Goodarzi, {Mark O.} and Pereira, {Mark A.} and Kim, {Young Jin} and Go, {Min Jin} and Stram, {Daniel O.} and Eranga Vithana and Khor, {Chiea Chuen} and Jianjun Liu and Jiemin Liao and Xingwang Ye and Yiqin Wang and Ling Lu and Young, {Terri L.} and Jeannette Lee and Thai, {Ah Chuan} and Cheng, {Ching Yu} and {Van Dam}, {Rob M.} and Yechiel Friedlander and Heng, {Chew Kiat} and Koh, {Woon Puay} and Chen, {Chien Hsiun} and Chang, {Li Ching} and Pan, {Wen Harn} and Bin Qi and Masato Isono and Wei Zheng and Qiuyin Cai and Yutang Gao and Ken Yamamoto and Keizo Ohnaka and Ryoichi Takayanagi and Yoshikuni Kita and Hirotsugu Ueshima and Hsiung, {Chao A.} and Jinrui Cui and Sheu, {Wayne H.H.} and Rotter, {Jerome I.} and Chen, {Yii Der I.} and Chris Hsu and Yukinori Okada and Michiaki Kubo and Atsushi Takahashi and Toshihiro Tanaka and {Van Rooij}, {Frank J.A.} and Ganesh, {Santhi K.} and Jinyan Huang and Tao Huang and Jianmin Yuan and Hwang, {Joo Yeon} and Gross, {Myron D.} and Assimes, {Themistocles L.} and Tetsuro Miki and Shu, {Xiao Ou} and Lu Qi and Chen, {Yuan Tson} and Xu Lin and Tin Aung and Wong, {Tien Yin} and Teo, {Yik Ying} and Kim, {Bong Jo} and Norihiro Kato and Tai, {E. Shyong}",
year = "2014",
month = "1",
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doi = "10.2337/db13-1815",
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pages = "2551--2562",
journal = "Diabetes",
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Chen, P, Takeuchi, F, Lee, JY, Li, H, Wu, JY, Liang, J, Long, J, Tabara, Y, Goodarzi, MO, Pereira, MA, Kim, YJ, Go, MJ, Stram, DO, Vithana, E, Khor, CC, Liu, J, Liao, J, Ye, X, Wang, Y, Lu, L, Young, TL, Lee, J, Thai, AC, Cheng, CY, Van Dam, RM, Friedlander, Y, Heng, CK, Koh, WP, Chen, CH, Chang, LC, Pan, WH, Qi, B, Isono, M, Zheng, W, Cai, Q, Gao, Y, Yamamoto, K, Ohnaka, K, Takayanagi, R, Kita, Y, Ueshima, H, Hsiung, CA, Cui, J, Sheu, WHH, Rotter, JI, Chen, YDI, Hsu, C, Okada, Y, Kubo, M, Takahashi, A, Tanaka, T, Van Rooij, FJA, Ganesh, SK, Huang, J, Huang, T, Yuan, J, Hwang, JY, Gross, MD, Assimes, TL, Miki, T, Shu, XO, Qi, L, Chen, YT, Lin, X, Aung, T, Wong, TY, Teo, YY, Kim, BJ, Kato, N & Tai, ES 2014, 'Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians', Diabetes, vol. 63, no. 7, pp. 2551-2562. https://doi.org/10.2337/db13-1815

Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians. / Chen, Peng; Takeuchi, Fumihiko; Lee, Jong Young; Li, Huaixing; Wu, Jer Yuarn; Liang, Jun; Long, Jirong; Tabara, Yasuharu; Goodarzi, Mark O.; Pereira, Mark A.; Kim, Young Jin; Go, Min Jin; Stram, Daniel O.; Vithana, Eranga; Khor, Chiea Chuen; Liu, Jianjun; Liao, Jiemin; Ye, Xingwang; Wang, Yiqin; Lu, Ling; Young, Terri L.; Lee, Jeannette; Thai, Ah Chuan; Cheng, Ching Yu; Van Dam, Rob M.; Friedlander, Yechiel; Heng, Chew Kiat; Koh, Woon Puay; Chen, Chien Hsiun; Chang, Li Ching; Pan, Wen Harn; Qi, Bin; Isono, Masato; Zheng, Wei; Cai, Qiuyin; Gao, Yutang; Yamamoto, Ken; Ohnaka, Keizo; Takayanagi, Ryoichi; Kita, Yoshikuni; Ueshima, Hirotsugu; Hsiung, Chao A.; Cui, Jinrui; Sheu, Wayne H.H.; Rotter, Jerome I.; Chen, Yii Der I.; Hsu, Chris; Okada, Yukinori; Kubo, Michiaki; Takahashi, Atsushi; Tanaka, Toshihiro; Van Rooij, Frank J.A.; Ganesh, Santhi K.; Huang, Jinyan; Huang, Tao; Yuan, Jianmin; Hwang, Joo Yeon; Gross, Myron D.; Assimes, Themistocles L.; Miki, Tetsuro; Shu, Xiao Ou; Qi, Lu; Chen, Yuan Tson; Lin, Xu; Aung, Tin; Wong, Tien Yin; Teo, Yik Ying; Kim, Bong Jo; Kato, Norihiro; Tai, E. Shyong.

