Genetic heterogeneity of G6PD deficiency: mutant alleles of G6PD in the Shekii district of Azerbaijan]

Examination on G6PD deficiency in 349 patients of Shekii district hospital (Azerbaijan) revealed 16 hemi-, 4 homo- and 9 heterozygotic carriers of the defect. Gd- frequency, calculated from the data obtained (7.7%), may be compared to neighbouring regions' frequencies (6-30%). Carriers of G6PD deficiency are residents of 11 villages located in Alasani-Aphtalan valley, highly endemic with malaria in the past; nearly all marriages are endogamic. Physico-chemical and kinetic study of 10 mutant forms of G6PD, according to WHO program, led to identification of 5 variants of the II class (Shekii, Bideiz, Shirin-Bulakh, Okhut I and Zakataly) and 2 variants of the III class (Okhut II and Martinique-like). Resemblance of the majority of variants in electrophoretic mobility and the level of erythrocyte enzyme activity permit to suggest the existence of a common parental mutant G6PD allele distributed in this area.     

Gd- allele distribution patterns in Azerbaijan. III. The identification of mutant forms of glucose-6-phosphate dehydrogenase

In 28 families with G6PD deficiency living in 3 settlements of Shekii district of Azerbaijan 11 G6PD variants of II and III classes differing by kinetic properties were identified according WHO program. 9 of them are characterized with the same electrophoretic mobility. Comparison of G6PD spectra in two subpopulations and in a mixed group permits to make a conclusion about existence of common and rare G6PD alleles in examined population. They distribute by gene drift supported by natural selection. Among 7 samples of G6PD with normal and increased activity two new variants of IV class -- Nukha and Bash-Kungut -- were found.     

Genetic polymorphism of G6PD in a Bulgarian population

Summary Considerable genetic heterogeneity in G6PD was found in the Bulgarian population-14 G6PD variants isolated from 117 hemizygous carriers of G6PD deficiency. Of these, G6PD Mediterranean type was a polymorphic variant and G6PD Corinth occured with high frequency. Two new variants were identified-G6PD Rudosem and G6PD Nedelino. In a selected group of 78 subjects with clinical manifestations, four variants were established: G6PD Mediterranian, G6PD Corinth, G6PD Seattle and G6PD Ohut II.     

Variants of glucose-6-phosphate dehydrogenase in a Vietnamese population

69 out of 2,304 Vietnamese males were found to be hemizygous carriers of the Gd- gene. The glucose-6-phosphate dehydrogenase (G6PD) deficiency had a polymorphic frequency in the Vietnamese population (0.0299). Genetic heterogeneity in G6PD was found - 3 G6PD variants were found among 13 G6PD-deficient males studied (G6PD Canton, G6PD Hanoi and G6PD Vin Fu). Two new variants were identified - G6PD Hanoi and G6PD Vin Fu.     

Patterns of Gd- allele distribution in Azerbaijan. IV. The incidence and polymorphism of erythrocytic glucose-6-phosphate dehydrogenase deficiency in the settlement of Kobi, Apsheron District

The frequency and polymorphism of erythrocyte G6Pd deficiency were studied in schoolchildren of Koby settlement, Apsheron district (n = 469). The total frequency of Gd- alleles was 3.6%. Out of 10 hemizygotes found 9 had Gd- alleles of the III class and 1 had Gd- allele of the II class. The mutant enzyme was isolated from 10 ml venous blood samples and studied according to WHO program. Three different mutant forms of G6PD were found, neither of them having been earlier described. One of these alleles was common for the population studied (n = 6).     

Identification of glucose 6-phosphate dehydrogenase deficiency in a population with a high frequency of thalassemia

High frequencies of both thalassemia trait (5.2%) and glucose 6-phosphate dehydrogenase (G6PD) deficiency for only males (1.3%) have been observed in the Calabrian population. The G6PD activity measurement was carried out on 1239 samples of whole blood from Calabrian subjects of both sexes (age range 10-55) by a differential pH-metry technique which was quite suitable to determine the G6PD deficiency in mass screenings. The analyzed subjects showed: only the thalassemia trait; or only the G6PD deficiency; or only the total iron serum deficiency; or G6PD deficiency associated with the thalassemia trait or with the total iron serum deficiency. The G6PD heterozygous subjects have an enzymatic activity which is masked by both the thalassemia trait and the total iron serum deficiency. In a population showing high frequencies of both thalassemia trait and G6PD deficiency, the comparison of G6PD activity of heterozygous subjects also affected with the thalassemia trait is more reliable if referred to the enzymatic activity of the carriers of the latter inherited anomaly rather than to G6PD activity of normal subjects.     

