α1 (Pi) types and subtypes in the Tyrolean population

Since nine patients with infantile liver cirrhosis or hepatopathy associated with the Pi ZZ phenotype had been observed in recent years in the Children's Hospital of the University of Innsbruck, Tyrol, the distribution of the Pi types and the PiM subtypes was determined in the Tyrolean population. Apparently healthy blood donors (868) from different regions of Tyrol were examined. Isoelectricfocusing was used for classification of Pi types. The frequency of the allele PiZ was 0.0138, which corresponded to the range observed in other Middle European populations. The frequencies for the suballeles of PiM were PiM1 = 0.7062, PiM2 = 0.1480, and PiM3 = 0.1037. PiS had a frequency of 0.0225, the other rare alleles occurred with a combined frequency of 0.0058.     

Genetic polymorphism of the alpha 1-antitrypsin system in the native population of the Kazakh SSR

Phenotypes of alpha 1-antitrypsin of 218 natives from three ethno-historical regions of the Kazakh SSR were detected by isoelectric focusing in ultrathin layer polyacrylamide gel. Gene frequencies of the PiM1, PiM2, PiM3 subtypes in the summary extract were as follows: 0.8477, 0.1372 and 0.0106, respectively; the total gene frequency of two rare variants (PiN and PiZ) was 0.0046. The observed distribution of Pi subtypes shows good agreement with the Hardi-Weinberg equation. The analysis of the interpopulation intraethnic variability of the alpha 1-antitrypsin phenotype and allele frequencies in Kazakhs revealed clear local diversity. The frequency of PiM1 in the natives from North-Central ethno-historical region was reliably lower and that of PiM2 higher than in populations from South-East and West regions. The extracts analysed did not differ in the PiM3 incidences. The results of these studies were compared with the literature data for alpha 1-antitrypsin polymorphism in populations of the Euro-Asia. It is shown that PiM1 and PiM2 frequencies in the Kazakhs differ from the corresponding mean values both in mongoloid and europeoid groups. At the same time, they do not correspond to the intermediate frequency estimations, which could be expected from the fact of mixed origin of the Kazakh people and their border-line geographical position between Europe and Asia. Possible reason for such discrepancy is discussed.     

Reliable classification of six Pi M subtypes by separator isoelectric focusing.

For the first time, segregation of three common PiM alleles in family material is verified by application of separator isoelectric focusing. A new nomenclature system for the Pi M subtypes is used, whereby the common subtypes are designated according to their physicochemical properties; the most anodal type is called Pi M1, the intermediary one Pi M2, and the most cathodal variant Pi M3 (previously called Pi M2). Pi gene frequencies from Finnish, Dutch and Black populations are presented. The PiM2 allele was rather high in Finns (0.12) but low (0.04) in the West African Bozo. The PiM3 was found with a frequency of 0.13 in Dutch, 0.08 in Finns and 0.02 in Bozo. A previous Finnish sample was retested with the new subtyping method and the six-subtype distribution was found to be in good Hardy-Weinberg equilibrium. The validity of the Pi polymorphism for population genetics, linkage analysis and parentage testing is discussed.     

alpha1-antitrypsin: common subtypes of Pi M.

More than 20 different alleles are so far known at the Pi locus, corresponding to a total variant phenotype frequency of about 10% in most western Europeans. The common phenotype Pi M constitutes the remaining major group. Now it has been possible to identify three subtypes M1, M1M2 and M2, corresponding to the gene products of two common alleles PiM1 and PiM2, segregating as autosomal codominant alleles. Preliminary gene frequencies are reported for eight populations, the PiM2 frequency varying from 0.20 in Maris (USSR) to 0.02 in Bantus (Kenya).     

Polymorphism of alpha-1-antitrypsin (Pi) in the Swiss population determined by isoelectric focusing with an immobilized pH gradient

The distribution of the phenotypes of alpha-1-antitrypsin (Pi) was investigated in a Swiss population sample of 1,148 unrelated individuals using isoelectric focusing with a immobilized pH gradient. A short focusing period of only 2 h using high-voltage is an additional asset of this modified method. All common as well as the rarer phenotypes were reliably detected. However, detection of Pi M4 required a narrower pH range as chosen for routine work. The allele frequencies found were: PiM1:0.7121; PiM2:0.1381; PiM3:0.0976; PiS:0.0383; PiZ:0.0113; PiVar(I, N, V.Vdon):0.0026.     

