Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.

Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.

Publication date: Oct 03, 2019

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

Sarnowski, C., Leong, A., Raffield, L.M., Wu, P., de Vries, P.S., DiCorpo, D., Guo, X., Xu, H., Liu, Y., Zheng, X., Hu, Y., Brody, J.A., Goodarzi, M.O., Hidalgo, B.A., Highland, H.M., Jain, D., Liu, C.T., Naik, R.P., , O’Connell, Perry, J.A., Porneala, B.C., Selvin, E., Wessel, J., Psaty, B.M., Curran, J.E., Peralta, J.M., Blangero, J., Kooperberg, C., Mathias, R., Johnson, A.D., Reiner, A.P., Mitchell, B.D., Cupples, L.A., Vasan, R.S., Correa, A., Morrison, A.C., Boerwinkle, E., Rotter, J.I., Rich, S.S., Manning, A.K., Dupuis, J., Meigs, J.B., Group, TOPMed Diabetes. Working., Group, TOPMed Hematology. Working., Group, TOPMed Hemostasis. Working., and National Heart, Lung. Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program. 05525. 2019 Am J Hum Genet (105):4.

Concepts Keywords
African American Incorporation precision diabetes
African Americans Hemoglobins
Asian Diabetes
Common Medicine
Diabetes Branches of biology
East Asians Clinical medicine
Frequency Blood tests
G6PD Glucose
Genetic Variation Glycated hemoglobin
Glycemia A1C
Glycemic Control Polymorphism
HbA1c Diabetes management
Hemizygous
Hemoglobin A1c
Heterozygous
Hispanic
Magnitude
Missense
Monomorphic
Omics
Variance

Semantics

Type Source Name
gene UNIPROT MAF
gene UNIPROT NR4A3
gene UNIPROT HBE1
gene UNIPROT HBG2
gene UNIPROT G6PD
gene UNIPROT FN3KRP
gene UNIPROT FN3K
gene UNIPROT HK1
gene UNIPROT GCK
gene UNIPROT MAP4K2
disease MESH Multi
disease MESH Diagnosis
gene UNIPROT IMPACT

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