841698
article-commentary2019
DSTXXX10.1177/1932296819841698Journal of Diabetes Science and TechnologyKlonoff
Editorial
Hemoglobinopathies and Hemoglobin
A1c in Diabetes Mellitus
David C. Klonoff, MD, FACP, FRCP (Edin), Fellow AIMBE1
Keywords
glycation gap, HbA1c, hemoglobin A1c, hemoglobinopathy, racial, sickle cell
Hemoglobinopathies are the most common genetically inher-
ited single-gene disorders in the world.1 Their associated neg-
ative economic impact affects mainly poorer countries.2
According to the World Health Organization, about 5.2% of
the world population and over 7% of pregnant women carry a
significant variant, and 1.1% of couples worldwide are at risk
for having children with a hemoglobin disorder.3 Sickle cell
trait or the hemoglobin S variant, which is the heterozygous
state for the sickle hemoglobin beta globin gene, is carried by
as many as 100 million individuals worldwide.4
Hemoglobinopathies are frequently linked to artifactually
altered hemoglobin A1c (HbA1c) concentrations.5 In blacks
with prediabetes, the presence of the hemoglobin S variant is
associated with a higher HbA1c concentration and this eleva-
tion is not an artifact.6 Blacks compared to non-Hispanic
whites (nHws) tend to have a higher HbA1c concentration for
the same degree of glycemia as measured by glycated serum
proteins (known as fructosamine) or blood glucose.7 This dis-
cordance is known as the glycation gap.8 The glycation gap is
a measure of disagreement between the magnitude of inte-
grated glycation of (1) hemoglobin within red blood cells
(RBC) and (2) circulating proteins within plasma. This dis-
cordance can result from alterations in glycation occurring
either in the RBC/hemoglobin compartment or the plasma
protein compartment.9 Racial discordances between HbA1c
concentrations and other measures of glycemic control are
unexplained.10 Identifying genes underlying racial differ-
ences in hemoglobin glycation would add credence that the
differences are real and that genetic strategies may be useful
for determining proper treatment based on the level of mean
glycemia suggested by HbA1c values.11 The hemoglobin S
variant hemoglobinopathy occurs more frequently in blacks
then in nHws.12 It is the thesis of this editorial article that the
higher prevalence of the hemoglobin S hemoglobinopathy
variant in the black population than in the nHw population is
associated with or contributes to the glycation gap in blacks.
Hemoglobin A1c
HbA1c is the most widely used analyte for measuring mean
glycemic control. HbA1c is a measure of the percentage of
Journal of Diabetes Science and Technology
2020, Vol. 14(1) 3­–7
© 2019 Diabetes Technology Society
Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/1932296819841698
https://doi.org/10.1177/1932296819841698
journals.sagepub.com/home/dst
hemoglobin molecules attached with glucose. The higher the
glucose concentrations over the previous 2-3 months, the
higher HbA1c will be.13 An HbA1c test is used to monitor
the average glucose concentrations of patients diagnosed
with diabetes and when elevated, to diagnose diabetes.14
Hemoglobinopathies
The term “hemoglobinopathy” includes all genetic hemoglo-
bin disorders. There are two main types of hemoglobinopa-
thies: (1) thalassemia syndromes and (2) structural
hemoglobin variants (abnormal hemoglobins). Both are
caused by mutations and/or deletions in the α- or β-globin
genes. When a gene defect causes a disorder in hemoglobin
synthesis with normal hemoglobin structure, this leads to
thalassemia. When a gene defect causes a change in hemo-
globin structure, this leads to an abnormal hemoglobin vari-
ant.15,16 Some hemoglobin variants are associated with
clinical diseases such as sickle cell anemia and related sick-
ling disorders,17 hemolysis due to unstable hemoglobins,18
and hemoglobins with increased or decreased oxygen affin-
ity.19 However, most structural variants of hemoglobin are
clinically silent and are only discovered incidentally, often
during the measurement of HbA1c in patients with diabe-
tes.16 According to a CDC survey published in 2014, in the
United States the incidence of sickle cell trait per 1000 new-
borns is 15.5 overall, 73.1 among blacks, and 3.0 among
nHws.12 According to Washington State Health Care Provider
Hemoglobinopathy Fact Sheet, about one in ten people of
African descent have the sickle cell trait.20 Prevalences of the
hemoglobin S variant as high as 20% to 40% have been
described in certain African tribes.21 Hemoglobin variants
including hemoglobin C, hemoglobin S, hemoglobin E, and
1
Diabetes Research Institute, Mills-Peninsula Medical Center, San Mateo,
CA, USA
Corresponding Author:
David C. Klonoff, MD, FACP, FRCP (Edin), Fellow AIMBE, Diabetes
Research Institute, Mills-Peninsula Medical Center, 100 S San Mateo Dr,
Rm 5147, San Mateo, CA 94401, USA.