Glucose-6-phosphate dehydrogenase deficiency in Saudi Arabia. A study in Al-Ula

This paper reports the frequency of glucose-6-phosphate dehydrogenase (G6PD) deficiency in the male and female population of A1-Ula in the northwestern province of Saudi Arabia. The frequency of G6PD deficiency in the male population was 0.098 and in the females it was 0.028. This frequency is significantly lower than those reported for other malaria endemic regions in Arabia. The population was further subgrouped on the basis of their haemoglobin phenotypes and the highest frequency of G6PD deficiency was obtained in male Hb S heterozygotes followed by the male Hb S homozygotes. Phenotyping of G6PD revealed the presence of G6PD-Mediterranean, G6PDA+, G6PDA- and G6PD Mediterranean-like, and the frequency of these variants in Al-Ula was different from those reported in other regions of Saudi Arabia.     

Glucose-6-phosphate dehydrogenase deficiency and infection: a study of hospitalized patients in Iran.

The Mediterranean variant of glucose-6-phosphate dehydrogenase (G6PD) is functionally deficient and found in a variety of cell types of affected individuals, including both erythocytes and neutrophils. To determine if the presence of this sex-linked gene is associated to any degree with the occurrence of severe bacterial infection, a study of hospitalized male patients in Iran was undertaken. As determined by erythrocyte assay, allele prevalence in male patients with infection was 22% vs. 12% in a patient group matched for the absence of other risk factors for infection and 6% in a second group who had additional risk factors for infection. When the control and patient groups were considered together the difference between the frequency of G6PD deficiency (10.2%) was significantly different from that found in the infected patients (p less than .05). Furthermore, the mean age of infected patients with G6PD deficiency was significantly less than that of infected patients without G6PD deficiency or non-infected control groups. These data suggest that host defenses may be altered in G6PD deficiency so that bacterial infections are more severe. Alternatively, G6PD deficiency and infection might represent concomittant risk factors which lead to hospitalization during bacterial infection. Potential mechanisms by which host defenses might be altered in G6PD deficiency are discussed.     

A New Glucose-6-Phosphate Dehydrogenase Variant, G6PD Orissa (44 Ala→Gly), is the Major Polymorphic Variant in Tribal Populations in India

Deficiency of glucose-6-phosphate dehydrogenase (G6PD) is usually found at high frequencies in areas of the world where malaria has been endemic. The frequency and genetic basis of G6PD deficiency have been studied in Africa, around the Mediterranean, and in the Far East, but little such information is available about the situation in India. To determine the extent of heterogeneity of G6PD, we have studied several different Indian populations by screening for G6PD deficiency, followed by molecular analysis of deficient alleles. The frequency of G6PD deficiency varies between 3% and 15% in different tribal and urban groups. Remarkably, a previously unreported deficient variant, G6PD Orissa (44 Ala→Gly), is responsible for most of the G6PD deficiency in tribal Indian populations but is not found in urban populations, where most of the G6PD deficiency is due to the G6PD Mediterranean (188 Ser→Phe) variant. The K of G6PD Orissa is fivefold higher than that of the normal enzyme. This may be due to the fact that the alanine residue that is replaced by glycine is part of a putative coenzyme-binding site.     

Prevalence and Molecular Identification of the Mediterranean Variant Among G6PD-Deficient Sistani and Balouch Males in Southeastern Iran

To determine the prevalence of G6PD deficiency and a Mediterranean mutation among males in southeastern Iran, we studied 1,097 Sistani and Balouch schoolboys. A questionnaire was used to collect demographic data and a history of malaria infection; blood samples were evaluated for G6PD deficiency and the G6PD Mediterranean mutation. Of the 1,097 boys screened, 175 were G6PD deficient (5.8 % of the Sistani boys and 19.3 % of the Balouch boys). The malaria survey indicated that among Balouch subjects, malaria infection was about 14 times that of Sistani subjects. Molecular characterization of G6PD-deficient samples revealed a general frequency of 85.1 % for the Mediterranean variant among all subjects (75 % among Sistani and 86.2 % among Balouch cases). The high prevalence of G6PD deficiency among Balouch populations confirms the hypothesis that the distribution of G6PD deficiency is concordant with the geographic distribution of malaria.     

