Measurement of Hemoglobin A<sub>1c</sub> in Patients With Sickle Cell Trait

Rohlfing, Curt L.; Hanson, Steven; Little, Randie R.

doi:10.1001/jama.2017.4643

Cited by 16 publications

(5 citation statements)

References 6 publications

(18 reference statements)

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“…Fetal hemoglobin is known to interfere with the measurement of HbA1c by some laboratory assays, [30][31][32] and so persistence of fetal hemoglobin may be a mechanism through which rs1039215 influences HbA1c measurements. While a small degree of analytic interference with SCT has been reported for the Tosoh 2.2 and G7 assays used by JHS, MESA, and ARIC to measure HbA1c (see NGSP website URL in the Web Resources section), 33,34 no interference has been reported for the Bio-Rad Variant II Turbo assay used by UKB 35 (Table S2). Thus, assay interference may explain the lack of association of rs334 with HbA1c in UKBB.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…Other assays have statistically significant interference, but the difference is not clinically significant. Use of an assay with such statistically significant interference may explain a report that for any level of mean glycemia, African Americans heterozygous for the common hemoglobin variant HbS had lower A1C by about 0.3 percentage points when compared with those without the trait (10,11). Another genetic variant, X-linked glucose-6-phosphate dehydrogenase G202A, carried by 11% of African Americans, was associated with a decrease in A1C of about 0.8% in hemizygous men and 0.7% in homozygous women compared with those without the trait (12).…”

Section: A1c Limitationsmentioning

confidence: 99%

6. Glycemic Targets: Standards of Medical Care in Diabetes—2019

2018

Diabetes Care

580

215

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The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. ASSESSMENT OF GLYCEMIC CONTROL Glycemic management is primarily assessed with the A1C test, which was the measure studied in clinical trials demonstrating the benefits of improved glycemic control. Patient self-monitoring of blood glucose (SMBG) may help with self-management and medication adjustment, particularly in individuals taking insulin. Continuous glucose monitoring (CGM) also has an important role in assessing the effectiveness and safety of treatment in many patients with type 1 diabetes, and limited data suggest it may also be helpful in selected patients with type 2 diabetes, such as those on intensive insulin regimens (1). A1C Testing Recommendations 6.1 Perform the A1C test at least two times a year in patients who are meeting treatment goals (and who have stable glycemic control). E 6.2 Perform the A1C test quarterly in patients whose therapy has changed or who are not meeting glycemic goals. E 6.3 Point-of-care testing for A1C provides the opportunity for more timely treatment changes. E

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“…One study claimed 0.29% (3.2 mmol/mol) higher HbA1c results in African Americans with sickle cell trait compared to those without this trait (35). However, this difference was most likely due to the use of a HbA1c method that shows a method-specific, statistically significant interference from sickle-cell trait (36).…”

Section: Interferences With Hba1cmentioning

confidence: 99%

The National Glycohemoglobin Standardization Program: Over 20 Years of Improving Hemoglobin A1c Measurement

2019

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BACKGROUND: Measurement of hemoglobin A1c (HbA1c) in the blood is integral to and essential for the management of patients with diabetes mellitus. HbA1c reflects the average blood glucose concentration over the preceding 8–12 weeks. While the clinical value of HbA1c was initially limited by very large difference in results among various methods, the investment of considerable effort to implement standardization has brought about a marked improvement in analysis. CONTENT: The focus of this review is on the substantial progress that has been achieved in enhancing the accuracy and therefore the clinical value of HbA1c assays. SUMMARY: The interactions between the NGSP and manufacturers of HbA1c methods have been instrumental in standardizing HbA1c. Proficiency testing using whole blood, thereby allowing accuracy-based assessment of methods in individual clinical laboratories, has made an important contribution to improving the HbA1c measurement in patient samples. These initiatives, supported by the efforts of the IFCC network, have led to a continuing enhancement of HbA1c methods. Many of the factors that previously influenced HbA1c results independently of blood glucose have been eliminated from most modern methods. These include carbamylation, labile intermediates and common hemoglobin variants. Nevertheless, some factors (e.g., race and aging), may alter HbA1c interpretation, but whether these differences have clinical implications remains contentious. HbA1c has a fundamental role in the diagnosis and management of diabetes. Ongoing improvements in HbA1c measurement and quality will further enhance the clinical value of this analyte.

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Measurement of Hemoglobin A_1c in Patients With Sickle Cell Trait

Abstract: We thank Michael W. Stevenson, JD (Cozen O'Connor's Immigration Law Group), for his careful review and editing of the article. Mr Stevenson did not receive compensation for his contribution.

Cited by 16 publications

References 6 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

6. Glycemic Targets: Standards of Medical Care in Diabetes—2019

The National Glycohemoglobin Standardization Program: Over 20 Years of Improving Hemoglobin A1c Measurement

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Measurement of Hemoglobin A1c in Patients With Sickle Cell Trait

Abstract: We thank Michael W. Stevenson, JD (Cozen O'Connor's Immigration Law Group), for his careful review and editing of the article. Mr Stevenson did not receive compensation for his contribution.

Cited by 16 publications

References 6 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

6. Glycemic Targets: Standards of Medical Care in Diabetes—2019

The National Glycohemoglobin Standardization Program: Over 20 Years of Improving Hemoglobin A1c Measurement

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Measurement of Hemoglobin A_1c in Patients With Sickle Cell Trait