A genome-wide association study identifies blood disorder-related variants influencing hemoglobin A1c with implications for glycemic status in U.S. hispanics/latinos

Jee Young Moon; Tin L. Louie; Deepti Jain; Tamar Sofer; Claudia Schurmann; Jennifer E. Below; Chao Qiang Lai; M. Larissa Aviles-Santa; Gregory A. Talavera; Caren E. Smith; Lauren E. Petty; Erwin P. Bottinger; Yii Der Ida Chen; Kent D. Taylor; Martha L. Daviglus; Jianwen Cai; Tao Wang; Katherine L. Tucker; José M. Ordovás; Craig L. Hanis; Ruth J.F. Loos; Neil Schneiderman; Jerome I. Rotter; Robert C. Kaplan; Qibin Qi

doi:10.2337/dc19-0168

A genome-wide association study identifies blood disorder-related variants influencing hemoglobin A_1c with implications for glycemic status in U.S. hispanics/latinos

Jee Young Moon, Tin L. Louie, Deepti Jain, Tamar Sofer, Claudia Schurmann, Jennifer E. Below, Chao Qiang Lai, M. Larissa Aviles-Santa, Gregory A. Talavera, Caren E. Smith, Lauren E. Petty, Erwin P. Bottinger, Yii Der Ida Chen, Kent D. Taylor, Martha L. Daviglus, Jianwen Cai, Tao Wang, Katherine L. Tucker, José M. Ordovás, Craig L. HanisRuth J.F. Loos, Neil Schneiderman, Jerome I. Rotter, Robert C. Kaplan, Qibin Qi

Epidemiology & Population Health

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

OBJECTIVE We aimed to identify hemoglobin A1c (HbA_1c)-associated genetic variants and examine their implications for glycemic status evaluated by HbA_1c in U.S. Hispanics/ Latinos with diverse genetic ancestries. RESEARCH DESIGN AND METHODS We conducted a genome-wide association study (GWAS) of HbA_1c in 9,636 U.S. Hispanics/Latinos without diabetes from the Hispanic Community Health Study/ Study of Latinos, followed by a replication among 4,729 U.S. Hispanics/Latinos from three independent studies. RESULTS Our GWAS and replication analyses showed 10 previously known and novel loci associated with HbA_1c at genome-wide significance levels (P < 5.0 × 10^-8). In particular, two African ancestry-specific variants, HBB-rs334 and G6PD-rs1050828, which are causal mutations for sickle cell disease and G6PD deficiency, respectively, had ∼10 times larger effect sizes on HbA_1c levels (β = 20.31% [23.4 mmol/mol]) and 20.35% [23.8 mmol/mol] per minor allele, respectively) compared with other HbA_1c-associated variants (0.03-0.04% [0.3-0.4 mmol/mol] per allele). A novel Amerindian ancestry-specific variant, HBM-rs145546625, was associated with HbA_1c and hematologic traits but not with fasting glucose. The prevalence of hyperglycemia (prediabetes and diabetes) defined using fasting glucose or oral glucose tolerance test 2-h glucose was similar between carriers of HBB-rs334 or G6PD-rs1050828 HbA_1c-lowering alleles and noncarriers, whereas the prevalence of hyperglycemia defined using HbA_1c was significantly lower in carriers than in noncarriers (12.2% vs. 28.4%, P < 0.001). After recalibration of the HbA_1c level taking HBB-rs334 and G6PD-rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to noncarriers (31.3% vs. 28.4%, P = 0.28). CONCLUSIONS This study in U.S. Hispanics/Latinos found several ancestry-specific alleles associated with HbA_1c through erythrocyte-related rather than glycemic-related pathways. The potential influences of these nonglycemic-related variants need to be considered when the HbA_1c test is performed.

Original language	English (US)
Pages (from-to)	1784-1791
Number of pages	8
Journal	Diabetes care
Volume	42
Issue number	9
DOIs	https://doi.org/10.2337/dc19-0168
State	Published - Sep 1 2019

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism
Advanced and Specialized Nursing

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10.2337/dc19-0168

Cite this

Moon, J. Y., Louie, T. L., Jain, D., Sofer, T., Schurmann, C., Below, J. E., Lai, C. Q., Aviles-Santa, M. L., Talavera, G. A., Smith, C. E., Petty, L. E., Bottinger, E. P., Chen, Y. D. I., Taylor, K. D., Daviglus, M. L., Cai, J., Wang, T., Tucker, K. L., Ordovás, J. M., ... Qi, Q. (2019). A genome-wide association study identifies blood disorder-related variants influencing hemoglobin A_1c with implications for glycemic status in U.S. hispanics/latinos. Diabetes care, 42(9), 1784-1791. https://doi.org/10.2337/dc19-0168