Frequency of glucose-6-phosphate dehydrogenase phenotypes and deficiency in Al-Baha

This investigation was conducted on 847 males and females in Al-Baha, the mountainous western province of Saudi Arabia, to determine the prevalence of glucose-6-phosphate dehydrogenase (G6PD) phenotypes and G6PD deficiency. Among the G6PD phenotypes, G6PD B+, G6PD A+, G6PD A-, G6PD Mediterranean and G6PD Mediterranean-like were identified with a gene frequency in the male population of 0.7769, 0.0119, 0.0020, 0.1255 and 0.0817, respectively, and in the females with a frequency of 0.722, 0.003, 0.003, 0.1128 and 0.1311, respectively. Heterozygous females with the phenotypes of G6PD B+/A+ and B+/A- were identified with a frequency of 0.0183 and 0.0090, respectively. The frequency of severe G6PD deficiency in this population was 0.1275 and 0.1158 in males and females, respectively.     

Erythrocyte glucose-6-phosphate dehydrogenase in the Niokolonko (Malinke of the Niokolo) of Eastern Senegal. Identification of a slow variant with normal activity (Tacoma-like).

In a survey of blood genetic markers in the Niokolonko of Eastern Senegal, three types of G6PD variants were discovered: (1) fast variants, common Negro G6PD A +; the frequency of the Gd A + gene was 0.183; (2) deficient G6PD A--, occurring with a fairly low frequency: 0.079, and (3) some individuals were carriers of a slow moving electrophoretic variant with normal activity. After purification, the analysis of kinetic parameters showed that this enzyme was closely similar to G6PD Tacoma. We proposed to label it 'G6PD Tacoma-like'. The incidence of this mutation in the whole group studied was 0.020. G6PD Tacoma-like may be common in some African tribes.     

Molecular characterization of glucose-6-phosphate dehydrogenase deficiency in Jeddah,Kingdom of Saudi Arabia

Background

The development of polymerase chain reaction (PCR)-based methods for the detection of known mutations has facilitated detecting specific red blood cell (RBC) enzyme deficiencies. We carried out a study on glucose-6-phosphate dehydrogenase (G6PD) deficient subjects in Jeddah to evaluate the molecular characteristics of this enzyme deficiency and the frequency of nucleotide1311 and IVS-XI-93 polymorphisms in the glucose-6-phosphate dehydrogenase gene.

Results

A total of 1584 unrelated Saudis (984 neonates and 600 adults) were screened for glucose-6-phosphate dehydrogenase deficiency. The prevalence of glucose-6-phosphate dehydrogenase deficiency was 6.9% (n = 110). G6PD Mediterranean mutation was observed in 98 (89.1%) cases, G6PD Aures in 11 (10.0%) cases, and G6PD Chatham in 1 (0.9%) case. None of the samples showed G6PD A￣ mutation. Samples from 29 deficient subjects (25 males and 4 females) were examined for polymorphism. The association of two polymorphisms of exon/intron 11 (c.1311T/IVS-XI-93C) was observed in 14 (42.4%) of 33 chromosomes studied. This association was found in 9 (31.0%) carriers of G6PD Mediterranean and in 4 (13.8%) carriers of G6PD Aures.

Conclusions

The majority of mutations were G6PD Mediterranean, followed by G6PD Aures and < 1% G6PD Chatham. We conclude that 1311T is a frequent polymorphism in subjects with G6PD Mediterranean and Aures variants in Jeddah.

     

Genetic heterogeneity at the glucose-6-phosphate dehydrogenase locus in southern Italy: a study on a population from the Matera district

Summary Glucose-6-phosphate dehydrogenase (G6PD) has been analyzed by gel electrophoresis and by quantitative assay in an unselected sample of 1524 schoolboys from the province of Matera (Lucania) in southern Italy. We have identified 43 subjects with a G6PD variant. Of these, 31 had severe G6PD deficiency, nine had mild to moderate deficiency, and three had a non-deficient electrophoretic variant. The overall rate of G6PD deficiency was 2.6%. The frequency of G6PD deficiency, ranging from 7.2% on the Ionian Coast to zero on the eastern side of the Lucanian Apennines, appears to be inversely related to the distance of each town examined from the Ionian Coast, suggesting that this geographic distribution may reflect, at least in part, gene flow from Greek settlers. Biochemical characterization has shown that most of the G6PD deficiency in this population is accounted for by G6PD Mediterranean. In addition, we have found several examples of two other known polymorphic variants (G6PD Cagliari and G6PD A^–): three new polymorphic variants. G6PD Metaponto (class III), G6PD Montalbano (class III), and G6PD Pisticci (class IV); and two sporadic variants, G6PD Tursi (class III) and G6PD Ferrandina (class II). These data provide further evidence for the marked genetic heterogeneity of G6PD deficiency within a relatively narrow geographic-area and they prove the presence in the Italian peninsula of a sene (Gd ^A–) regarded as characteristically African.     