Alpha-1-antitrypsin: frequencies of PiM subtypes and serum concentration in the Japanese population

PiM subtypes were determined by isoelectric focusing of the sera of 746 Japanese at the age of 16-60 years. The gene frequencies were calculated: PiM1 = 0.7855, PiM2 = 0.1528 and PiM3 = 0.0617. The serum concentration of alpha-1-antitrypsin was measured by laser-nephelometric immunoassay of the sera of 284 individuals. A statistically significant difference (p less than 0.01) in the serum concentration was found between M1 (2.63 +/- 0.67 g/l) and M1M2 (2.39 +/- 0.59 g/l).     

Alpha1-antitrypsin: further genetic heterogeneity revealed by isoelectric focusing.

Alpha1-antitrypsin is a major human serum protein that shows an extensive polymorphism. Genetic heterogeneity has previously been demonstrated by starch gel electrophoresis. By applying analytical isoelectric focusing (pH 3.5--5.0) to this system, we found a common variant, Pi M3, with an isoelectric point between those of Pi M1 and Pi M2. The gene frequency of this variant was .11 in U.S. whites and .054 in blacks. When PiM3 and PiM1 are included in the Pi system, the heterozygosity at the Pi locus is five times greater in whites and 10 times greater in blacks than that detected by earlier electrophoretic techniques.     

Distribution of alpha-1-antitrypsin phenotypes in Sweden

The distribution of phenotypes of alpha-1-antitrypsin (Pi) in 1,062 unrelated Swedes was determined by isoelectric focusing with carrier ampholytes. The frequencies calculated were: PiM1 = 0.6940, PiM2 = 0.1384, PiM3 = 0.1139, PiZ = 0.0231, PiS = 0.0245, PiF = 0.0038, Pivar = 0.0024. A mother-child material consisting of 194 pairs is also presented.     

Inheritance of PiM subtypes. A study of 151 families with a total of 242 children and of 142 mother-child pairs.

Pi phenotypes were classified by isoelectric focusing in sera of 151 families with a total of 242 children and in sera of 142 mother-child pairs. The six common subtypes of PiM are genetically determined by three alleles named PiM1, PiM2, and PiM3. No exceptions to the postulated mode of inheritance have been found. The possibility of further heterogeneity of the intermediate variant PiM3 is discussed.     

Distribution of alpha-1-antitrypsin (Pi) phenotypes in Denmark determined by separator isoelectric focusing in agarose gel

The distribution of phenotypes of alpha 1-antitrypsin (Pi) in 909 unrelated Danes was determined by the use of separator isoelectric focusing in agarose gel. The frequencies calculated were: PiM1 = 0.728, PiM2 = 0.136, PiM3 = 0.082, PiZ = 0.023, PiS = 0.022, PiF = 0.006, Pivar = 0.003. The segregation of phenotypes in 39 families with 94 children is presented. The advantages and disadvantages of the method are discussed.     

Gc and Tf subtypes in Greece

PAGIF was used to investigate the distribution of Gc and Tf subtypes in a Greek population sample. The gene frequencies were compared to those reported for other European populations.     

Analysis of common CFTR polymorphisms 5T, M470V and R75Q in healthy Serbian population

Three common CFTR polymorphisms, 5T, M470V and R75Q, have been shown to be relatively frequent in Serbian patients with monosymptomatic CF disorders. Since there is a variation in distribution of common polymorphisms among different populations, it was important to compare their frequencies in patients with the frequencies in healthy population in order to assess the possible role of these polymorphisms in the monosymptomatic CF disorders. Samples obtained from 100 healthy Serbian individuals were analyzed for the presence of CFTR 5T, M470V and R75Q variants by PSM, RFLP and DGGE methods, respectively. Allele 5T was present in two individuals, giving the allelic frequency of 1% (2/200 alleles). The frequency obtained for allele M470 was 45% (90/200 alleles), while V470 allele was present with the frequency of 55% (110/200 alleles). Polymorphism R75Q was present in two individuals, with allelic frequency of 1% (2/200 alleles). Our study has shown that the frequencies of two common polymorphisms, 5T and M470V, differ significantly in Serbian population in comparison with other South European populations. Since it appears that Serbian population has a specific distribution of studied CFTR gene variants, it would also be interesting to analyze other common variants of this gene in our population. Such data can also be potentially useful as anthropogenetic markers in population studies.     