Email: dklonoff@diabetestechnology.org
4 Journal of Diabetes Science and Technology 14(1)
hemoglobin D traits, as well as elevated fetal hemoglobin are
the most common hemoglobin variants that may interfere
with HbA1c measurements.22
Laboratories use many different methods for measuring
HbA1c based on charge or structure and some of these meth-
ods can give inaccurate results if patients have certain hemo-
globinopathies because by using methods that separate by
migration based on molecular charge, a hemoglobin variant
molecule can migrate similarly to HbA1c and create a falsely
elevated or depressed reading.23 A clinician should be suspi-
cious that an A1c result is inaccurate due to the presence of a
hemoglobinopathy interfering with the HbA1c assay if (1) the
HbA1c value is much higher or much lower than expected;
(2) the HbA1c value is over 15%; (3) the HbA1c value does
not correlate with self-monitored blood glucose results; or (4)
a patient’s HbA1c result is radically different from a previous
HbA1c result following a change in laboratory HbA1c meth-
ods.24 When such suspicion is present, then the patient’s sam-
ple should be tested for HbA1c with a method that is known
not to have interference from the most common hemoglobin
variants.25 A falsely high or low HbA1c reading can lead to
overtreatment or undertreatment of diabetes.11
Racial Differences in Hemoglobin A1c
The HbA1c concentration might fail to reflect mean glyce-
mia in two circumstances related to genetics. The first is a
genetically determined hemoglobinopathy, as described
above. This situation produces an artifact whereby the hemo-
globin variant is being measured instead of or in addition to
HbA1c.5 The second situation is a racial effect that can result
in the HbA1c concentration being truly higher in people of
some races than other races.26 Blacks and populations of
Middle-East ancestry, compared to nHws have been shown
on average to have higher HbA1c values, even after adjust-
ment for factors likely to affect glycemia, although there are
much wider differences within races than between races.9,27,28
In a study of 3189 individuals with impaired glucose toler-
ance, from five racial and ethnic groups who were eligible
for the Diabetes Prevention Program (DPP), but who did not
have type 2 diabetes,29 after adjustment for factors that dif-
fered among groups or might affect glycemia (ie, age, gen-
der, education, marital status, blood pressure, adiposity,
hematocrit, fasting and postglucose load glucose concentra-
tions, glucose area under the curve, beta-cell function, and
insulin resistance) racial differences in HbA1c persisted.
Postadjustment mean HbA1c values were 5.78% for nHws,
5.93% for Hispanics, 6.00% for Asians, 6.12% for American
Indians, and 6.18% for blacks (P < .001). The authors con-
cluded that among patients with impaired glucose tolerance,
“HbA1c may not be valid for assessing and comparing gly-
cemic control across racial and ethnic groups or as an indica-
tor of health care disparities.”30
A similar conclusion about the lack of validity of HbA1c as
a sole determining factor of mean glycemia when comparing
racial/ethnic groups was supported by a study that used continu-
ous glucose monitoring data. In 2017, using continuous glucose
monitoring to assess mean glycemia, Bergenstal and colleagues
found blacks with type 1 diabetes to have HbA1c values that
were on average, 0.4% HbA1c units higher than those of whites
at any given average glucose concentration.9 This reason for this
difference between the two groups has not been elucidated.30 A
difference in glycation or in RBC lifespan between the races has
been suggested.11,31
Genetic Differences and Hemoglobinopathies in
HBA1C
One of the largest studies to understand genetic factors in
responsible for a difference in HbA1c values between races
was published in February 2019 by Hivert and colleagues.
