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.     

Alpha-1 antitrypsin gene polymorphism in Chronic Obstructive Pulmonary Disease (COPD)

Alpha-1-antitrypsin (AAT) plays an important role in the pathogenesis of emphysema, the pathological lesion underlying the majority of the manifestations of Chronic Obstructive Pulmonary Disease (COPD). In this study we tested the hypothesis that common AAT polymorphisms influence the risk of developing COPDs. We investigated PiM1 (Ala213Val), PiM2 (Arg101His), PiM3 (Glu376Asp), PiS (Glu264Val) and PiZ (Glu342Lys) SERPINA1 alleles in 100 COPD patients and 200 healthy controls. No significant differences were observed in allele frequencies between COPD patients and controls, neither did haplotype analysis show significant differences between the two groups. A cross-sectional study revealed no significant relationship between common SERPINA1 polymorphisms (PiM1, PiM2, PiM3) and the emphysematous type of COPD. In addition, FEV(1) annual decline, determined during a two-year follow up period, revealed no difference among carriers of the tested polymorphisms.     

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 in North American species of Canis

alpha 1-Antitrypsin (A1AT) is a major protease inhibitor present in all mammalian sera that have thus far been investigated. A1AT is also highly polymorphic and is therefore a useful genetic marker. Previously reported A1AT polymorphism in domestic dogs consisted of two alleles designated as PiM and PiS which exhibited frequencies of 0.72 and 0.28, respectively, in a group of randomly collected mongrel dogs. North American species of Canis, which included gray wolves (n = 29), Mexican wolves (n = 20), coyotes (n = 24), wolf-dog crosses (n = 9), and red wolves (n = 27) were tested for A1AT polymorphism. A1AT phenotypes were determined by isoelectric focusing, followed by direct immunoblotting using a specific antiserum. A1AT concentrations were determined by radial immunodiffusion. Concentrations of A1AT were similar to those found in domestic dogs (2.26 +/- 0.3, +/- SD mg/ml, +/- SD) and tended to be higher in females than in males, possibly indicating that A1AT may be hormonally influenced in females. Three phenotypic band patterns were observed (M, MS, S). The allele frequencies for domestic dogs and gray wolves were very similar, 0.72 and 0.67 for PiM and 0.28 and 0.33 for PiS, respectively. The Mexican wolves had a significantly lower frequency of PiS = 0.10. Coyotes and red wolves were all found to be monomorphic for the PiS allele and were indistinguishable from each other in that respect.     

Variants of the mannose-binding lectin gene in the Benin population: heterozygosity for the p.G57E allele may confer a selective advantage

Human mannose-binding lectin (MBL) plays an important role in innate immunity. MBL deficiency is associated with mutations in the promoter region and in exon 1 of the MBL2 gene. Such deficiency has been correlated with elevated incidence of infections in infancy and in immunocompromised adults. We determined the distribution profile of the MBL2 gene variants in the general population of Benin (West Africa) and in a vulnerable subset of children with sickle cell disease (SCD) (SS homozygotes). Five hundred forty-two healthy individuals (274 newborns, 268 adults) and 128 patients with SCD (35 newborns, 93 children) were screened for the common variant alleles in the MBL2 secretor haplotype region (exon 1 and promoter). The p.G57E variant allele was the most frequent allele compared to p.G54D (27.5% vs. 1.6%, respectively). The p.R52C allele was not found in this population. There was no difference in allele or genotype frequencies between healthy newborns and newborns with SCD. Alleles associated with MBL deficiency were more frequent in adults than in newborns (69.8% vs. 57.3%, respectively; p = 0.002). This enrichment was exclusively due to an elevated proportion of heterozygotes for the p.G57E allele (47.0% vs. 35.3%, respectively; p = 0.004), supporting a potential selective advantage of this genotype. Our results, compared to those reported in other African countries, support the implication of the MBL2 gene in various major infections in Africa, such as meningitis and tuberculosis in HIV-positive patients.     

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.     

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.     

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.     

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.     

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.     

Genetic variants of serum alpha1-antitrypsin (Pi types) in Portuguese.

The results of Pi typing on 330 Portuguese from the area of Lisbon are reported. We found six phenotypes and four alleles out of the 24 described in the literature. The allele PiM is the most frequent as in other populations, PiS shows a high frequency (0.1152), and PiF is absent, which agrees satisfactorily with former studies carried out in Spain. These results are compared with others and the entity of the Iberian population is evoked.     

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.     

Protease inhibitor system in horses: classification and detection of a new allele

A method of horizontal thin layer polyacrylamide gel electrophoresis at acid pH has been developed for the separation of the prealbumins in equine plasma. Using this method, it has been possible to split the S allele into two, S₁ and S₂, bringing the total number of prealbumin alleles in Thoroughbred horses to eight. The gene frequencies of these eight alleles in Australian Thoroughbreds are presented. All eight prealbumin types exhibit antiprotease activity and therefore, it is suggested that the name prealbumin (Pr) should be abandoned in favour of protease inhibitor (Pi) although at this stage it is not known whether this incorporates the Pi1 and Pi2 described by Juneja et al. (1979).     

An alpha 1-antitrypsin variant, Pi B Alhambra (Lys to Asp, Glu to Asp), with rapid anodal electrophoretic mobility.

