Evidence that Microdeletions in the α Globin Gene Protect Against the Development of Sickle Cell Glomerulopathy in Humans

Abstract. There is a large variability in the severity of the clinical manifestations of sickle cell anemia (SSA), including renal involvement. Haplotypes in the β-globin gene cluster associated with the geographical origin of the sickle mutation, as well as microdeletions in the α-globin genes, could provide an epigenetic influence on the heterogeneous outcome in SSA. It has been determined that the cause of progressive renal insufficiency in SSA is a glomerulopathy, clinically detected by the presence of macroalbuminuria (albumin excretion rate >300 mg/g creatinine). To investigate the role of the α-globin gene microdeletion and β-globin gene cluster haplotypes on the degree of glomerular involvement, 76 adult SSA patients (hemoglobin SS) were studied to determine the relationship between these genetic markers and the development of sickle cell glomerulopathy. Macroalbuminuria was present in 22 (29%) of 76 adult SSA patients. The coinheritance of microdeletions in one or two of the four α-globin genes (α-thalassemia) was associated with a lower prevalence of macroalbuminuria (13%) versus patients with intact α-globin genes (40%, P = 0.01). By contrast, there was no association between albuminuria and β-globin gene haplotypes (Central African Republic [CAR] versus non-CAR haplotypes). Patients with α-globin gene microdeletions had lower mean corpuscular volumes and mean corpuscular hemoglobin concentration than patients with all four α genes (86 ± 2 versus 99 ± 3 fl, and 33.9 ± 0.2 versus 34.9 ± 0.2%, respectively, P < 0.05). There were no such hematologic differences between CAR and non-CAR β-globin haplotypes. There were no differences in duration of disease (age), hemoglobin levels, reticulocyte index, and lactate dehydrogenase levels between those with and without glomerulopathy, but the mean arterial pressure was higher (87 ± 1 mmHg) in patients with intact α gene locus versus those with microdeletions (80 ± 2 mmHg, P < 0.05). It is concluded that the coinheritance of microdeletions in the α-globin gene locus in SSA patients confers “renoprotection” by mechanisms not related to the degree of anemia or the severity of hemolysis, but could be related to a reduced mean corpuscular volume or to a lower erythrocyte hemoglobin concentration.

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Rapid and reliable β-globin gene cluster haplotyping of sickle cell disease patients by FRET Light Cycler and HRM assays

Clinica Chimica Acta ◽

10.1016/j.cca.2011.03.025 ◽

2011 ◽

Vol 412 (13-14) ◽

pp. 1257-1261 ◽

Cited By ~ 17

Author(s):

Philippe Joly ◽

Philippe Lacan ◽

Caroline Garcia ◽

Angelique Delasaux ◽

Alain Francina

Keyword(s):

Sickle Cell Disease ◽

Gene Cluster ◽

Sickle Cell ◽

Globin Gene ◽

Cell Disease ◽

Globin Gene Cluster ◽

Light Cycler

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Variants of ZBTB7A (LRF) and its β-globin gene cluster binding motifs in sickle cell anemia

Blood Cells Molecules and Diseases ◽

10.1016/j.bcmd.2016.04.001 ◽

2016 ◽

Vol 59 ◽

pp. 49-51 ◽

Cited By ~ 8

Author(s):

Elmutaz M. Shaikho ◽

Alawi H. Habara ◽

Abdulrahman Alsultan ◽

A.M. Al-Rubaish ◽

Fahad Al-Muhanna ◽

...

Keyword(s):

Gene Cluster ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Globin Gene ◽

Binding Motifs ◽

Globin Gene Cluster

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Fetal Haemoglobin and β -globin Gene Cluster Haplotypes among Sickle Cell Patients in Chhattisgarh

JOURNAL FOR CLINICAL AND DIAGNOSTIC RESEARCH ◽

10.7860/jcdr/2013/4381.2744 ◽

2013 ◽

Author(s):

Sanjana Bhagat

Keyword(s):

Gene Cluster ◽

Sickle Cell ◽

Globin Gene ◽

Fetal Haemoglobin ◽

Globin Gene Cluster

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Production of F cells in sickle cell anemia: regulation by a genetic locus or loci separate from the beta-globin gene cluster

Blood ◽

10.1182/blood.v64.5.1053.1053 ◽

1984 ◽

Vol 64 (5) ◽

pp. 1053-1058 ◽

Cited By ~ 29

Author(s):

SH Boyer ◽

GJ Dover ◽

GR Serjeant ◽

KD Smith ◽

SE Antonarakis ◽

...