Glucose 6-phosphate dehydrogenase deficiency and incidence of hematologic malignancy.

We have evaluated the hypothesis of a negative association between glucose 6-phosphate dehydrogenase (G6PD) deficiency and cancer in a cohort of 481 Sardinian males with hematological malignancies. The frequency of G6PD deficiency in the patients was not different from the incidence in a group of 16,219 controls. The same conclusion resulted from the comparison of the frequency of expression of the GdB gene in 23 heterozygous women having a clonal hematologic disease and a control group of 37 healthy heterozygotes. Therefore at present there is no evidence that G6PD deficiency has a protective effect against development of hematologic neoplasms.     

Genetic screening of the G2019S mutation of the LRRK2 gene in Southwest European, North African, and Sephardic Jewish subjects

The G2019S mutation in exon 41 of the leucine-rich repeat kinase 2 (LRRK2) gene accounts for 3-6% of familial dominant Parkinson's disease (PD) and for 1-2% of sporadic PD. It seems that there is a north-south gradient of G2019S frequency in Europe in PD patients, and the frequency of the mutation is up to 41% in North African cases. To obtain a precise estimate of G2019S frequency in populations with relatively elevated incidence of mutation carriers, we have tested for the presence of the G2019S in the south Mediterranean countries. Three thousand one hundred healthy European subjects were compared for the G2019S incidence with 597 healthy Arab subjects originating from five populations in North Africa and with 361 healthy Sephardi Jews from five other populations. The main incidence of G2019S carriers is 1/46 in our sample of North African Arabs, the most elevated carrier incidence (1/30) being found in Moroccan Berbers. An elevated incidence (1/72) is also found in our sample of Sephardi Jews. These results contrast with the ones we found (1/1550) in a sample of 3100 healthy subjects originating from 15 populations of southern Europe. Six microsatellite markers were used in the 20 G2019S carriers we found, to conduct a haplotype analysis. Our finding on the elevated incidence of the G2019S mutation in North African Arabs and in Sephardi Jews, Berbers being the people where the mutation probably originates from, has some important consequences for future genetic diagnosis and counseling for PD in these populations.     

African Glucose-6-Phosphate Dehydrogenase Alleles Associated with Protection from Severe Malaria in Heterozygous Females in Tanzania

X-linked Glucose-6-phosphate dehydrogenase (G6PD) A- deficiency is prevalent in sub-Saharan Africa populations, and has been associated with protection from severe malaria. Whether females and/or males are protected by G6PD deficiency is uncertain, due in part to G6PD and malaria phenotypic complexity and misclassification. Almost all large association studies have genotyped a limited number of G6PD SNPs (e.g. G6PD202 / G6PD376), and this approach has been too blunt to capture the complete epidemiological picture. Here we have identified 68 G6PD polymorphisms and analysed 29 of these (i.e. those with a minor allele frequency greater than 1%) in 983 severe malaria cases and controls in Tanzania. We establish, across a number of SNPs including G6PD376, that only female heterozygotes are protected from severe malaria. Haplotype analysis reveals the G6PD locus to be under balancing selection, suggesting a mechanism of protection relying on alleles at modest frequency and avoiding fixation, where protection provided by G6PD deficiency against severe malaria is offset by increased risk of life-threatening complications. Our study also demonstrates that the much-needed large-scale studies of severe malaria and G6PD enzymatic function across African populations require the identification and analysis of the full repertoire of G6PD genetic markers.     

Origin and spread of the glucose-6-phosphate dehydrogenase variant (G6PD-Mediterranean) in the Middle East.

A common glucose-6-phosphate dehydrogenase (G6PD) variant characterized by severe enzyme deficiency and B-like electrophoretic mobility is called "G6PD-Mediterranean" because it is found in different populations around the Mediterranean Sea. Sequence analysis of Italian subjects has revealed that the molecular basis of G6PD-Mediterranean is a single C-T transition at nucleotide position 563, causing a serine phenylalanine replacement at amino acid position 188. Most G6PD-Mediterranean subjects also have a silent C-T transition (without amino acid replacement) at nucleotide position 1311. Twenty-one unrelated individuals from Saudi Arabia, Iraq, Iran, Jordan, Lebanon, and Israel with both severe G6PD deficiency and B-like electrophoretic mobility were tested for both mutations by using amplification followed by digestion with appropriate restriction enzymes. All but one had the 563 mutation, and, of these, all but one had the 1311 mutation. Another 24 unrelated Middle Eastern individuals with normal G6PD activity or not known to be G6PD deficient were similarly tested. Four had the silent mutation at position 1311 in the absence of the deficiency mutation at position 563. We conclude that (1) the large majority of Middle Eastern subjects with the G6PD-Mediterranean phenotype have the same mutation found in Italy, (2) the silent mutation is an independent polymorphism in the Middle East, with a frequency of about .13, and (3) the mutation leading to the G6PD-Mediterranean deficiency has probably arisen on a chromosome that already carried the silent mutation.     

