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Eur Respir J 2006; 27:77-84
Copyright ©ERS Journals Ltd 2006

Estimated numbers and prevalence of PI*S and PI*Z alleles of {alpha}1-antitrypsin deficiency in European countries

I. Blanco1, F. J. de Serres2, E. Fernandez-Bustillo3, B. Lara4 and M. Miravitlles4

1 Internal Medicine Division, Respiratory Diseases Branch, Hospital Valle del Nalon, Langreo, Principado de Asturias, 3 Bio-statistics Unit, Hospital Universitario Central de Asturias, Oviedo, Principado de Asturias, and 4 Servei de Pneumologia, Institut Clinic del Torax, IDIBAPS, Red Respira RTIC 03/11 ISCIII, Hospital Clinic, Barcelona, Catalonia, Spain. 2 Laboratory of Molecular Toxicology, Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.

CORRESPONDENCE: I. Blanco, Dept of Internal Medicine, Respiratory Diseases Branch, Hospital Valle del Nalón, 33920 Langreo, Principado de Asturias, Spain. Fax: 34 985652006. E-mail: ignacio.blanco{at}sespa.princast.es/ignablanco{at}yahoo.es

Keywords: {alpha}1-Antitrypsin deficiency, {alpha}1-protease inhibitor, Europe, genetic epidemiology, protease inhibitor phenotypes

Received: May 30, 2005
Accepted August 15, 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The current study focuses on developing estimates of the numbers of individuals carrying the two most common deficiency alleles, PI*S and PI*Z, for {alpha}1-antitrypsin deficiency (AT-D) in Europe.

Criteria for selection of epidemiological studies were: 1) AT phenotyping performed by isoelectrofocusing or antigen–antibody crossed electrophoresis; 2) rejection of "screening studies"; 3) statistical precision factor score of ≥5 for Southwest, Western and Northern Europe, ≥4 for Central Europe, ≥3 for Eastern Europe; and 4) samples representative of the general population.

A total of 75,390 individuals were selected from 21 European countries (one each from Austria, Belgium, Latvia, Hungary, Serbia-Montenegro, Sweden and Switzerland; two each from Denmark, Estonia and Lithuania; three each from Portugal and the UK; four each from Finland, the Netherlands, Norway and Spain; five each from Russia and Germany; six from Poland; eight from Italy; and nine from France). The total AT-D populations of a particular phenotype in the countries selected were: 124,594 ZZ; 560,515 SZ; 16,323,226 MZ; 630,401 SS; and 36,716,819 MS. The largest number of ZZ (5,000–15,000) were in Italy, Spain, Germany, France, the UK, Latvia, Sweden and Denmark, followed by Belgium, Portugal, Serbia-Montenegro, Russia, The Netherlands, Norway and Austria (1,000–2,000), with <1,000 in each of the remaining countries.

A remarkable lack in number of reliable epidemiological studies and marked differences among these European countries and regions within a given country was also found.

Although {alpha}1-antitrypsin (AT) deficiency (AT-D) is one of the most common hereditary disorders in Europe, AT-D prevalence varies markedly from one country to another, as well as from one region to another within a given country 1.

AT is the most prevalent proteases inhibitor in the human serum, and is secreted mainly by hepatocytes 2. The AT gene is highly pleomorphic, with ~100 alleles having been identified to date. Variants are classified according to the protease inhibitor (PI) system, by means of isoelectrofocusing (IEF). Variants that confer an increased risk for developing diseases are those in which deficiency or null alleles are combined in homozygous or heterozygous states that encode AT plasma concentrations <60%. Most pathology related to AT-D is linked to the Z allele and, in clinical practice, 96% of patients have a ZZ phenotype 3–6. The remaining 4% mostly belongs to SZ, MZ and, in a smaller amount, to other rare deficiency or null phenotypes. The risk of developing diseases for PI SS and PI MS phenotypes has been the topic of longstanding controversy, but no clear evidence on the relationship among these phenotypes with AT-D-associated diseases has been established to date 2, 5, 6.

AT-D is not properly a disease, but a predisposition for the development of a number of diseases throughout life, mainly pulmonary emphysema and several types of hepatopathies in both children and adults 2, 3.