In: Diabetes, Vol. 63, No. 7, 01.01.2014, p. 2551-2562.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians

AU - Chen, Peng

AU - Takeuchi, Fumihiko

AU - Lee, Jong Young

AU - Li, Huaixing

AU - Wu, Jer Yuarn

AU - Liang, Jun

AU - Long, Jirong

AU - Tabara, Yasuharu

AU - Goodarzi, Mark O.

AU - Pereira, Mark A.

AU - Kim, Young Jin

AU - Go, Min Jin

AU - Stram, Daniel O.

AU - Vithana, Eranga

AU - Khor, Chiea Chuen

AU - Liu, Jianjun

AU - Liao, Jiemin

AU - Ye, Xingwang

AU - Wang, Yiqin

AU - Lu, Ling

AU - Young, Terri L.

AU - Lee, Jeannette

AU - Thai, Ah Chuan

AU - Cheng, Ching Yu

AU - Van Dam, Rob M.

AU - Friedlander, Yechiel

AU - Heng, Chew Kiat

AU - Koh, Woon Puay

AU - Chen, Chien Hsiun

AU - Chang, Li Ching

AU - Pan, Wen Harn

AU - Qi, Bin

AU - Isono, Masato

AU - Zheng, Wei

AU - Cai, Qiuyin

AU - Gao, Yutang

AU - Yamamoto, Ken

AU - Ohnaka, Keizo

AU - Takayanagi, Ryoichi

AU - Kita, Yoshikuni

AU - Ueshima, Hirotsugu

AU - Hsiung, Chao A.

AU - Cui, Jinrui

AU - Sheu, Wayne H.H.

AU - Rotter, Jerome I.

AU - Chen, Yii Der I.

AU - Hsu, Chris

AU - Okada, Yukinori

AU - Kubo, Michiaki

AU - Takahashi, Atsushi

AU - Tanaka, Toshihiro

AU - Van Rooij, Frank J.A.

AU - Ganesh, Santhi K.

AU - Huang, Jinyan

AU - Huang, Tao

AU - Yuan, Jianmin

AU - Hwang, Joo Yeon

AU - Gross, Myron D.

AU - Assimes, Themistocles L.

AU - Miki, Tetsuro

AU - Shu, Xiao Ou

AU - Qi, Lu

AU - Chen, Yuan Tson

AU - Lin, Xu

AU - Aung, Tin

AU - Wong, Tien Yin

AU - Teo, Yik Ying

AU - Kim, Bong Jo

AU - Kato, Norihiro

AU - Tai, E. Shyong

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [ P value = 1.3 × 10 -23], HBS1L/MYB [8.5 × 10-15], MYO9B [9.0 × 10-12], and CYBA [1.1 × 10-8] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (<7.0 mmol/L) but elevated HbA1c (≥6.5%), 36.1% had HbA1c <6.5% after adjustment for these six variants. Our East Asian GWAS meta-analysis has identified novel variants associated with HbA1c as well as demonstrated that the effects of known variants are largely transferable across ethnic groups. Variants affecting erythrocyte parameters rather than glucose metabolism may be relevant to the use of HbA1c for diagnosing diabetes in these populations.

AB - Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [ P value = 1.3 × 10 -23], HBS1L/MYB [8.5 × 10-15], MYO9B [9.0 × 10-12], and CYBA [1.1 × 10-8] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (<7.0 mmol/L) but elevated HbA1c (≥6.5%), 36.1% had HbA1c <6.5% after adjustment for these six variants. Our East Asian GWAS meta-analysis has identified novel variants associated with HbA1c as well as demonstrated that the effects of known variants are largely transferable across ethnic groups. Variants affecting erythrocyte parameters rather than glucose metabolism may be relevant to the use of HbA1c for diagnosing diabetes in these populations.

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