Do tribal communities show an inverse relationship between sickle cell disorders and glucose-6-phosphate dehydrogenase deficiency in malaria endemic areas of Central-Eastern India?

Tribal communities in India constitute the largest tribal population in the world. There are about 635 biological isolates (tribes and subtribes), which constituted 8.08% (about 84.3 million) of the total population of India as per the 2001 census. Out of 635 scheduled tribes (aborigines), 62 live in the state of Orissa alone forming about 10.8% of the tribal population of India. Orissa state occupies an important place, being the 3rd in rank for the highest concentration of tribal population in the country. In India, tribal communities are highly vulnerable to hereditary diseases and have a high degree of malnutrition, morbidity and mortality. The sickle cell haemoglobinopathy and glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency are important genetic and public health problems in Central-Eastern part of India. In order to map out these genetic disorders among the tribal people, a cross-section of 15 major tribal communities from different parts of Orissa was randomly screened for haemoglobin variants and G6PD deficiency. The high frequency of sickle cell haemoglobinopathy (0-22.4%) and G6PD deficiency (4.3-17.4%), with beta-thalassemia trait (0-8.5%) taking almost an intermediate position, was observed. For G6PD deficiency, hemizygous males as well as female heterozygotes and female homozygotes were detected. Twelve cases showed compound heterozygosity for sickle cell haemoglobinopathy and G6PD deficiency. There seems to be a trend towards an inverse relationship between the sickle cell allele and G6PD deficiency, and sickle cell and beta-thalassemia allele in a cross-section of malaria endemic (Plasmodium falciparum) tribal communities in Orissa. When the frequency of sickle cell allele decreases in a cross-section of malaria endemic tribal population, the frequency of G6PD enzyme deficiency and beta-thalassemia allele increases and vice versa. Natural selection had played a major role in favour of sickle cell, beta-thalassemia and G6PD mutation alleles so that they had probably evolved as a protective mechanism against the lethal effects of malaria in this part of the country. However, the calculated values of 0.074, 0.218 and 0.337, respectively, of Pearson's correlation co-efficient (r), showed no correlation between sickle cell disorders and G6PD deficiency, sickle cell disorders and beta-thalassemia, and G6PD deficiency and beta-thalassemia.     

The prevalence of factor V Leiden,prothrombin G20210A and methylenetetrahydrofolate reductase polymorphism C677T among G6PD deficient individuals from Western Iran

It has been suggested that the allele frequency of thrombophilic mutations is affected by glucose-6-phosphate dehydrogenase (G6PD) deficiency. The prevalence of thrombophilic mutations were studied in sixty G6PD deficient individuals including 57 males and three females with the mean age of 15 ± 3.08 and 110 age and sex matched healthy individuals consisted of 95 males and 15 females with the mean age of 16.19 ± 2.17 from the Kermanshah Province of Iran. Using a combination of PCR-RFLP technique, single strand conformation polymorphism (SSCP) analysis and DNA sequencing polymorphic G6PD mutations were identified. The factor V Leiden, prothrombin G20210A and methylenetetrahydrofolate reductase (MTHFR) C677T were detected by PCR-RFLP method using MnlI, HindIII and HinfI restriction enzymes, respectively. Three mutations, G6PD Mediterranean, G6PD Chatham and G6PD Cosenza were identified in 60 G6PD deficient individuals with highest prevalence of G6PD Mediterranean (91.6%). In G6PD deficient individuals the prevalence of factor V Leiden tended to be higher (5%) compared to healthy individuals (2.7%). The prevalence of prothrombin G20210A mutation in G6PD deficient individuals was 1.7%. However, in normal subjects the prevalence of this mutation was 2.7%. The frequency of T allele in G6PD deficient individuals were insignificantly higher (29.16%) than those in healthy individuals (26.8%). Our finding indicates that the prevalence of factor V Leiden, prothrombin G20210A and MTHFR C677T in G6PD deficient individuals is not statistically different compared to normal subjects and G6PD deficiency is not associated with these thrombophilic mutations in Western Iran.