This study assessed three types of genetic markers to explain
racial differences in HbA1c values between blacks and nHws.
The genetic markers included (1) genetic variants causing
hemoglobinopathies and erythrocyte disorders; (2) genetic
variants associated with HbA1c discovered in a recent
genome wide association study of loci affecting HbA1c or
erythrocyte biology;32 and (3) principal component analysis
of factors intended to determine whether individuals in a
dataset are descended from a homogenous population or from
a population containing genetically distinct subgroups. These
types of genetic studies were performed on 2658 participants
in the Diabetes Prevention Program (DPP) all of whom had
prediabetes but not type 2 diabetes.28,33
The group of self-identified black participants in this
study (n = 537), compared to the group of self-identified
nHws (n = 1476) had a higher mean HbA1c value by 0.4%
HbA1c units, despite comparable fasting and 2-hour post-
prandial glucose concentrations. The first principal compo-
nent explained 60% of the difference in these HbA1c values,
which confirmed an association of higher HbA1c with
African descent, but the study was not able to determine a
cause for the association, such as genetic, environmental,
behavioral, or socioeconomic factors.
The genetic risk score based on the genome wide associa-
tion meta-analysis explained 14% of the difference. The
investigators cautioned, however, that the set of 60 loci from
their genome risk score might be incomplete because the
genome wide association study from which they were
derived identified only two loci specific for people of African
descent.
The presence of a hemoglobinopathy, as long as it was the
sickle cell variant hemoglobinopathy (having one normal
gene and one sickle gene), explained 16% of the difference
in HbA1c between blacks and nHws. The investigators stud-
ied seven genes associated with hemoglobinopathies and
found that in blacks the sickle cell variant was associated
with a higher HbA1c value by 0.44% HbA1c units. The
association was essentially the same after adjustment for
fasting glucose, BMI, and waist circumference. Five variants
Klonoff 5

of hemoglobin F were associated with lower HbA1c values Table 1. The 21 Methods Most Often Used to Measure
in blacks of a magnitude of less than 0.1% HbA1c units. Six HbA1c, and Whether, in the Presence of Hemoglobin S, the
genetic variants for enzymes associated with RBC biology Method Produces a Higher (↑) or Lower (↓) Reading Because of
Interference, According to NGSP.22
were studied and one of them, the G6PD variant, was associ-
ated with lower HbA1c by 0.6% HbA1c units, but the other Interference
variants had a minimal effect on a difference in HbA1c val- Method from HbS
ues between the two racial groups.
