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Letters to the Editor |
Department of Laboratory Medicine, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea
aAddress correspondence to this author at: Department of Laboratory Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-Dong, Gangnam-Gu, Seoul 135-710, Korea. Fax 82-2-3410-2719; e-mail changski{at}skku.edu.
To the Editor:
Glycohemoglobin assays are important for evaluating long-term glycemic control in patients with diabetes (1). Ion-exchange HPLC is commonly used for measuring hemoglobin A1c (Hb A1c), but hemoglobin variants (Hbvar) or increased fetal Hb concentrations may affect the quantification of Hb A1c by HPLC. The presence of Hbvar or high Hb F concentrations can be recognized by the separate elution of variant peaks or by abnormally high peaks on HPLC, and these abnormal findings arise mostly from genetic alterations in the globin genes (2)(3).
In Koreans, only limited data are available on the incidence and molecular genetic background of Hbvar and high Hb F concentrations. We therefore investigated patients who had abnormal peaks on their Hb A1c analyses and characterized them by molecular methods.
Of the 27 006 patients who were tested for Hb A1c at Samsung Medical Center in Seoul, Korea, from May 2004 to October 2004, we investigated 25 patients who had abnormal results [variant peaks or high Hb F values (>5%)] on the Bio-Rad Variant II Turbo HPLC System. We carried out DNA studies of the globin genes by PCR and sequencing of all the coding exons, promoters, and introns of the ß-, 
1-, 2-, A
-, and G-globin genes (4)(5). In the group with increased Hb F, we performed a gene dosage analysis on exon 1 of the ß-globin gene with the LightCycler (Roche Diagnostics), with albumin coamplified as the reference gene.
Ten patients had variant peaks (Fig. 1
). Among them, 5 patients had variant peaks between the A1c and A0 peaks (mean retention time, 0.73 min), which were identified as Hb G Coushatta (ß22Glu
Ala). One patient with variant peaks at the E, D window (retention time, 0.87 min) had Hb Hoshida (ß43GluGln). All 4 patients with abnormal peaks at the S window on HPLC (mean retention time, 0.91 min) had Hb Queens (1 34LeuArg). All 10 patients with variant peaks were heterozygous, and they had abnormal bands within the Hb S/Hb G/Hb D area on cellulose acetate Hb electrophoresis.
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Hb G Coushatta has been found in Koreans, Chinese, and in some Japanese families (6). This variant usually leads to underestimation of Hb A1c, as we noted in our patients. The abnormal peak between Hb A1c and Hb A0 seemed to be that of glycated Hb G Coushatta, as Ogawa et al. (7) have indicated, and Hb G Coushatta is thought to coelute with the normal Hb A0 peak. Hb Hoshida has been reported in a few Japanese families and in 1 Yugoslavian family, and Hb Queens has been found in Koreans, Chinese, Japanese, and Vietnamese (6).
We found increased Hb F concentrations in 15 patients. Gene dosage analysis revealed that the ratios of the ß-globin gene to the albumin gene were 
0.5 in 2 patients, which suggested heterozygous deletion of the ß-globin gene. One of the 2 patients had no phenotypic abnormality other than the increased Hb F (19.5%), suggesting deletional hereditary persistence of fetal Hb. The other patient had a history of chronic microcytic hypochromic anemia. The increased Hb A2 concentration, the decreased osmolality fragility, and the typical findings on the peripheral blood smear suggested deletional ß-thalassemia minor. The remaining 13 patients showed negative results for all molecular analyses on the ß- and -globin genes. Only the XmnI site sequence variation (c.–158CT) on the promoter of the G-globin gene was noted in 10 patients, including 1 homozygote. This sequence variation has been shown to influence the Hb F concentrations in apparently healthy individuals (8). Hereditary persistence of fetal Hb was suspected because no phenotypic or laboratory abnormalities other than the increased Hb F concentrations were seen.
In conclusion, the incidences of Hbvar and high Hb F concentrations were estimated to be 1 in 2700 and 1 in 1800, respectively. The most common Hbvar in Koreans were Hb G Coushatta and Hb Queens, which could be presumed from their characteristic HPLC patterns. The known sequence variations in the ß-, G-, or A-globin genes that cause high Hb F are rare in Koreans. Considering that Hbvar and high Hb F concentrations are not uncommon, more effort should be made to estimate the correct Hb A1c value in Korean patients with diabetes.
References
-globin genes by DGGE and SSCA. Hum Mutat 1996;7:114-122.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]T) promoter mutation is responsible for the increased transcription of the 3' gamma gene in the Atlanta type of hereditary persistence of fetal hemoglobin. Blood 1994;83:3350-3355.Ala) found by dissociation of blood glucose from values of HbA1C measured by HPLC. Intern Med 2003;42:781-787.[Web of Science][Medline]
[Order article via Infotrieve] Xmn I (C-T) polymorphism in normal individuals. Blood 1992;79:832-833.The following articles in journals at HighWire Press have cited this article:
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  S.-T. Lee, C. W. Weykamp, Y.-W. Lee, J.-W. Kim, and C.-S. Ki Effects of 7 Hemoglobin Variants on the Measurement of Glycohemoglobin by 14 Analytical Methods Clin. Chem., December 1, 2007; 53(12): 2202 - 2205. [Abstract] [Full Text] [PDF]
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