Recognition of rare hemoglobin variants by hemoglobin A 1c measurement procedures

Strickland, Sydney Webb; Campbell, Sean T.; Little, Randie R.; Bruns, David E.; Bazydlo, Lindsay A.L.

doi:10.1016/j.cca.2017.11.012

Cited by 17 publications

(11 citation statements)

References 23 publications

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“…Low-frequency (0.5% < MAF < 5%) and rare (MAF < 0.5%) genetic variants and their associated impact on the diagnostic accuracy of HbA1c have not been systematically examined but are suspected to occur. 5,6 Further, previous GWAS have shown that the combined effect of HbA1c-related common variants causes differences in HbA1c that were three times greater in individuals of African ancestry compared with those of European ancestry (0.8 [%-units] versus 0.25 [%-units]). 3 This relatively large difference in HbA1c was mainly driven by a single African-ancestry-specific missense variant (rs1050828-T, p.Val98Met) in the Glucose-6-phosphatase Dehydrogenase gene (G6PD [MIM: 305900]), which causes G6PD deficiency (MIM: 300908).…”

Section: Introductionmentioning

confidence: 99%

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

Sarnowski

Leong

Raffield

et al. 2019

The American Journal of Human Genetics

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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) ¼ 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF ¼ 12% in African-Americans, MAF ¼ 2% in Hispanics) lowered HbA1c (À0.88% in hemizygous males, À0.34% 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 ¼ 0.5%; À0.98% in hemizygous males, À0.46% 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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Section: Introductionmentioning

confidence: 99%

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

Sarnowski

Leong

Raffield

et al. 2019

The American Journal of Human Genetics

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“…The accuracy of HbA1c in patients with thalassemia is method dependent. Popular methods for the determination of HbA1c include ion exchange HPLC, boronate affinity chromatography, immunoturbidimetry and capillary electrophoresis 2 , 4 . HbA1c can be accurately measured using appropriate methods in most patients with abnormal hemoglobin 2 .…”

Section: Discussionmentioning

confidence: 99%

Discordantly high glycated hemoglobin might assist in diagnosing α‐thalassemia, but not diabetes: A case report

Gao

Jin

Huang

et al. 2022

J of Diabetes Invest

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Glycated hemoglobin (HbA1c) is an important method for monitoring blood glucose and diagnosing diabetes. High‐performance liquid chromatography is more commonly used in the laboratory for the detection of HbA1c. Although HbA1c detected by high‐performance liquid chromatography is susceptible to abnormal hemoglobin, there are few reports that it is affected by α‐thalassemia. Previous reports have generally concluded that α‐thalassemia does not affect or lower HbA1c. Here, we report a case of discordantly high HbA1c inconsistent with fasting blood glucose. Finally, the patient was diagnosed with α‐thalassemia and insulin resistance. α‐Thalassemia might lead to a discordantly high HbA1c result, which could be attributed to elevated hemoglobin H. In this case, glycated albumin might accurately reflect the real average level of blood glucose. When finding discordant HbA1c, patients should be advised to undergo thalassemia and hemoglobinopathy screening by diabetologists/endocrinologists or primary care physicians to avoid a missed diagnosis of hematopathy.

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“…This occurs when Glutamate catalyzes and/or participates in the glycation of susceptible proteins [ 15 , 16 ] when located less than 5.0 Å [ 17 ] from AGE-modification sites in these proteins. Amino groups with lower pK a values are expected to be more reactive toward glycation due to their greater nucleophilicity [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Signature of Glycylglutamic Acid Structure

Hoff¹,

Rath²,

Lisko³

et al. 2021

ijbb

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Recognition of rare hemoglobin variants by hemoglobin A 1c measurement procedures

Cited by 17 publications

References 23 publications

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

Discordantly high glycated hemoglobin might assist in diagnosing α‐thalassemia, but not diabetes: A case report

Signature of Glycylglutamic Acid Structure

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