A variant of human alpha 1-antitrypsin (alpha 1 AT) was found by acid starch gel electrophoresis and by thin-layer electrofocusing. The variant has an anodal migration velocity almost identical to PiB. It is designated as Pi B Alhambra. Pi B Alhambra was purified to homogeneity from a heterozygous PiM1/PiB Alhambra subject. Specific trypsin inhibitory activity and composition of amino acids and carbohydrates were similar to those of normal PiM1. The structural difference between the normal and the variant inhibitors was elucidated by peptide mapping of their tryptic digests. Two amino acid substitutions, Lys to Asp and Glu to Asp, were found. The amino acid substitution, Gly to Asp, has been found in a common PiM2 variant [1]. The Pi B Alhambra variant presumably originated by two steps of mutation: generation of PiM2 from wild type PiM1 by the substitution Gly to Asp, and subsequent generation of Pi B Alhambra from PiM2 by another substitution, Lys to Asp.     

Allelotyping the Hras1 minisatellite: formation of carcinogenic risk groups and predicting the course of non-small cell lung cancer]

PCR-based typing of Hras1 minisatellite alleles was carried out in 226 non-small cell lung cancer (NSCLC) patients and 207 unaffected controls. Application of this method permitted detection of four common (a1 to a4) and 25 other alleles, differing from any common allele by one or more repeat units. Depending on their frequency in control group, these alleles were defined as intermediate or rare (the frequency over 0.5% or less than 0.5%, respectively). It was established that the frequency of rare alleles in the group of NSCLC patients (7.1%) was statistically significantly higher than in healthy individuals (2.2%, p = 0.002), while the difference in the distribution of common and intermediate alleles between the compared groups was not statistically significant. In addition, rare Hras1 alleles were more frequent (p = 0.02) among nonsmoking patients compared to the patients subjected to of tobacco carcinogens. The presence of "heavy" (a3-a4) alleles was associated with an increased risk of low-differentiated and/or actively metastasizing tumors and also with the risk of lung cancer in the patients under 50 years of age (p < 0.05). These data indicate that an approach including application of modern highly sensitive techniques of Hras1 allele typing in combination with preliminary examination of healthy control population can be employed for identifying carcinogenic risk groups as well as for prognosis of the NSCLC clinical course.     

Do supervised weekly exercise programs maintain functional exercise capacity and quality of life, twelve months after pulmonary rehabilitation in COPD?

Background

Individuals with severe Z α1-antitrypsin (AAT) deficiency have a considerably increased risk of developing chronic obstructive lung disease (COPD). It has been hypothesized that compensatory increases in levels of other protease inhibitors mitigate the effects of this AAT deficiency. We analysed plasma levels of AAT, α1-antichymotrypsin (ACT) and secretory leukocyte protease inhibitor (SLPI) in healthy (asymptomatic) and COPD subjects with and without AAT deficiency.

Methods

Studied groups included: 71 asymptomatic AAT-deficient subjects (ZZ, n = 48 and SZ, n = 23, age 31 ± 0.5) identified during Swedish neonatal screening for AAT deficiency between 1972 and 1974; age-matched controls (MM, n = 57, age 30.7 ± 0.6); older asymptomatic ZZ (n = 10); healthy MM (n = 20, age 53 ± 9.6); and COPD patients (ZZ, n = 10, age 47.4 ± 11 and MM, n = 10, age 59.4 ± 6.7). Plasma levels of SLPI, AAT and ACT were analysed using ELISA and immunoelectrophoresis.

Results

No significant difference was found in plasma ACT and SLPI levels between the healthy MM and the ZZ or SZ subjects in the studied groups. Independent of the genetic variant, subjects with COPD (n = 19) had elevated plasma levels of SLPI and ACT relative to controls (n = 153) (49.5 ± 7.2 vs 40.7 ± 9.1 ng/ml, p < 0.001 and 0.52 ± 0.19 vs 0.40 ± 0.1 mg/ml, p < 0.05, respectively).

Conclusion

Our findings show that plasma levels of ACT and SLPI are not elevated in subjects with genetic AAT deficiency compared MM controls and do not appear to compensate for the deficiency of plasma AAT.     

Genotype dependence of cytogenetic and epidemiological characteristics in the liquidators of the accident at the ChNPP

The dependence of the level of unstable chromosome aberrations and nononcological diseases on the genotype in 57 liquidators of the ChNPP accident was studied. Candidate genes presumably affecting radiosensitivity were highly polymorphic loci of xenobiotic detoxication genes (glutathione-S-transferases GSTM1, GSTT1, GSTP1) and the 5,10-methylenetetrahydrofolate reductase gene (MTHFR) involved in DNA methylation and synthesis. An increased frequency (0.014 +/- 0.001 per cell) of unstable chromosome aberrations, including radiation-specific dicentrics and centric rings (0.0015 +/- 0.0002 per cell), has been found to be preserved in the group of liquidators examined in 2006-2007. No associations of polymorphism for each of the studied genes with cytogenetic parameters were revealed. Increased frequencies of chromosome aberrations were recorded in homozygous carriers of a deletion at the GSTM1 locus in combination with homozygosity for minor alleles at the MTHFR and GSTP1 loci (p = 0.00002 and p = 0.0233, respectively). The number of homozygous carriers of the minor allele GSTP1 was increased among patients with chronic obstructive pulmonary disease and in liquidators with acute circulation disturbances (p = 0.014 and p = 0.04, respectively). Double homozygotes for GSTM1 and GSTT1 deletions were significantly more frequent among subjects with benign tumors (cysts, polyps, p = 0.015) and with benign thyroid tumors (p = 0.017). This genotype has proved to be protective for patients with severe cardiovascular diseases (acute circulation disturbances, p = 0.027).     

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).