Abbott Architect c Enzymatic No
Alere Afinion No
Sickle Cell Trait Hemoglobinopathy and Arkray ADAMS A1c HA-8180V (Menarini) No
Differences in HbA1c Beckman AU system (reagent lot Yes↑
OSR6192, lot B00389 not yet evaluated)
It has not been settled as to whether the presence of sickle trait Beckman Synchron System No
hemoglobinopathy affects mean HbA1c values. This relation- Bio-Rad D-10 (A1c program) No
ship has been assessed in six studies. (1) The aforementioned Bio-Rad D-100 (A1c program) No
Hivert study found higher mean HbA1c values in prediabetic Bio-Rad Variant II NU No
subjects with sickle cell trait compared to without the sickle Bio-Rad Variant II Turbo No
cell trait (delta 0.44%, P = 2.1 x 10-8),33 and so did the (2) Bio-Rad Variant II Turbo 2.0 No
Senegal study (delta 0.51%, with no P value presented) which Ortho-Clinical Vitros No
assessed a group of 203 subjects, over half of whom did not Polymer Tech Systems A1cNOW Yes↑
have diabetes.34 Both studies were published in February Roche Cobas Integra Gen.2 No
2019. (3) In 2017 the combined Coronary Artery Risk Roche/Hitachi (Tina Quant II) No
Development in Young Adults study and the Jackson Heart Sebia Capillarys 2 Flex Piercing No
Study demonstrated lower mean HbA1c values in subjects Siemens Advia A1c (new version) No
with the sickle cell trait (delta −0.38%, P < .001). Diabetes Siemens DCA 2000/Vantage No
Siemens Dimension No
was not an entry criterion in this analysis and mean HbA1c
Tosoh G7 No
concentrations in subjects in this study were 5.7-6.0%.35 (4)
Tosoh G8 Yes↓ (No for
The Africans in America Study in 2015, where a history of ver. 5.24)
diabetes was an exclusion factor, did not report a significant Trinity (Primus) HPLC (affinity) No
mean difference between subjects with and without the sickle
trait, but the HbA1c values in subjects with sickle cell trait,
compared to the HbA1c values in subjects without this trait,
with the measuring assays.33,40,41 NGSP is an organization
were about 10% less sensitive and 10% more specific in mak-
that standardizes HbA1c test results to those of the Diabetes
ing a diagnosis, suggesting that the values were approximately
Control and Complications Trial (DCCT) and United
10% higher in the hemoglobinopathy subjects.36 In two older
Kingdom Prospective Diabetes Study (UKPDS), which
retrospective studies HbA1c results were compared between
established the direct relationships between HbA1c value
blacks with and without the sickle cell trait and the studies
and outcome risks in patients with diabetes.42 NGSP sets
found less of an association of higher HbA1c in the presence
accuracy requirements. A list of the 21 most widely used
of sickle cell trait compared to the absence of sickle cell trait,
HbA1c assays and whether they are susceptible to interfer-
compared to the two studies reported this year. (5) In 2010 the
ence from hemoglobin S, which is present with sickle cell
HbA1c value was higher in the presence of the trait (delta
trait, is found in Table 1.22
0.2%, P = .06) in a community population where diabetes
was neither an inclusion nor an exclusion factor.37 (6) In 2012
the mean HbA1c was lower in a type 2 diabetes cohort among
Future Hemoglobinopathy Research
subjects with compared to without the sickle cell variant
(delta −0.4%, 95% CI = 1.18-0.93).38 In this study, HbA1c The data comparing HbA1c values in blacks with and with-
was measured by ion exchange chromatography, a method out the hemoglobin S variant has been collected mainly in
that is known for generating falsely decreased levels for gly- prediabetic and type 1 populations, but no study has looked
cated hemoglobins in patients with the hemoglobin S vari- at this phenomenon in patients with type 2 diabetes subjects
ant.39 The combination of findings in these six studies with an NGSP-approved accurate method for measuring
suggests that in type 2 diabetes elevated HbA1c concentra- HbA1c in the presence of this variant. This editorial article
tions out of proportion to mean glycemia, in blacks compared has presented evidence supporting the hypothesis that the
to nHws, could be associated with the presence of the sickle hemoglobin S hemoglobinopathy variant is associated with
cell hemoglobinopathy variant. or contributes to the presence of a glycation gap between
There has been debate as to whether the HbA1c differ- glycated hemoglobin in RBCs and glycated serum proteins
ences in these sickle trait studies were due to interference in blacks (compared to nHws) with type 2 diabetes.
