A Genome-Wide Association Study Identifies Blood Disorder-Related Variants Influencing Hemoglobin A1c With Implications for Glycemic Status in U.S. Hispanics/Latinos

Diabetes Care. 2019 Sep;42(9):1784-1791. doi: 10.2337/dc19-0168. Epub 2019 Jun 18.


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 = -0.31% [-3.4 mmol/mol]) and -0.35% [-3.8 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Alleles
  • Blood Glucose / metabolism
  • Diabetes Mellitus / ethnology
  • Diabetes Mellitus / genetics*
  • Fasting / blood
  • Female
  • Genetic Variation / genetics*
  • Genome-Wide Association Study
  • Glucose Tolerance Test
  • Glycated Hemoglobin / genetics*
  • Hematologic Diseases / ethnology
  • Hematologic Diseases / genetics*
  • Hispanic or Latino / genetics*
  • Humans
  • Hyperglycemia / epidemiology
  • Hyperglycemia / ethnology
  • Hyperglycemia / genetics
  • Male
  • Middle Aged
  • Phenotype
  • Prediabetic State / ethnology
  • Prediabetic State / genetics
  • Prevalence
  • United States / epidemiology


  • Blood Glucose
  • Glycated Hemoglobin A
  • hemoglobin A1c protein, human