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Lower HbA1c seen with sickle trait, but questions remain

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Anne Paxton

March 2017—Perhaps unusually for news about clinical diagnostics research, an article in the Feb. 7 issue of JAMA created a mild stir with findings that HbA1c results in patients with sickle cell trait, the most common hemoglobin variant in the U.S., may systematically underestimate past glycemia (Lacy ME, et al. 317[5]:507–515).

The article, titled “Association of sickle cell trait with hemoglobin A1c in African Americans,” reports on what is likely the largest study to date of the association between sickle cell trait (SCT) and HbA1c for given levels of fasting or two-hour glucose levels among African Americans. Pooling data from two long-term studies—the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS)—the JAMA authors looked retrospectively at more than 4,500 participants to conclude that HbA1c was lower in people with sickle cell trait than those without, and that the difference was greater at high glucose concentrations.

National Public Radio segments, stories in the mass media, and Twitter posts surfaced with the news that “Sickle cell trait skews common diabetes test.” Because of the scale of the study and its publication in a high-profile journal, “there’s been a huge amount of interest,” says study coauthor David B. Sacks, MB ChB, chief of clinical chemistry, Department of Laboratory Medicine, National Institutes of Health Clinical Center, and a member of the CAP Chemistry Resource Committee.

The researchers collected data on visits of participants in the CARDIA and JHS studies, scheduled at about five-year intervals, and used generalized estimating equations (GEE) to examine the association of SCT with HbA1c levels, controlling for fasting or two-hour glucose measurements. The study excluded participants without SCT data, without any concurrent HbA1c and glucose measurements, or with hemoglobin variants HbSS, HbCC, or HbAC.

The SCT status of participants—with sickle cell trait defined as the presence of one abnormal allele for HbS—was determined in CARDIA with available DNA samples using single-gene, single-nucleotide polymorphism genotyping and in JHS through whole exome sequencing using data from baseline. Two assays certified in the NGSP (formerly the National Glycohemoglobin Standardization Program), a Tosoh 2.2 and Tosoh G7 (variant mode), were used to measure HbA1c using high-performance liquid chromatography.

Based on this analytic sample—9,062 concurrent measures of fasting glucose and HbA1c levels—the researchers found that in unadjusted GEE analyses, for a given fasting glucose, HbA1c values were statistically significantly lower in those with (5.72 percent) versus those without (6.01 percent) SCT (mean HbA1c difference, – 0.29 percent; 95 percent CI, – 0.35 percent to – 0.23 percent). Adjusting for key risk factors and analyzing 2,001 concurrent measures of two-hour glucose and HbA1c concentration for those with SCT versus those without produced similar findings.

The study authors hypothesize that, although data are limited, the presence of HbS results in a shorter lifespan for red blood cells, leading to less available time for hemoglobin glycation, which in turn may influence the interpretation of HbA1c in relationship to the glucose values they purport to represent. Another possible explanation is that the presence of HbS can result in assay interference with HbA1c measurement techniques.

Interestingly, the findings of the JAMA study stand in contrast with those of two previous studies with smaller sample sizes. In one, Bleyer and colleagues looked at 385 African American inpatients, most with diabetes, and, despite higher baseline HbA1c values, did not find that SCT significantly altered the relationship between HbA1c and serum glucose (Bleyer AJ, et al. Diabet Med. 2010;27[9]:1012–1016). A second study examined a cohort of 216 African immigrants without diabetes and found no significant difference in the sensitivity of HbA1c by variant hemoglobin status in the detection of prediabetes (Sumner AE, et al. Diabetes Care. 2015;38[2]:213–219).

Important factors of the JAMA study should not escape attention, Dr. Sacks cautions. “One of the very important ones for clinical laboratories is the test method used to measure HbA1c.” In the JAMA study, all the assays were done using a single high-performance liquid chromatography method, which is less commonly employed in the U.S. than immunoassay. “So other methods need to be studied to understand the findings. One cannot reach the conclusion that this is true for all HbA1c measurements; you may get different results with other assays.”

In fact, he was a coauthor of the Sumner study of African immigrants to the U.S. in which that very thing happened. “We used more than one method to measure HbA1c and we found there was no significant difference in sensitivity of HbA1c in people with sickle trait compared to people without it.” Immunoassay, Dr. Sacks notes, is unable to detect that a patient has sickle cell trait before analysis, whereas with capillary electrophoresis and HPLC methods, “you can actually look at the tracing and usually see the variant hemoglobin.”

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