Knowledge of the AT-D prevalence in every community is essential from a public health perspective. The current study specifically attempts to determine estimates of the prevalence and number of subjects carrying the most common defective alleles, PI*S and PI*Z, in each of the individual European countries. The current study estimates the total number of ZZ, SZ and MZ individuals in each European country, and goes beyond earlier publications by others 7–10, in which only the allele frequencies for PI*M, PI*S and PI*Z were reported for individual cohorts in individual cities or geographical regions. Moreover, the present approach is a step beyond other recently published reports, where the numbers of subjects at risk were calculated from data reported by a mixture of reliable and unreliable epidemiological studies 1, 11.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Sources of the control cohort data used in the present study
The authors of the present study worked independently and with different methodological approaches on AT-D epidemiology, and have published their research in different peer-reviewed journals 1, 8, 9, 11. The authors' individual databases were combined to generate a common database used in the present meta-analysis. The present study utilises available data from epidemiological studies performed by others to determine the frequencies of deficiency allele combinations for PI*S and PI*Z, in the healthy control cohorts of individual case studies from European countries. The data from these individual cohorts for a given country were combined to obtain mean frequencies for the PI*M, PI*S and PI*Z alleles. The allele frequencies were then used to calculate the total numbers of individuals in each of the five major defective phenotypic classes of interest (namely, PI MS, PI MZ, PI SS, PI SZ and PI ZZ) in the total population of each of these countries and all of Europe.

The formulas for developing estimates of the allele frequencies gene prevalence, the numbers of deficiency allele combinations and 95% confidence intervals (95% CI) were discussed in several earlier papers 9, 11. Allele frequencies have been expressed as the total number of PI*S and PI*Z, whether in homo- or heterozygotes, per 1,000 alleles of all PI types.

The prevalence of each phenotype was calculated by applying the Hardy-Weinberg equilibrium statistical formula. The data on the number of individuals in different countries were obtained from the World Factbook database, updated in July 2004 12.

To assess the statistical reliability of each survey, the coefficient of variation for PI*S and PI*Z frequencies in each control cohort was calculated. This coefficient of variation provides an estimate of the precision (or better, the imprecision) of results from each survey. The formulas for developing estimates of numerical precision factor scores (PFS) to obtain a value scale from 0 to 12 with which to assess the statistical quality in terms of precision (or imprecision) of each selected survey were discussed in earlier papers 9, 11.

Criteria for selection of studies
Reliable selected studies for the present meta-analysis should fulfil the following criteria: 1) AT phenotyping performed by IEF or antigen–antibody crossed electrophoresis; 2) rejection of "screening studies"; 3) statistical precision factor score of ≥5 for Southwest, Western and Northern Europe, ≥4 for Central Europe, ≥3 for Eastern Europe; and 4) samples representative of the general population.

Criterion 1: Laboratory techniques for the phenotypic identification of PI*S and PI*Z deficiency alleles
In most of the selected surveys, phenotypic characterisation was carried out by means of the IEF method. This technique provides a reliable detection of individuals carrying either normal or S and Z variant alleles, but not null alleles. There is no evidence that the phenotypic identification of PI*S and PI*Z deficiency alleles in the IEF technique is complicated by phenocopies (i.e. mutations in other codons that would give a polypeptide chain with isoelectric points identical to those of the PI*S and PI*Z variants) 6. Thus, present evidence supports the widespread use of IEF for the rapid, inexpensive, and critical identification of the S and Z variants.

Starch gel electrophoresis is a less reliable method. The antigen–antibody crossed electrophoresis technique is an expensive and time-consuming method, and although it does give reliable results, since 1976, antigen–antibody crossed electrophoresis has been gradually replaced by IEF. To the current authors' knowledge, no studies from European IEF diagnosis were later corroborated with follow-up DNA-sequencing studies to provide confirmation at the molecular level.

Criterion 2: Screening studies
Surveys in which phenotypes were identified by selecting sera with AT serum levels below normal values were omitted because they could give an excessive number of Z alleles. In addition, they could introduce bias, as moderate deficiency phenotypes, such as MS, SS and MZ, could express AT serum concentrations over a given cut-off value.