Polymorphisms of DNA repair genes ERCC2 and XRCC1 in populations of Russia

We have conducted a comparative study of allele frequencies of single nucleotide polymorphisms (SNPs) rs1799793 and rs13181 of the ERCC2 gene as well as rs1799782 and rs25487 of the XRCC1 gene in population samples from European regions of Russia as well as in populations of Izhemsk and Priluzsk Komi and Yakuts. Significant differences in the distribution of polymorphic variants of the ERCC2 gene were demonstrated between populations of Yakuts and populations of Russians and Komi. In case of XRCC1 gene Izhemsk Komi population exhibited dissimilar allele frequencies compared to other populations.     

Rare variants of blood proteins in human populations

Rare variants of blood proteins occur, due to mutations (mutant alleles) in monomorphic loci encoding various proteins. A number of authors studied the distribution of these variants in human populations using the method of electrophoresis. The population of USA, South America, Japan, Europe was analysed. 1334 rare variants (1.0.10(-3)) were discovered out of 1,329,558 alleles (test locus in 664,779 individuals). 7 mutant alleles (3.6.10(-6)) were found among 1,957,305 alleles. The low frequency of occurrence of mutations in the loci encoding rare blood protein variants, when testing the speed of mutagenicity and its alteration, necessitates electrophoresis of blood proteins to be done in large scales. A method was proposed, based on accounting rare variants in children with congenital disorders, which are supposed to have a heavy load of mutations. The data collected demonstrated that the majority of rare variants in a given generation were obtained from parents. Accumulation of rare protein variants at low concentrations, as neutral alleles, in conditions of low mutation frequency in monomorphic loci takes place in the population. Comparison of frequencies of rare variants among healthy newborns and the children with congenital disorders revealed their identity (1.0.10(-3)), as compared to 1.05.10(-3)). Simplification of the method for scoring mutations judging by rare blood protein variants, which is necessary for monitoring for gene mutations in human populations, stimulates development of novel approaches.     

Subtypes of serum group specific component (Gc) in normal conditions and in pathology

In the framework of the ecogenetic research programme, the data are presented on the genetic polymorphism of the vitamin D-binding protein (Gc) in various USSR populations. Blood serum samples were studied, taken from the Russians of the town Yegorievsk, Moscow Region (p = 321) and 113 Russian patients with tuberculosis using the method of isoelectrofocusing. The information was obtained of the Gc frequencies in two population units of Buryats of Aginsky and Ost-Ordynsky Autonomous Districts of Chita and Irkutsk Regions, including the Olkhon island (on the lake Baikal), in totality, 593 individuals and 13 local groups. The position of the studied Russian and Buryat groups within the gene frequency co-ordinate space is well in line with the estimated area of their localization, with regard to the world distribution. Among the Buryat populations studied, there is distinct heterogeneity for which the factor Gc1F plays a leading role within the Gc system/responsible for 92% of all possible genetic variability. Gc factor frequencies in Buryats range within the following limits: 1F.-0.3864-0.6023, 1S-0.1895-0.4535, 2-0.1364-0.2581. For the Russians of Yegorievsk and the patients with tuberculosis of Moscow and Moscow Region following allele frequencies are established: 1-F0.1169, 1S-0.5476, 2-0.1364 and 1F-0.1106, 1S-0.5531, 2-0.3363, respectively, which indicates that no association exists between Gc variants and tuberculosis. The correlation of the Gc allele frequency distribution with the ratio of insulin-independent diabetes (type 2) world-wide indicates that expression of high frequency of diseases is accompanied with comparatively rare characteristic combination of frequencies of three Gc alleles.     

Alpha-1-antitrypsin phenotypes in newborns from Central and Southern Italy.