6 Journal of Diabetes Science and Technology 14(1)
This hypothesis can be tested by performing a well-con-
trolled prospective trial in blacks with type 2 diabetes and
nHws with type 2 diabetes comparing results of (1) mean glu-
cose concentrations and time in range using continuous glu-
cose monitoring;43 (2) accurate HbA1c measurements not
affected by sickle cell trait by averaging HbA1c results from
two different NGSP–approved instruments for measuring Hb
A1c that are not affected by artifactual interference from
hemoglobin S;22 and (3) both hemoglobin electrophoresis and
high performance liquid chromatography to check for the
presence of hemoglobin S.44 This study will establish (1) to
what extent blacks have a glycation gap relative to nHws in
type 2 diabetes, that is, whether the black and nHw popula-
tions with type 2 diabetes have similar or dissimilar glycemic
control for a given mean glucose concentration and time in
range, and glycosylated serum protein concentration; and (2)
whether the level of mean glycemic control in the black cohort,
as measured by either continuous glucose monitoring or
HbA1c, is associated with the presence of hemoglobin S. In
the black population, if the presence of the hemoglobin S vari-
ant is associated with a gap between predicted mean glycemia
(as measured by continuous glucose monitoring) and HbA1c
concentrations, then this difference will represent a glycation
gap linked to the presence of the hemoglobin S variant hemo-
globinopathy. In that case, it will be demonstrated that the
presence of the hemoglobin S variant is associated with
HbA1c concentrations in type 2 diabetes not only potentially
as an artifact, but actually as a physiologic phenomenon.
The use of continuous glucose monitoring to assess glyce-
mia in a study of the glycation gap in patients with type 2 dia-
betes has not been reported in the medical literature. Likewise
there are no reports in the medical literature of a study corre-
lating the presence of the hemoglobin S variant with double-
checked accurate (in the presence of the hemoglobin S variant)
measures of HbA1c concentrations and double-checked
assays for the presence of this variant. It is now time to test the
hypothesis linking the presence of a hemoglobinopathy with
heretofore-unexplained elevations of HbA1c concentrations
out of proportion to continuously measured glucose and other
metrics of mean glycemia in patients with type 2 diabetes.
Abbreviations
DCCT, Diabetes Control and Complications Trial; DPP, Diabetes
Prevention Program; HbA1c, hemoglobin A1c; nHws, non-Hispanic
whites; UKPDS, United Kingdom Prospective Diabetes Study.
Acknowledgments
The author thanks Robert Cohen, MD, and Sultan Meo, MBBS,
MPhil, PhD, for helpful advice and Annamarie Sucher for her
expert editorial assistance.
Declaration of Conflicting Interests
The author declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: DCK is a consultant for Abbott, Ascensia, EOFlow,
Lifecare, Merck, Novo, Roche Diagnostics, and Voluntis.
Funding
The author received no financial support for the research, author-
ship, and/or publication of this article.
References
1. Goonasekera HW, Paththinige CS, Dissanayake VHW.
Population screening for hemoglobinopathies. Annu Rev
Genomics Hum Genet. 2018;19:355-380.
2. Weatherall DJ. The inherited diseases of hemoglobin are an
emerging global health burden. Blood. 2010;115:4331-4336.
3. Modell B, Darlison M. Global epidemiology of haemoglobin
disorders and derived service indicators. Bull World Health
Organ. 2008;86:480-487.
4. Goldsmith JC, Bonham VL, Joiner CH, et al. Framing the
research agenda for sickle cell trait: building on the current
understanding of clinical events and their potential implica-
tions. Am J Hematol. 2012;87:340-346.
5. Little RR, Roberts WL. A review of variant hemoglobins
interfering with hemoglobin A1c measurement. J Diabetes Sci
Technol. 2009;3(3):446-451.
6. Ziemer DC, Kolm P, Weintraub WS, et al. Glucose-
independent, black-white differences in hemoglobin A1c lev-
els: a cross-sectional analysis of 2 studies. Ann Intern Med.
2010;152:770-777.
7. Cavagnolli G, Pimentel AL, Freitas PA, et al. Effect of ethnic-
ity on HbA1c levels in individuals without diabetes: systematic
review and meta-analysis. PLOS ONE. 2017;12:e0171315.
8. Cohen RM, Holmes YR, Chenier TC, et al. Discordance
between HbA1c and fructosamine: evidence for a glycosyl-
ation gap and its relation to diabetic nephropathy. Diabetes
Care. 2003;26:163-167.