Criterion 3: Numerical precision factor score for assessing the statistical quality in terms of precision (or imprecision) of each selected survey
As the coefficient of variation depends on the sample size and the PI*S and PI*Z allelic frequencies, the current authors used different cut-off values of PFS for European countries. In general, PI*Z frequencies in Europe range between 0 and 30 per 1,000, but PI*S frequencies fluctuate between a wider range of 5–150 per 1,000. Therefore, cohorts from countries having excessively high PI*S frequencies will give a deceptively higher PFS than others with much lower PI*S frequencies, but similar or higher PI*Z frequencies. Thus, PFS should be adapted for different regions and countries, adjusting the PFS rise by PI*S frequencies.

Consequently, the current authors considered that an appropriate value for the PFS for the Iberian Peninsula, Western Europe and Northern Europe (where PI*S frequencies are of ~25–150 per 1,000, and PI*Z frequencies are ~12–30 per 1,000) should be ≥5. An appropriate PFS for Central Europe (where PI*S frequencies decrease to 15–30 per 1,000, and PI*Z frequencies are ~5–10 per 1,000) should be ≥4. Finally, for Eastern and far distant regions of Southern and Northern Europe (where both PI*S and PI*Z frequencies are very low), the current authors have accepted a PFS value of ≥3 for selection.

Criterion 4: Cohort composition
Only the data of the control group cohort phenotypes in each paper (i.e. blood donors, workers, healthy unrelated persons, newborns, school or college students, general population selected at random, etc.) were used in the present study. Most individuals from selected cohorts were Caucasians, except a cohort of Lapps from Finland. Surveys carried out on hospital-based populations or in patients with AT-D related diseases (i.e. lung and liver diseases) were omitted because they could give an excessive number of Z-deficient alleles. It should be pointed out that a number of studies carried out in small isolated communities with small sample sizes, significant intermarriage and peculiar genetic traits were rejected due to their low PFS. Since most of these cohorts were not representative of the general population of a given country, these facts should not be considered a methodological defect, but an appropriate approach that should make the estimation more realistic. Examples of these former rejected studies were: Chuetas Jews from Majorca; Gypsies from Hungary; Aromunds, Musequiars, Pindonians, Moskopolians, Gramostians and Fraseriots from the Balkans, Romania, Greece, etc.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
A total of 68 out of 197 cohorts, having a total of 75,390 individuals, was selected from 21 countries in Europe 13–71. The mean PFS of these selected control cohorts gave a value of 6.9 on a scale of 0–12 points.

Selected studies were distributed as follows: one each from Austria 13, Belgium 14, Latvia 18, Hungary 34, Serbia-Montenegro 62, Sweden 67 and Switzerland 68; two each from Denmark 15, 16, Estonia 17, 18 and Lithuania 18, 41; three each from Portugal 53–56 and the UK 69–71; four each from Finland 19–22, the Netherlands 42–44, Norway 45–47 and Spain 62–66; five each from Russia 57–61 and Germany 29–33; six from Poland 48–53; eight from Italy 35–42; and nine from France 23–28.

With an estimated total population of 588,985,731 individuals for these 21 countries, the AT-D total population consisted of 124,594 (95% CI: 114,604–135,446) PI ZZ; 560,515 (95% CI: 522,960–600,730) PI SZ; 16,323,226 (95% CI: 15,637,279–17,038,228) PI MZ; 36,716,819 (95% CI: 35,677,978–37,783,871) PI MS; and 630,401 (95% CI: 596,592–666,087) PI SS phenotypes.

The data on total population, sample size, mean PFS, calculated frequencies for PI*S and PI*Z, and calculated prevalence in each country are shown for each of the selected countries (table 1Go). Estimates of the numbers of each of the five phenotypic classes for the deficiency alleles PI*S and PI*Z for each of the 21 countries in Europe are shown in table 2Go. Estimates of ZZ, SZ and MZ prevalence are given by means of isogenic lines (lines of equal gene prevalence) in maps shown in figures 1Go–Go3Go. The calculated numbers of ZZ, SZ and MZ individuals for every country are given graphically in figures 4Go–Go6Go for comparison.


