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Meta-Analysis
. 2014 Jul;63(7):2551-62.
doi: 10.2337/db13-1815. Epub 2014 Mar 19.

Multiple Nonglycemic Genomic Loci Are Newly Associated With Blood Level of Glycated Hemoglobin in East Asians

Peng Chen  1 Fumihiko Takeuchi  2 Jong-Young Lee  3 Huaixing Li  4 Jer-Yuarn Wu  5 Jun Liang  6 Jirong Long  7 Yasuharu Tabara  8 Mark O Goodarzi  9 Mark A Pereira  10 Young Jin Kim  3 Min Jin Go  3 Daniel O Stram  11 Eranga Vithana  12 Chiea-Chuen Khor  13 Jianjun Liu  14 Jiemin Liao  15 Xingwang Ye  4 Yiqin Wang  4 Ling Lu  4 Terri L Young  16 Jeannette Lee  1 Ah Chuan Thai  17 Ching-Yu Cheng  18 Rob M van Dam  19 Yechiel Friedlander  20 Chew-Kiat Heng  21 Woon-Puay Koh  22 Chien-Hsiun Chen  5 Li-Ching Chang  23 Wen-Harn Pan  23 Qibin Qi  24 Masato Isono  2 Wei Zheng  7 Qiuyin Cai  7 Yutang Gao  25 Ken Yamamoto  26 Keizo Ohnaka  27 Ryoichi Takayanagi  28 Yoshikuni Kita  29 Hirotsugu Ueshima  30 Chao A Hsiung  31 Jinrui Cui  9 Wayne H-H Sheu  32 Jerome I Rotter  33 Yii-Der I Chen  33 Chris Hsu  11 Yukinori Okada  34 Michiaki Kubo  35 Atsushi Takahashi  36 Toshihiro Tanaka  37 Frank J A van Rooij  38 Santhi K Ganesh  39 Jinyan Huang  40 Tao Huang  40 Jianmin Yuan  41 Joo-Yeon Hwang  42 CHARGE Hematology Working GroupMyron D Gross  43 Themistocles L Assimes  44 Tetsuro Miki  45 Xiao-Ou Shu  7 Lu Qi  46 Yuan-Tson Chen  47 Xu Lin  4 Tin Aung  48 Tien-Yin Wong  15 Yik-Ying Teo  49 Bong-Jo Kim  3 Norihiro Kato  2 E-Shyong Tai  50
Affiliations
Free PMC article
Meta-Analysis

Multiple Nonglycemic Genomic Loci Are Newly Associated With Blood Level of Glycated Hemoglobin in East Asians

Peng Chen et al. Diabetes. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Manhattan plot of genome-wide meta-analysis of stage 1 cohorts. The −log10 of the association P values (y-axis) are plotted against the genomic coordinates (x-axis). The horizontal line in the plot indicates the genome-wide significance (5 × 10−8). The most relevant gene of each signal was labeled on the top of it, with the novel loci presented in brown and known loci in blue.
Figure 2
Figure 2
The bivariate plot of the effect directions in our meta-analysis and in previous reports. For the index SNPs in the previous GWAS, we plotted the reported effect (x-axis) versus the AGEN effect (y-axis). Whenever available, we used the effects reported by Soranzo et al. (3). The solid dots represent the SNPs that were significant (P value ≤0.05) in our study, while the hollow red dots represent the insignificant ones. The CDKAL1 top SNP reported in Koreans was specially marked by a diamond. EA, East Asian.
Figure 3
Figure 3
Regional association plots of the novel loci. The −log10 of association P values are plotted against the genomic coordinates. The index SNPs are indicated in purple, with circles for stage 1 and squares for stage 1+2. Other SNPs are colored from red to blue as per their LD with the index SNP. Chr, chromosome.

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References

    1. Paré G, Chasman DI, Parker AN, et al. . Novel association of HK1 with glycated hemoglobin in a non-diabetic population: a genome-wide evaluation of 14,618 participants in the Women’s Genome Health Study. PLoS Genet 2008;4:e1000312. - PMC - PubMed
    1. Franklin CS, Aulchenko YS, Huffman JE, et al. . The TCF7L2 diabetes risk variant is associated with HbA₁(C) levels: a genome-wide association meta-analysis. Ann Hum Genet 2010;74:471–478 - PubMed
    1. Soranzo N, Sanna S, Wheeler E, et al. . Common variants at 10 genomic loci influence hemoglobin A1(C) levels via glycemic and nonglycemic pathways [published correction appears in Diabetes 2011;60:1050–1051]. Diabetes 2010;59:3229–3239 - PMC - PubMed
    1. Ryu J, Lee C. Association of glycosylated hemoglobin with the gene encoding CDKAL1 in the Korean Association Resource (KARE) study. Hum Mutat 2012;33:655–659 - PubMed
    1. Ferreira MA, Hottenga JJ, Warrington NM, et al. . Sequence variants in three loci influence monocyte counts and erythrocyte volume. Am J Hum Genet 2009;85:745–749 - PMC - PubMed

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