Keyword(s):

Gene Cluster ◽

Sickle Cell ◽

Genetic Locus ◽

Globin Gene ◽

The United States ◽

Beta Globin ◽

Cell Production ◽

Beta Globin Gene ◽

Globin Gene Cluster ◽

Sib Pairs

Abstract Levels of fetal hemoglobin (HbF) bearing reticulocytes (F reticulocytes) range from 2% to 50% in patients with sickle cell (SS) anemia. To learn whether any portion of such variation in F cell production is regulated by loci genetically separable from the beta- globin gene cluster, percentages of F reticulocytes were compared in 59 sib pairs composed solely of SS members, including 40 pairs from Jamaica and 19 from the United States. We reasoned that differences in F reticulocyte levels might arise (1) from any of several kinds of artifact, (2) via half-sib status, or (3) because one or more genes regulating F cell production segregate separately from beta S. We minimized the role of artifact by assay of fresh samples from 84 SS individuals, including both members of 38 sib pairs. In 78 of the 84 subjects, serial values for percent F reticulocytes fell within 99.9% confidence limits or were alike by t test (P greater than or equal to .05). This left 32 sib pairs for which F reticulocyte levels in each member were reproducible. When sib-sib comparisons were limited to these 32 pairs, percentages of F reticulocytes were grossly dissimilar within 12 Jamaican and 3 American sibships. Within them, the probability that sibs were alike was always less than or equal to .005 and usually less than or equal to 10(-4). We next minimized the contribution of half-sibs among Jamaicans by a combination of paternity testing and sib-sib comparison of beta-globin region DNA restriction fragment length polymorphisms, especially among discordant pairs. We thereafter concluded that at least seven to eight Jamaican pairs were composed of reproducibly discordant full sibs. There is thus little doubt that there are genes regulating between-patient differences in F cell production that are separate from the beta-globin gene cluster. Still unanswered is (1) whether or not these genes are actually linked to beta S, (2) why F reticulocyte levels in Americans tend to be lower than in Jamaicans, and (3) whether or not differences in F cell production among SS patients are regulated by several major loci or by only one.

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The Senegal DNA haplotype is associated with the amelioration of anemia in African-American sickle cell anemia patients

Blood ◽

10.1182/blood.v77.6.1371.1371 ◽

1991 ◽

Vol 77 (6) ◽

pp. 1371-1375 ◽

Cited By ~ 49

Author(s):

RL Nagel ◽

S Erlingsson ◽

ME Fabry ◽

H Croizat ◽

SM Susuka ◽

...

Keyword(s):

New York ◽

Gene Cluster ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Globin Gene ◽

Inhibitory Effect ◽

Hemoglobin F ◽

Globin Gene Cluster ◽

Alpha Gene ◽

Hbf Level

Abstract We have previously determined that in African sickle cell anemia (SS) patients three different beta-like globin gene cluster haplotypes are associated with different percent G gamma (one of the two types of non- alpha chains comprising hemoglobin F [HbF]), mean percent HbF, and percent dense cells. We report now that in adult New York SS patients, the presence of at least one chromosome with the Senegal haplotype is associated with higher Hb levels (1.2 g/dL higher) than is found for any other non-Senegal haplotype (P less than .004). The percent reticulocytes and the serum bilirubin levels were lower in these patients. When the effect of alpha-gene number was analyzed by examining a sample of SS patients with concomitant alpha-thalassemia, the same results were obtained. Because the HbF level is significantly higher among the Senegal haplotype carriers in this sample, the inhibitory effect on sickling of this Hb variant may be one of the reasons for the haplotype effect. We conclude that the Senegal beta- like globin gene cluster haplotype is associated with an amelioration of the hemolytic anemia that characterizes sickle cell disease.

