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

Authors: MOON, JEE-YOUNG - Albert Einstein College Of Medicine; LOUIE, TIN - University Of Washington; JAIN, DEEPTI - University Of Washington; SOFER, TAMAR - Brigham & Women'S Hospital; SCHURMANN, CLAUDIA - The Icahn School Of Medicine At Mount Sinai; BELOW, JENNIFER - Vanderbilt University; Lai, Chao Qiang; AVILES-SANTA, M. LARISSA - National Institutes Of Health (NIH); TALAVERA, GREGORY - San Diego State University; SMITH, CAREN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; PETTY, LAUREN - University Of Texas; BOTTINGER, ERWIN - The Icahn School Of Medicine At Mount Sinai; CHEN, YII-DER - Harbor-Ucla Medical Center; TAYLOR, KENT - Harbor-Ucla Medical Center; DAVIGLUS, MARTHA - University Of Illinois; CAI, JIANWEN - University Of North Carolina; WANG, TAO - Albert Einstein College Of Medicine; TUCKER, KATHERINE - University Of Massachusetts; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; HANIS, CRAIG - University Of Texas; LOOS, RUTH - The Icahn School Of Medicine At Mount Sinai; SCHNEIDERMAN, NEIL - University Of Miami; ROTTER, JEROME - Harbor-Ucla Medical Center; KAPLAN, ROBERT - Albert Einstein College Of Medicine; QI, QIBIN - Albert Einstein College Of Medicine

Submitted to: Diabetes Care
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/24/2019
Publication Date: 6/18/2019
Citation: Moon, J., Louie, T., Jain, D., Sofer, T., Schurmann, C., Below, J.E., Lai, C., Aviles-Santa, M., Talavera, G.A., Smith, C.E., Petty, L.E., Bottinger, E.P., Chen, Y.I., Taylor, K.D., Daviglus, M.L., Cai, J., Wang, T., Tucker, K.L., Ordovas, J.M., Hanis, C.L., Loos, R.J., Schneiderman, N., Rotter, J.I., Kaplan, R.C., Qi, Q. 2019. 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. 42(8). https://doi.org/10.2337/dc19-0168.
DOI: https://doi.org/10.2337/dc19-0168

Interpretive Summary: Type 2 diabetes (T2D) is particularly common in American Hispanics/Latinos populations. Hemoglobin A1c (HbA1c) is hemoglobin with glucose attached. The percent of HbA1c in blood reveals the average amount of glucose in the blood over the last few months, and its measurement is used as a clinical biomarker for the risk or presence of T2D. This study aimed to identify genetic variants that were associated with blood HbA1c by conducting a whole genome search for such variants in a set of 9,636 US Hispanics/Latinos, followed by replication in an additional set of 4729 individuals of the same ancestry. This study, the first to be conducted in Hispanics, found seven variants that were previously shown to be associated with HbA1c in non-Hispanic Whites, and three novel variants. In particular, two new African-origin mutations at the sickle-cell gene HBB and G6PD deficiency gene had large effects on HbA1c level. Surprisingly, one novel American-origin variant in the HBM gene was associated with HbA1c, but not glucose level. In summary, this study found several HbA1c-associated variants in red blood cell-related genes, but not in genes involved in blood sugar metabolic pathways. This finding expands the understandings of red blood cell-related genetic determinants of HbA1c and their implications in HbA1c testing of T2D status in US Hispanics/Latinos.

Technical Abstract: OBJECTIVE: We aimed to identify hemoglobin A1c (HbA1c)-associated genetic variants and examine their implications for glycemic status evaluated by HbA1c in US Hispanics/Latinos with diverse genetic ancestries. RESEARCH DESIGN and METHODS: We conducted a genome-wide association study (GWAS) of HbA1c in 9,636 US Hispanics/Latinos without diabetes from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), followed by a replication among 4,729 US Hispanics/Latinos from 3 independent studies. RESULTS: Our GWAS and replication analyses showed 10 previously known and novel loci associated with HbA1c at genome-wide significance levels (P<5.0x10^-8). In particular, two African-ancestral variants HBB-rs334 and G6PD-rs1050828, which are causal mutations for sickle cell disease and G6PD deficiency, respectively, had approximately 10-time larger effect sizes on HbA1c levels (beta=-0.31% (-3.41mmol/mol) and -0.35% (-3.85mmol/mol) per minor allele, respectively) compared to other HbA1c-associated variants (0.03~0.04% per allele). A novel Amerindian-ancestral 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 (OGTT) 2-hour glucose was similar between carriers of HBB-rs334 or G6PD-rs1050828 HbA1c-lowering alleles and non-carriers, while the prevalence of hyperglycemia defined using HbA1c was significantly lower in carriers than non-carries (12.2% vs. 28.4%, P<0.001). After recalibrating HbA1c level taking HBB-rs334 and G6PD-rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to non-carriers (31.3% vs. 28.4%, P=0.28). CONCLUSIONS: This study in US Hispanics/Latinos found several ancestry-specific alleles associated with HbA1c through erythrocyte-related rather than glycemic-related pathways. The potential influences of these non-glycemic related variants need to be considered when the HbA1c test is performed.