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. HanisRuth J.F. Loos, Neil Schneiderman, Jerome I. Rotter, Robert C. Kaplan, Qibin Qi

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1784-1791
Number of pages8
JournalDiabetes care
Issue number9
StatePublished - Sep 1 2019

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialized Nursing


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