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  		Table 1— Estimates of the protease inhibitor(PI)*S and PI*Z gene frequency and phenotype prevalence of each of the five phenotypic classes in the 21 European countries studied

 

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  		Table 2— Estimates of the numbers of each of the five phenotypic classes for the deficiency alleles protease inhibitor(PI)*S and PI*Z for each of the 21 European countries studied

 


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  		Fig. 1— Distribution of protease inhibitor ZZ prevalence in Europe. The highest prevalence is in the South of the Scandinavian Peninsula, Latvia and Denmark, and it progressively decreases towards the South and the East of Europe. ------: isogenes (lines of equal prevalence).

 


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  		Fig. 2— Distribution of protease inhibitor SZ prevalence in Europe. The highest prevalence is in the Iberian peninsula and Southern France and gradually decreases towards the North, South and East of the continent. ------: isogenes (lines of equal prevalence).

 


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  		Fig. 3— Distribution of protease inhibitor MZ prevalence in Europe. The highest prevalence is in the South of the Scandinavian Peninsula, Baltic Republics, Denmark and the UK, and progressively decreases towards the East, South and North of the continent. ------: isogenes (lines of equal prevalence).

 


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  		Fig. 4— Estimates of the numbers of individuals of phenotype protease inhibitor ZZ in each of 21 countries in Europe with 95% confidence intervals indicated on each estimate.

 


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  		Fig. 5— Estimates of the numbers of individuals of phenotype protease inhibitor SZ in each of 21 countries in Europe with 95% confidence intervals indicated on each estimate.

 


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  		Fig. 6— Estimates of the numbers of individuals of phenotype protease inhibitor MZ in each of 21 countries in Europe with 95% confidence intervals indicated on each estimate.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
Tables 1Go and 2Go demonstrate that both the PI*S and PI*Z alleles are found in all 21 European countries; very striking differences for the distribution of PI*S and PI*Z AT-D alleles are demonstrated among these European countries, and even within different regions of the same country. With an estimated total population of 588,985,731 individuals for the listed European countries, the number of PI ZZ phenotypes consists of 124,594 individuals. The largest numbers of PI ZZ individuals were found in Italy, Spain, Germany, France, the UK, Latvia, Sweden and Denmark, with 5,000–15,000 individuals in each of these eight countries. On the contrary, the lowest number of individuals of the PI ZZ phenotype was found in Finland, Hungary, Poland, Estonia, Lithuania and Switzerland (with <1,000 for every of these six countries). The seven remaining European countries yielded a moderate number of PI ZZ individuals, with ~1,000–2,000 for each of them. These calculated numbers are a reflection of both the specific PI*Z frequency and the total population of each country.

The current authors are aware that these data should be considered an approximation, since their calculations might have bias related to the samples' composition and to the sources of the subjects recruited. Is important to note that, in several countries, there is a remarkable lack of epidemiological studies in extensive geographical regions; there are also marked differences in the contribution of AT-D data in the different regions of the same country. The unbalanced contributions of different regions of a given country should be taken into account for most of the European countries in the present study.

In addition to the protease inhibitor ZZ individuals, the present authors have calculated that there are 560,515 protease inhibitor SZ and 16,323,226 protease inhibitor MZ individuals in Europe, and an impressive number of almost 37 million individuals with protease inhibitor MS and protease inhibitor SS phenotypes. Although both MS and SS phenotypes are currently not considered to be at increased risk for development of diseases, and that the penetrance (the number of subjects who develop clinical disease) of MZ and SZ phenotypes is clearly lower if compared with protease inhibitor ZZ, it is the authors' intention to provide these numbers to illustrate: 1) the very large numbers of individuals with the S and Z deficiency alleles in the European 21 countries studied; and 2) the need for follow-up epidemiological studies to extend these original observations.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
The authors thank E. Steele (NIEHS ITSS Contract) for help with the original design of the Microsoft Excel spreadsheets used in data processing. The authors also acknowledge the expert editorial assistance of J. Blanco.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