Moon, JY, Louie, TL, Jain, D, Sofer, T, Schurmann, C, Below, JE, Lai, CQ, Aviles-Santa, ML, Talavera, GA, Smith, CE, Petty, LE, Bottinger, EP, Chen, YDI, Taylor, KD, Daviglus, ML, Cai, J, Wang, T, Tucker, KL, Ordovás, JM, Hanis, CL, Loos, RJF, Schneiderman, N, Rotter, JI, Kaplan, RC & Qi, Q 2019, 'A genome-wide association study identifies blood disorder-related variants influencing hemoglobin A_1c with implications for glycemic status in U.S. hispanics/latinos', Diabetes care, vol. 42, no. 9, pp. 1784-1791. https://doi.org/10.2337/dc19-0168

@article{13b8cda5fc70495396c25057ecb303d2,

title = "A genome-wide association study identifies blood disorder-related variants influencing hemoglobin A1c with implications for glycemic status in U.S. hispanics/latinos",

abstract = "OBJECTIVE We aimed to identify hemoglobin A1c (HbA1c)-associated genetic variants and examine their implications for glycemic status evaluated by HbA1c in U.S. Hispanics/ Latinos with diverse genetic ancestries. RESEARCH DESIGN AND METHODS We conducted a genome-wide association study (GWAS) of HbA1c in 9,636 U.S. Hispanics/Latinos without diabetes from the Hispanic Community Health Study/ Study of Latinos, followed by a replication among 4,729 U.S. Hispanics/Latinos from three independent studies. RESULTS Our GWAS and replication analyses showed 10 previously known and novel loci associated with HbA1c at genome-wide significance levels (P < 5.0 × 10-8). In particular, two African ancestry-specific variants, HBB-rs334 and G6PD-rs1050828, which are causal mutations for sickle cell disease and G6PD deficiency, respectively, had ∼10 times larger effect sizes on HbA1c levels (β = 20.31% [23.4 mmol/mol]) and 20.35% [23.8 mmol/mol] per minor allele, respectively) compared with other HbA1c-associated variants (0.03-0.04% [0.3-0.4 mmol/mol] per allele). A novel Amerindian ancestry-specific variant, HBM-rs145546625, was associated with HbA1c and hematologic traits but not with fasting glucose. The prevalence of hyperglycemia (prediabetes and diabetes) defined using fasting glucose or oral glucose tolerance test 2-h glucose was similar between carriers of HBB-rs334 or G6PD-rs1050828 HbA1c-lowering alleles and noncarriers, whereas the prevalence of hyperglycemia defined using HbA1c was significantly lower in carriers than in noncarriers (12.2% vs. 28.4%, P < 0.001). After recalibration of the HbA1c level taking HBB-rs334 and G6PD-rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to noncarriers (31.3% vs. 28.4%, P = 0.28). CONCLUSIONS This study in U.S. Hispanics/Latinos found several ancestry-specific alleles associated with HbA1c through erythrocyte-related rather than glycemic-related pathways. The potential influences of these nonglycemic-related variants need to be considered when the HbA1c test is performed.",

author = "Moon, {Jee Young} and Louie, {Tin L.} and Deepti Jain and Tamar Sofer and Claudia Schurmann and Below, {Jennifer E.} and Lai, {Chao Qiang} and Aviles-Santa, {M. Larissa} and Talavera, {Gregory A.} and Smith, {Caren E.} and Petty, {Lauren E.} and Bottinger, {Erwin P.} and Chen, {Yii Der Ida} and Taylor, {Kent D.} and Daviglus, {Martha L.} and Jianwen Cai and Tao Wang and Tucker, {Katherine L.} and Ordov{\'a}s, {Jos{\'e} M.} and Hanis, {Craig L.} and Loos, {Ruth J.F.} and Neil Schneiderman and Rotter, {Jerome I.} and Kaplan, {Robert C.} and Qibin Qi",

note = "Publisher Copyright: {\textcopyright} 2019 by the American Diabetes Association.",

year = "2019",

month = sep,

day = "1",

doi = "10.2337/dc19-0168",

language = "English (US)",

volume = "42",

pages = "1784--1791",

journal = "Diabetes care",

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TY - JOUR

T1 - A genome-wide association study identifies blood disorder-related variants influencing hemoglobin A1c with implications for glycemic status in U.S. hispanics/latinos

AU - Moon, Jee Young

AU - Louie, Tin L.

AU - Jain, Deepti

AU - Sofer, Tamar

AU - Schurmann, Claudia

AU - Below, Jennifer E.

AU - Lai, Chao Qiang

AU - Aviles-Santa, M. Larissa

AU - Talavera, Gregory A.

AU - Smith, Caren E.

AU - Petty, Lauren E.

