One haplotype is associated with the Swiss type of hereditary persistence of fetal hemoglobin in the Yugoslavian population

Ефремов, Г. Д.; Gjorgovski, I.; Stojanovski, Nikola; Díaz-Chico, J. C.; Harano, Teruo; Kutlar, Ferdane; Huisman, T. H. J.

doi:10.1007/bf00272379

Cited by 34 publications

(18 citation statements)

References 20 publications

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“…DNA haplotyping of the β-globin gene cluster from 23 members of unrelated families with the Swiss type of HPFH has shown that this condition is associated with a chromosome and a haplotype that is identical to the Senegal (#3) [− + + − + + + + +] type (33).…”

Section: The Swiss Type Of Hereditary Persistence Of Fetal Hemoglobinmentioning

confidence: 99%

Thalassemias and Other Hemoglobinopathies in the Republic of Macedonia

Ефремов

2007

Hemoglobin

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This paper summarizes the results on the epidemiology and molecular basis of thalassemias and other hemoglobinopathies in the Republic of Macedonia. Over the past 40 years, population surveys of more than 22,000 participants (school children and workers) from all over the country, have shown that the average incidence of beta-thalassemia (thal) trait is 2.6%, ranging from less than 1% in the northeast to 10% in the south. The frequency of deltabeta-thal is 0.2%, while the frequency of the Swiss type of hereditary persistence of fetal hemoglobin (HPFH) is 0.3%. Screening of 9,619 newborns has shown that the frequency of alpha-thal trait is 1.5%, of which alpha-thal-2 is 1.45% and alpha-thal-1 is 0.05%. The molecular basis of the different forms of beta-thal and other hemoglobinopathies has been completely defined. Among the Macedonians, over 450 beta-thal chromosomes have been studied. Fifteen different beta-thal mutations have been detected, four of which [IVS-I-110 (G-->A), IVS-I-6 (T-->C), IVS-I-1 (G-->A), codon 39 (C-->T)] account for 85% of all beta-thal chromosomes. Among the Albanians, 48 beta-thal chromosomes have been studied. Eight different mutations have been detected, four of which [codon 39, -30 (T-->A), IVS-I-110, IVS-I-1] account for 85% of all beta-thal chromosomes. Four new mutations [-101 (C-->A), -87 (C-->G), -30, polyadenylation signal (poly A) (AATAAA-->AATGAA)] have been characterized. Molecular analyses of DNA from over 20 unrelated cases with deltabeta-thal have shown that this condition is caused by a 13 kb deletion (Sicilian type); in two families a deletion of 18 to 23 kb (Macedonian type of deltabeta-thal) was discovered. Molecular analyses of alpha-thal in the Republic of Macedonia have shown the following types of molecular defects: 20.5 kb deletion, 17.5 kb deletion, 3.7 kb deletion, poly A mutation (AATAAA-->AATGAA), and Hb Icaria [alpha142, Term-->Lys, TAA-->AAA (alpha2)]. The incidence of abnormal hemoglobins (Hbs) in the Republic of Macedonia is 0.4%. Three different alpha chain variants among 10 families, seven different beta chain variants among 33 families, two gamma chain variants in two newborns, one variant with an extended alpha chain, and Hb Lepore among 105 families, have been observed. Structural analysis of numerous cases with Hb Lepore showed that the variant was of the Washington-Boston type.

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Section: The Swiss Type Of Hereditary Persistence Of Fetal Hemoglobinmentioning

confidence: 99%

Thalassemias and Other Hemoglobinopathies in the Republic of Macedonia

Ефремов

2007

Hemoglobin

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“…Even within families with heterocellular hereditary persistence of fetal hemoglobin (HPFH) in which increased Hb F was associated with XmnI-G␥ T/T or T/C genotypes, the association is not complete. 12 Nearly half of the family members with these XmnI-G␥ genotypes do not have increased Hb F levels, suggesting that the effect of the XmnI-G␥ site is modulated by the presence of an intermediary factor(s). The most consistent change caused by the T allele at G␥Ϫ158 is a high proportion of G␥ chains.…”

Section: Introductionmentioning

confidence: 99%

Quantitative trait locus on chromosome 8q influences the switch from fetal to adult hemoglobin