9. Bergenstal RM, Gal RL, Connor CG, et al. Racial differences
in the relationship of glucose concentrations and hemoglobin
A1c levels. Ann Intern Med. 2017;167:95-102.
10. Campbell L, Pepper T, Shipman K. HbA1c: a review of non-
glycaemic variables. J Clin Pathol. 2019;72:12-19.
11. Cohen RM, Franco RS, Smith EP, et al. When HbA1c and
blood glucose do not match: How much is determined by race,
by genetics, by differences in mean red blood cell age? J Clin
Endocrinol Metab. 2019;104:707-710.
12. Ojodu J, Hulihan MM, Pope SN, et al. Incidence of sickle cell
trait—United States, 2010. MMWR Morb Mortal Wkly Rep.
2014;63:1155-1158.
13. Little RR, Rohlfing C, Sacks DB. The national glycohemoglobin
standardization program: over 20 years of improving hemoglo-
bin A1c measurement [published online ahead of print December
7, 2018]. Clin Chem. doi:10.1373/clinchem.2018.296962.
14. American Diabetes Association. Classification and diagno-
sis of diabetes: standards of medical care in diabetes—2019.
Diabetes Care. 2019;42(suppl 1):S13-S28.
15. Kohne E. Hemoglobinopathies: clinical manifestations, diag-
nosis, and treatment. Dtsch Arztebl Int. 2011;108:532-540.
16. Sabath DE. Molecular diagnosis of thalassemias and hemo-
globinopathies: an ACLPS critical review. Am J Clin Pathol.
2017;148:6-15.
Klonoff
17. Piccin A, Murphy C, Eakins E, et al. Insight into the complex
pathophysiology of sickle cell anaemia and possible treat-
ment [published online ahead of print January 22, 2019]. Eur J
Haematol. doi:10.1111/ejh.13212.
18. Teixeira C, Pina D, Freitas MI. Automated detection of unsta-
ble hemoglobin variants by Sysmex XE-Series analyzers. Clin
Chem Lab Med. 2017;55:e243-e246.
19. Jones RT, Shih TB. Hemoglobin variants with altered oxygen
affinity. Hemoglobin. 1980;4:243-261.
20. Washington State Department of Health. Health care provider
hemoglobinopathy fact sheet: hemoglobin S–2011. Available
at: https://www.doh.wa.gov/Portals/1/Documents/5220/HbS
FactSheet.pdf. Accessed March 13, 2019.
21. Naik RP, Haywood C, Jr. Sickle cell trait diagnosis: clinical
and social implications. Hematology Am Soc Hematol Educ
Program. 2015;2015:160-167.
22. NGSP. HbA1c methods: effects of hemoglobin variants
(HbC, HbS, HbE and HbD traits) and elevated fetal hemoglo-
bin (HbF)—2018. Available at: http://www.ngsp.org/interf
.asp. Accessed March 13, 2019.
23. Radin MS. Pitfalls in hemoglobin A1c measurement: when
results may be misleading. J Gen Intern Med. 2014;29:388-394.
24. National Institute of Diabetes and Digestive and Kidney
Diseases. Sickle cell trait & other hemoglobinopathies & dia-
betes (for providers)—2014. Available at: https://www-niddk
-nih-gov.ucsf.idm.oclc.org/health-information/diagnostic-tests
/sickle-cell-trait-hemoglobinopathies-diabetes. Accessed March
13, 2019.
25. Hanley T. Considerations in choosing hemoglobin A1c meth-
ods—2015. Available at: https://www.aacc.org/publications/cln
/articles/2015/april/considerations-in-choosing-hemoglobin
-a1c-methods. Accessed March 13, 2019.
26. Herman WH, Dungan KM, Wolffenbuttel BH, et al. Racial and
ethnic differences in mean plasma glucose, hemoglobin A1c,
and 1,5-anhydroglucitol in over 2000 patients with type 2 dia-
betes. J Clin Endocrinol Metab. 2009;94:1689-1694.
