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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 ,  Journal Article
Sarnowski, C; Leong, A; Raffield, LM; Wu, P; de Vries, PS; DiCorpo, D; Guo, X; Xu, H; Liu, Y; Zheng, X; Hu, Y; Brody, JA; Goodarzi, MO ...
Published in: Am J Hum Genet
October 3, 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.

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Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

October 3, 2019

Volume

105

Issue

4

Start / End Page

706 / 718

Location

United States

Related Subject Headings

  • Precision Medicine
  • Population Groups
  • Polymorphism, Single Nucleotide
  • Male
  • Humans
  • Glycated Hemoglobin
  • Genetics & Heredity
  • Genetic Variation
  • Female
  • Diabetes Mellitus
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Sarnowski, C., Leong, A., Raffield, L. M., Wu, P., de Vries, P. S., DiCorpo, D., … National Heart, Lung, and Blood Institute TOPMed Consortium, . (2019). Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program. Am J Hum Genet, 105(4), 706–718. https://doi.org/10.1016/j.ajhg.2019.08.010
Sarnowski, Chloé, Aaron Leong, Laura M. Raffield, Peitao Wu, Paul S. de Vries, Daniel DiCorpo, Xiuqing Guo, et al. “Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.Am J Hum Genet 105, no. 4 (October 3, 2019): 706–18. https://doi.org/10.1016/j.ajhg.2019.08.010.
Sarnowski C, Leong A, Raffield LM, Wu P, de Vries PS, DiCorpo D, et al. Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program. Am J Hum Genet. 2019 Oct 3;105(4):706–18.
Sarnowski, Chloé, et al. “Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.Am J Hum Genet, vol. 105, no. 4, Oct. 2019, pp. 706–18. Pubmed, doi:10.1016/j.ajhg.2019.08.010.
Sarnowski C, Leong A, Raffield LM, Wu P, de Vries PS, DiCorpo D, Guo X, Xu H, Liu Y, Zheng X, Hu Y, Brody JA, Goodarzi MO, Hidalgo BA, Highland HM, Jain D, Liu C-T, Naik RP, O’Connell JR, Perry JA, Porneala BC, Selvin E, Wessel J, Psaty BM, Curran JE, Peralta JM, Blangero J, Kooperberg C, Mathias R, Johnson AD, Reiner AP, Mitchell BD, Cupples LA, Vasan RS, Correa A, Morrison AC, Boerwinkle E, Rotter JI, Rich SS, Manning AK, Dupuis J, Meigs JB, TOPMed Diabetes Working Group, TOPMed Hematology Working Group, TOPMed Hemostasis Working Group, National Heart, Lung, and Blood Institute TOPMed Consortium. Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program. Am J Hum Genet. 2019 Oct 3;105(4):706–718.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

October 3, 2019

Volume

105

Issue

4

Start / End Page

706 / 718

Location

United States

Related Subject Headings

  • Precision Medicine
  • Population Groups
  • Polymorphism, Single Nucleotide
  • Male
  • Humans
  • Glycated Hemoglobin
  • Genetics & Heredity
  • Genetic Variation
  • Female
  • Diabetes Mellitus