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A Genome-Wide Association Study Identifies Blood Disorder-Related Variants Influencing Hemoglobin A
- Source :
- Diabetes Care
- Publication Year :
- 2019
-
Abstract
- OBJECTIVE: We aimed to identify hemoglobin A(1c) (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 = −0.31% [−3.4 mmol/mol]) and −0.35% [−3.8 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.
- Subjects :
- Adult
Blood Glucose
Glycated Hemoglobin
Male
Cardiovascular and Metabolic Risk
endocrine system diseases
nutritional and metabolic diseases
Genetic Variation
Fasting
Hispanic or Latino
Glucose Tolerance Test
Middle Aged
Hematologic Diseases
United States
Prediabetic State
Phenotype
Hyperglycemia
Diabetes Mellitus
Prevalence
Humans
Female
Alleles
Genome-Wide Association Study
Subjects
Details
- ISSN :
- 19355548
- Volume :
- 42
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Diabetes care
- Accession number :
- edsair.pmid..........6fdd0299108fd722656068953f9c08d6