27. Carson AP, Muntner P, Selvin E, et al. Do glycemic marker
levels vary by race? Differing results from a cross-sectional
analysis of individuals with and without diagnosed diabetes.
BMJ Open Diabetes Res Care. 2016;4:e000213.
28. Hellgren M, Hjörleifsdottir Steiner K, Bennet L. Haemoglobin
A1c as a screening tool for type 2 diabetes and prediabetes in
populations of Swedish and Middle-East ancestry. Prim Care
Diabetes. 2017 Aug;11(4):337-343.
29. Diabetes Prevention Program. Design and methods for a clini-
cal trial in the prevention of type 2 diabetes. Diabetes Care.
1999;22:623-634.
30. Herman WH, Ma Y, Uwaifo G, et al. Differences in A1C
by race and ethnicity among patients with impaired glucose
7
tolerance in the Diabetes Prevention Program. Diabetes Care.
2007;30(10):2453-2457.
31. Selvin E, Sacks DB. Variability in the relationship of hemoglo-
bin A1c and average glucose concentrations: how much does
race matter? Ann Intern Med. 2017;167:131-132.
32. Wheeler E, Leong A, Liu CT, et al. Impact of common genetic
determinants of hemoglobin A1c on type 2 diabetes risk and
diagnosis in ancestrally diverse populations: a transethnic
genome-wide meta-analysis. PLOS MED. 2017;14:e1002383.
33. Hivert MF, Christophi CA, Jablonski KA, et al. Genetic ances-
try markers and difference in A1c between African American
and white in the diabetes prevention program. J Clin Endocrinol
Metab. 2019;104:328-336.
34. Skinner S, Diaw M, Ndour Mbaye M, et al. Evaluation of
agreement between hemoglobin A1c, fasting glucose, and fruc-
tosamine in Senegalese individuals with and without sickle-
cell trait. PLOS ONE. 2019;14:e0212552.
35. Lacy ME, Wellenius GA, Sumner AE, et al. Association of
sickle cell trait with hemoglobin A1c in African Americans.
JAMA. 2017;317:507-515.
36. Sumner AE, Thoreson CK, O’Connor MY, et al. Detection of
abnormal glucose tolerance in Africans is improved by com-
bining A1C with fasting glucose: the Africans in America
study. Diabetes Care. 2015;38:213-219.
37. Bleyer AJ, Vidya S, Sujata L, et al. The impact of sickle cell
trait on glycated haemoglobin in diabetes mellitus. Diabet
Med. 2010;27:1012-1016.
38. Ama V, Kengne AP, Nansseu NJ, et al. Would sickle cell trait
influence the metabolic control in sub-Saharan individuals
with type 2 diabetes? Diabet Med. 2012;29:e334-e337.
39. Torke NS, Mehta PS, Vohra RM, et al. Comparative analy-
sis of glycosylated hemoglobins by ion-exchange column
chromatography and high-performance liquid chromatogra-
phy in patients with hemoglobinopathies. Am J Clin Pathol.
1988;90:697-701.
40. Rohlfing C, Hanson S, Little RR. Measurement of hemoglobin
A1c in patients with sickle cell trait. JAMA. 2017;317:2237.
41. Lacy ME, Wellenius GA, Wu WC. Measurement of hemo-
globin A1c in patients with sickle cell trait-reply. JAMA.
2017;317:2237-2238.
42. NGSP. Available at: http://www.ngsp.org. Accessed March
13, 2019.
43. Lu J, Ma X, Zhou J, et al. Association of time in range, as
assessed by continuous glucose monitoring, with diabetic
retinopathy in type 2 diabetes. Diabetes Care. 2018;41:2370-
2376.
44. Underwood C. What is a hemoglobin electrophoresis test? 2017.
Available at: https://www.healthline.com/health/hemoglobin
-electrophoresis. Accessed March 13, 2019.