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The β‐Globin Gene Cluster Haplotypes in Sickle Cell Anemia Patients from Northeast Brazil: A Clinical and Molecular View

Hemoglobin ◽

10.1081/hem-120040310 ◽

2004 ◽

Vol 28 (3) ◽

pp. 267-271 ◽

Cited By ~ 16

Author(s):

Elisângela Vitória Adorno ◽

Ângela Zanette ◽

Isa Lyra ◽

Cyntia Cajado Souza ◽

Leandro Ferraz Santos ◽

...

Keyword(s):

Gene Cluster ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Globin Gene ◽

Northeast Brazil ◽

Globin Gene Cluster

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Molecular analysis of the β-globin gene cluster haplotypes in a Sudanese population with sickle cell anaemia

International Journal of Laboratory Hematology ◽

10.1111/j.1751-553x.2011.01388.x ◽

2012 ◽

Vol 34 (3) ◽

pp. 262-266 ◽

Cited By ~ 12

Author(s):

A. Y. ELDERDERY ◽

J. MILLS ◽

B. A. MOHAMED ◽

A. J. COOPER ◽

A. O. MOHAMMED ◽

...

Keyword(s):

Gene Cluster ◽

Molecular Analysis ◽

Sickle Cell ◽

Sickle Cell Anaemia ◽

Globin Gene ◽

Globin Gene Cluster

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Epigenetic Analysis of Beta-Globin Gene Cluster during Hematopoiesis.

Blood ◽

10.1182/blood.v112.11.1863.1863 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1863-1863

Author(s):

Supachai Ekwattanakit ◽

Suchada Riolueang ◽

Vip Viprakasit

Keyword(s):

Dna Methylation ◽

Gene Cluster ◽

Methylation Level ◽

Globin Gene ◽

Clinical Severity ◽

Globin Genes ◽

Erythroid Cells ◽

Global Methylation ◽

Cpg Dinucleotides ◽

Globin Gene Cluster

Abstract Hemoglobin (Hb) switching is described as temporal, tissue- and stage-specific patterns of globin gene expression; from embryonic to fetal and adult Hb in parallel to developmental stages of erythropoiesis. DNA methylation, one of the epigenetic mechanisms, was associated with inactivated chromatin domain and repressive transcription. To study the role of the DNA methylation on the beta (β)-globin genes, we analyzed CpG dinucleotides in 87 kb regions around β-globin gene cluster, including 5’upstream locus control regions (LCR; DNAse I Hypersensitive site (HS) 1–5), 3’HS1, the promoter regions of the G-and A-gamma (Gγ and Aγ), and β-globin genes, in several representative cells. These cells were primary adult erythroid cells culture (three different stages: early, intermediate, and late), fetal cord blood DNA, and neutrophil cell line (non-erythroid). Using bisulphite modification, followed by nested PCR and in vitro translation, the cleavage products were analysed by MALDI-TOF Mass Spectrometry to quantify the DNA methylation level. The results were consistent with bisulphite sequencing. We found that the promoters of Gγ and Aγ-globin genes were significantly hypomethylated in fetal cells (44% and 47% global methylation), when γ-globin genes were fully expressed, while they were heavily methylated in non-erythroid (86% and 95%). There was also a decreasing trend of the DNA methylation level at Gγ and Aγ-globin genes during adult erythroid differentiation from 80% and 82%, in early stage, to 67% and 66% in late stage (p=0.12 and 0.04). At β-globin promoter, the global methylation level changed from 90% in non-erythroid to 81%, 42%, and 26% in fetal, early and late adult erythroid cells, respectively. Moreover, we found the significant changes at 5’HS4, 3, and 1 as all erythroid cells were hypomethylated compare to non-erythroid. While at the insulators, 5’HS5 and 3’HS1, all tested CpG dinucleotides were heavily methylated in all cells. This is the first report that demonstrates the differences in DNA methylation at β-globin LCR between erythroid and non-erythroid cells. These epigenetic marks were associated with globin genes expression and might be useful to predict clinical severity in patients with β-thalassemia intermedia.

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