Garner

Silver

Best

et al. 2004

Blood

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The switch from fetal to adult hemoglobin is incomplete; the residual fetal hemoglobin in adults is restricted to a subset of erythrocytes called F cells. F-cell levels are influenced by a sequence variant (C 3 T) at position ؊158 upstream of the ␥-globin gene, termed the XmnI-G␥ polymorphism. How the G␥؊158 C 3 T variant influences the expression of the G␥-globin gene is unknown but is likely to involve the interaction of a multiprotein transcription complex. In a recent genome-wide linkage study of a large Asian Indian kindred, a genetic interaction between the XmnI-G␥ site and a locus on chromosome 8q was reported to influence adult F-cell levels. We report the replication of linkage to chromosome 8q in a sample of European twin pairs. This result provides strong evidence that a quantitative trait locus exists on chromosome 8q that influences the developmental switch from fetal to adult hemoglobin. IntroductionResidual amounts of fetal hemoglobin (Hb F) continue to be synthesized throughout adult life and are restricted to a subset of erythrocytes termed F cells (FCs). 1 There is a good correlation between the percentages of Hb F and FCs, indicating that increased Hb F can be ascribed to the higher number of F cells produced. 2 The heritability of FC levels was estimated to be 0.89 in the European population. 3 Epidemiologic studies have shown FCs to be influenced by age, 4 sex, 5 and a DNA sequence variant (C 3 T) at position Ϫ158 upstream of the G␥-globin gene, referred to as the XmnI-G␥ polymorphism. [6][7][8] The XmnI-G␥ polymorphism is common in several populations; the "T" variant, which creates a cleavage site for the XmnI restriction enzyme, has been shown to be associated with increased FC levels. 7 The frequency of the XmnI-G␥ restriction site is approximately 0.33 in Europeans, and the genotype accounts for 13% to 32% of the total phenotypic variance. 8 The G␥Ϫ158 T variant predisposes toward increased Hb F production in adult life, particularly in conditions of erythroid stress, such as ␤-thalassemia 9-11 and sickle cell anemia. 9 However, unlike rare mutations in the ␥-globin promoter that are associated with clearly defined phenotypes of elevated Hb F levels of 10% to 35% in heterozygotes, 2 the G␥Ϫ158 variant does not always raise Hb F levels in otherwise healthy individuals. Even within families with heterocellular hereditary persistence of fetal hemoglobin (HPFH) in which increased Hb F was associated with XmnI-G␥ T/T or T/C genotypes, the association is not complete. 12 Nearly half of the family members with these XmnI-G␥ genotypes do not have increased Hb F levels, suggesting that the effect of the XmnI-G␥ site is modulated by the presence of an intermediary factor(s). The most consistent change caused by the T allele at G␥Ϫ158 is a high proportion of G␥ chains.Linkage has been reported between 3 regions of the genome and adult Hb F or FC levels. Chromosome Xp22.2-p22.3 has been linked to FC levels in sickle cell disease and healthy individuals. 13 A locus has been mapped to chromosome 6q2...

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“…10,11 Some studies have suggested that this cluster is involved in the variability of HbF expression and FC number in individuals with one (heterozygote) or two copies of the b thalassaemic (b thal) or the sickle cell gene, whereas others failed to confirm these findings. 12,13 Studies of sequence variations in the Locus Control Region hypersensitive site-2 (b LCR 5'HS2), 14 ± 16 the second intron of the A g gene (Ag IVS2), 17 the promoter region of the b globin gene 18,19 and the -158 5' of the Gg gene 20,21 have found a genetic association with HbF levels, FC number or both.…”

Section: Introductionmentioning

confidence: 99%

Foetal haemoglobin in normal healthy adults: relationship with polymorphic sequences cis to the β globin gene

et al. 2002

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We evaluated the effects of polymorphic markers within the b globin gene cluster on HbF expression in two groups. These groups were randomly selected from a survey of HbF distribution in a large population study of unrelated healthy Algerian adults (n=827). The first group contained individuals with normal HbF levels (0.1 ± 0.5%) and the second group contained individuals with raised HbF levels (0.8 ± 2.3%). Of the various polymorphic markers analysed, only the 7309 Gg A?G, the 7158 Gg C?T, the Gg IVS2 TC (TG) 9 AG (TG) 2 (CG) 2 and the 7540 b (AT) 9 T 5 sequence configurations were significantly associated with increased HbF levels. More than 84% of the subjects with elevated HbF levels carried one or several of these four marker configurations, suggesting that the b globin gene cluster exerts a significant effect on HbF expression in healthy individuals.

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One haplotype is associated with the Swiss type of hereditary persistence of fetal hemoglobin in the Yugoslavian population

Cited by 34 publications

References 20 publications

Thalassemias and Other Hemoglobinopathies in the Republic of Macedonia

Thalassemias and Other Hemoglobinopathies in the Republic of Macedonia

Quantitative trait locus on chromosome 8q influences the switch from fetal to adult hemoglobin

Foetal haemoglobin in normal healthy adults: relationship with polymorphic sequences cis to the β globin gene

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