The results of Pi typing on 500 infants from Central and Southern Italy are reported. Phenotype determinations were performed on umbilical cord serum. We observed nine different phenotypes; each of these is present in other European populations. The frequencies of the Pi alleles in our group were found to be, on the whole, comparable to those found in other populations widely separated geographically. However, the frequency of the Pi S gene in our sample (0.0670) was greater than that observed in Northern and Central European and American groups. Our Pi S frequency was similar to that found in a French group and lower than that of Spanish and Portuguese groups. Our data thus confirm the higher Pi S gene frequency in Latin populations.     

alpha1-Antitrypsin variants in different racial groups in Malaysia.

In a study of Malaysians of different racial groups, 1,510 sera (908 from Malays, 371 from Chinese and 231 from Indians) were identified for their protease inhibitor (Pi) types. The gene frequencies for the alleles PiM, PiS and PiX in Malays were, respectively, 0.979, 0.015, and 0.007. In Chinese, the frequencies were 0.981, 0.019 and 0.000, and in Indians they were 0.976, 0.24, and 0.000. It is interesting that the usually rare PiX type is found in appreciable frequency in the Malays. Two different types with unusual behavior and obscure origin were also found.     

Polymorphism of alpha-1-antitrypsin in hematological malignancies

Alpha-1-antitrypsin (AAT) or serine protease inhibitor A1 (SERPINA1) is an important serine protease inhibitor in humans. The main physiological role of AAT is to inhibit neutrophil elastase (NE) released from triggered neutrophils, with an additional lesser role in the defense against damage inflicted by other serine proteases, such as cathepsin G and proteinase 3. Although there is a reported association between AAT polymorphism and different types of cancer, this association with hematological malignancies (HM) is, as yet, unknown. We identified AAT phenotypes by isoelectric focusing (in the pH 4.2-4.9 range) in 151 serum samples from patients with HM (Hodgkins lymphomas, non-Hodgkins lymphomas and malignant monoclonal gammopathies). Healthy blood-donors constituted the control group (n = 272). The evaluated population of patients as well as the control group, were at Hardy-Weinberg equilibrium for the AAT gene (χ(2) = 4.42, d.f.11, p = 0.96 and χ(2) = 4.71, d.f.11, p = 0.97, respectively). There was no difference in the frequency of deficient AAT alleles (Pi Z and Pi S) between patients and control. However, we found a significantly higher frequency of PiM1M1 homozygote and PiM1 allele in HM patients than in control (for phenotype: f = 0.5166 and 0.4118 respectively, p = 0.037; for allele: f = 0.7020 and 0.6360 respectively, p = 0.05). In addition, PiM homozygotes in HM-patients were more numerous than in controls (59% and 48%, respectively, p = 0.044). PiM1 alleles and PiM1 homozygotes are both associated with hematological malignancies, although this is considered a functionally normal AAT variant.     

Classification of α 1-antitrypsin (Pi) phenotypes by isoelectrofocusing

Summary Pi phenotypes have been determined by isoelectrofocusing in a sample of 538 healthy individuals from Southern Germany. Further subdivision of the common PiM phenotype is described. A procedure for the delineation of six common subtypes is presented. It is assumed that the six subtypes are determined by three alleles which are provisionally called Pi^Ma, Pi^Mb, and Pi^Mc. Their frequencies in this sample were 0.75, 0.06, and 0.15, respectively.Supported in part by INSERM, contract No. AT-FA-58     

Polymorphisms of DNA repair genes <Emphasis Type="Italic">ERCC</Emphasis>2 and <Emphasis Type="Italic">XRCC</Emphasis>1 in populations of Russia

We have conducted a comparative study of allele frequencies of single nucleotide polymorphisms (SNPs) rs1799793 and rs13181 of the ERCC2 gene as well as rs1799782 and rs25487 of the XRCC1 gene in population samples from European regions of Russia as well as in populations of Izhemski and Priluzski Komi and Yakuts. Significant differences in the distribution of polymorphic variants of the ERCC2 gene were demonstrated between populations of Yakuts and populations of Russians and Komi. In case of XRCC1 gene Izhemski Komi population exhibited dissimilar allele frequencies compared to other populations.