AU - Bottinger, Erwin P.

AU - Chen, Yii Der Ida

AU - Taylor, Kent D.

AU - Daviglus, Martha L.

AU - Cai, Jianwen

AU - Wang, Tao

AU - Tucker, Katherine L.

AU - Ordovás, José M.

AU - Hanis, Craig L.

AU - Loos, Ruth J.F.

AU - Schneiderman, Neil

AU - Rotter, Jerome I.

AU - Kaplan, Robert C.

AU - Qi, Qibin

PY - 2019/9/1

Y1 - 2019/9/1

N2 - OBJECTIVE We aimed to identify hemoglobin A1c (HbA1c)-associated genetic variants and examine their implications for glycemic status evaluated by HbA1c in U.S. Hispanics/ Latinos with diverse genetic ancestries. RESEARCH DESIGN AND METHODS We conducted a genome-wide association study (GWAS) of HbA1c in 9,636 U.S. Hispanics/Latinos without diabetes from the Hispanic Community Health Study/ Study of Latinos, followed by a replication among 4,729 U.S. Hispanics/Latinos from three independent studies. RESULTS Our GWAS and replication analyses showed 10 previously known and novel loci associated with HbA1c at genome-wide significance levels (P < 5.0 × 10-8). In particular, two African ancestry-specific variants, HBB-rs334 and G6PD-rs1050828, which are causal mutations for sickle cell disease and G6PD deficiency, respectively, had ∼10 times larger effect sizes on HbA1c levels (β = 20.31% [23.4 mmol/mol]) and 20.35% [23.8 mmol/mol] per minor allele, respectively) compared with other HbA1c-associated variants (0.03-0.04% [0.3-0.4 mmol/mol] per allele). A novel Amerindian ancestry-specific variant, HBM-rs145546625, was associated with HbA1c and hematologic traits but not with fasting glucose. The prevalence of hyperglycemia (prediabetes and diabetes) defined using fasting glucose or oral glucose tolerance test 2-h glucose was similar between carriers of HBB-rs334 or G6PD-rs1050828 HbA1c-lowering alleles and noncarriers, whereas the prevalence of hyperglycemia defined using HbA1c was significantly lower in carriers than in noncarriers (12.2% vs. 28.4%, P < 0.001). After recalibration of the HbA1c level taking HBB-rs334 and G6PD-rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to noncarriers (31.3% vs. 28.4%, P = 0.28). CONCLUSIONS This study in U.S. Hispanics/Latinos found several ancestry-specific alleles associated with HbA1c through erythrocyte-related rather than glycemic-related pathways. The potential influences of these nonglycemic-related variants need to be considered when the HbA1c test is performed.

AB - OBJECTIVE We aimed to identify hemoglobin A1c (HbA1c)-associated genetic variants and examine their implications for glycemic status evaluated by HbA1c in U.S. Hispanics/ Latinos with diverse genetic ancestries. RESEARCH DESIGN AND METHODS We conducted a genome-wide association study (GWAS) of HbA1c in 9,636 U.S. Hispanics/Latinos without diabetes from the Hispanic Community Health Study/ Study of Latinos, followed by a replication among 4,729 U.S. Hispanics/Latinos from three independent studies. RESULTS Our GWAS and replication analyses showed 10 previously known and novel loci associated with HbA1c at genome-wide significance levels (P < 5.0 × 10-8). In particular, two African ancestry-specific variants, HBB-rs334 and G6PD-rs1050828, which are causal mutations for sickle cell disease and G6PD deficiency, respectively, had ∼10 times larger effect sizes on HbA1c levels (β = 20.31% [23.4 mmol/mol]) and 20.35% [23.8 mmol/mol] per minor allele, respectively) compared with other HbA1c-associated variants (0.03-0.04% [0.3-0.4 mmol/mol] per allele). A novel Amerindian ancestry-specific variant, HBM-rs145546625, was associated with HbA1c and hematologic traits but not with fasting glucose. The prevalence of hyperglycemia (prediabetes and diabetes) defined using fasting glucose or oral glucose tolerance test 2-h glucose was similar between carriers of HBB-rs334 or G6PD-rs1050828 HbA1c-lowering alleles and noncarriers, whereas the prevalence of hyperglycemia defined using HbA1c was significantly lower in carriers than in noncarriers (12.2% vs. 28.4%, P < 0.001). After recalibration of the HbA1c level taking HBB-rs334 and G6PD-rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to noncarriers (31.3% vs. 28.4%, P = 0.28). CONCLUSIONS This study in U.S. Hispanics/Latinos found several ancestry-specific alleles associated with HbA1c through erythrocyte-related rather than glycemic-related pathways. The potential influences of these nonglycemic-related variants need to be considered when the HbA1c test is performed.

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