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Fetal hemoglobin in sickle cell anemia: molecular characterization of the unusually high fetal hemoglobin phenotype in African Americans.

ABSTRACT: Fetal hemoglobin (HbF) is a major modifier of disease severity in sickle cell anemia (SCA). Three major HbF quantitative trait loci (QTL) are known: the Xmn I site upstream of (G)?- globin gene (HBG2) on chromosome 11p15, BCL11A on chromosome 2p16, and HBS1L-MYB intergenic polymorphism (HMIP) on chromosome 6q23. However, the roles of these QTLs in patients with SCA with uncharacteristically high HbF are not known. We studied 20 African American patients with SCA with markedly elevated HbF (mean 17.2%). They had significantly higher minor allele frequencies (MAF) in two HbF QTLs, BCL11A, and HMIP, compared with those with low HbF. A 3-bp (TAC) deletion in complete linkage disequilibrium (LD) with the minor allele of rs9399137 in HMIP was also present significantly more often in these patients. To further explore other genetic loci that might be responsible for this high HbF, we sequenced a 14.1 kb DNA fragment between the (A)?-(HBG1) and ?-globin genes (HBD). Thirty-eight SNPs were found. Four SNPs had significantly higher major allele frequencies in the unusually high HbF group. In silico analyses of these four polymorphisms predicted alteration in transcription factor binding sites in 3.

SUBMITTER: Akinsheye I

PROVIDER: S-EPMC3302931 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Fetal hemoglobin in sickle cell anemia: molecular characterization of the unusually high fetal hemoglobin phenotype in African Americans.

Akinsheye Idowu I Solovieff Nadia N Ngo Duyen D Malek Anita A Sebastiani Paola P Steinberg Martin H MH Chui David H K DH

American journal of hematology 20111203 2

Fetal hemoglobin (HbF) is a major modifier of disease severity in sickle cell anemia (SCA). Three major HbF quantitative trait loci (QTL) are known: the Xmn I site upstream of (G)γ- globin gene (HBG2) on chromosome 11p15, BCL11A on chromosome 2p16, and HBS1L-MYB intergenic polymorphism (HMIP) on chromosome 6q23. However, the roles of these QTLs in patients with SCA with uncharacteristically high HbF are not known. We studied 20 African American patients with SCA with markedly elevated HbF (mean ...[more]

PMID: 22139998

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Project description:Hemoglobin A1c (HbA1c) reflects past glucose concentrations, but this relationship may differ between those with sickle cell trait (SCT) and those without it.To evaluate the association between SCT and HbA1c for given levels of fasting or 2-hour glucose levels among African Americans.Retrospective cohort study using data collected from 7938 participants in 2 community-based cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS). From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011); from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013). All visits were scheduled at approximately 5-year intervals. Participants without SCT data, those without any concurrent HbA1c and glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded. Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examine the association of SCT with HbA1c levels, controlling for fasting or 2-hour glucose measures.Presence of SCT.Hemoglobin A1c stratified by the presence or absence of SCT was the primary outcome measure.The analytic sample included 4620 participants (mean age, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrent measures of fasting glucose and HbA1c levels. In unadjusted GEE analyses, for a given fasting glucose, HbA1c values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT (mean HbA1c difference, -0.29%; 95% CI, -0.35% to -0.23%). Findings were similar in models adjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose and HbA1c concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a mean HbA1c difference of -0.30% (95% CI, -0.39% to -0.21%). The HbA1c difference by SCT was greater at higher fasting (P?=?.02 for interaction) and 2-hour (P?=?.03) glucose concentrations. The prevalence of prediabetes and diabetes was statistically significantly lower among participants with SCT when defined using HbA1c values (29.2% vs 48.6% for prediabetes and 3.8% vs 7.3% for diabetes in 572 observations from participants with SCT and 6877 observations from participants without SCT; P<.001 for both comparisons).Among African Americans from 2 large, well-established cohorts, participants with SCT had lower levels of HbA1c at any given concentration of fasting or 2-hour glucose compared with participants without SCT. These findings suggest that HbA1c may systematically underestimate past glycemia in black patients with SCT and may require further evaluation.

Dataset Information

Fetal hemoglobin in sickle cell anemia: molecular characterization of the unusually high fetal hemoglobin phenotype in African Americans.

Publications

Fetal hemoglobin in sickle cell anemia: molecular characterization of the unusually high fetal hemoglobin phenotype in African Americans.

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