  1. de Serres FJ. Worldwide racial and ethnic distribution of alpha-1-antitrypsin deficiency: details of an analysis of published genetic epidemiological surveys. Chest 2002;122:1818–1829.[Abstract/Free Full Text]
  2. Stoller JK, Snider GL, Brantly ML, et al. American Thoracic Society/European Respiratory Society Statement: Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2003;168:818–855.[Free Full Text]
  3. Stockley RA. Alpha(1)-antitrypsin: more than just deficiency. Thorax 2004;59:363–364.[Free Full Text]
  4. DeMeo DL, Silverman EK. {alpha}1-Antitrypsin deficiency. 2: genetic aspects of {alpha}1-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax 2004;59:259–264.[Abstract/Free Full Text]
  5. Needham M, Stockley RA. Alpha 1-antitrypsin deficiency. 3: clinical manifestations and natural history. Thorax 2004;59:441–445.[Abstract/Free Full Text]
  6. Hersh CP, Dahl M, Ly NP, Berkey CS, Nodestgaard BG, Silverman EK. Chronic obstructive pulmonary disease in {alpha}1-antitrypsin PI MZ heterozygotes: a meta-analysis. Thorax 2004;59:843–849.[Abstract/Free Full Text]
  7. Hutchison DCS. {alpha}-1-Antitrypsin deficiency in Europe: geographical distribution of Pi types S and Z. Respir Med 1998;92:367–377.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  8. Miravitlles M. Alpha(1)-antitrypsin deficiency: epidemiology and prevalence. Respir Med 2000;94:S12–S15.
  9. Blanco I, Fernandez E, Bustillo E. Alpha-1-antitrypsin PI phenotypes S and Z in Europe: an analysis of the published surveys. Clin Genet 2001;60:31–41.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  10. Luisetti M, Seersholm N. Alpha(1)-antitrypsin deficiency. 1: Epidemiology of alpha(1)-antitrypsin deficiency. Thorax 2004;59:164–169.[Abstract/Free Full Text]
  11. de Serres FJ, Blanco I, Bustillo EF. Genetic epidemiology of alpha-1 antitrypsin deficiency: France, Italy, Portugal and Spain. Clin Genet 2003;63:1–20.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  12. World Factbook database. www.odci.gov/cia/publications/factbook/index.html
  13. Bohme A, Cleve H, Schonitzer D, et al. Alpha 1-antitrypsin (Pi) types and subtypes in the Tyrolean population. Hum Genet 1983;63:193–194.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  14. Kimpen J, Legius E, Bosmans E, et al. Alpha-1-proteinase inhibitor gene frequencies in Belgium. Gene Geogr 1990;4:159–163.[Medline] [Order article via Infotrieve]
  15. Thymann M. Distribution of alpha-1-antitrypsin (Pi) phenotypes in Denmark determined by separator isoelectric focusing in agarose gel. Hum Hered 1986;36:19–23.[ISI][Medline] [Order article via Infotrieve]
  16. Dahl M, Nordestgaard BG, Lange P, Vestbo J, Tybjaerg-Hansen A. Molecular diagnosis of intermediate and severe alpha(1)-antitrypsin deficiency: MZ individuals with chronic obstructive pulmonary disease may have lower lung function than MM individuals. Clin Chem 2001;47:56–62.[Abstract/Free Full Text]
  17. Uibo R, Parik J, Maaroos H-I, Samloff IM. Alpha-1-antitrypsin allo- and phenotypes in gastric and duodenal ulcer. Scand J Gastroenterol 1991;26:105–108.
  18. Beckman L, Sikstöm C, Mikelsaar AV, Krumina A, Kucinskas V. {alpha}-1-Antitrypsin (PI) alleles of West European influence in the Baltic Sea region. Hum Hered 1999;49:52–55.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  19. Arvilommi H. Studies on serum Pi- and C3-polymorphism in Finland. Acta Pathol Microbiol Scand 1972;234: Suppl. 1–50.
  20. Fagerhol MK, Eriksson AW, Monn E. Serum Pi types in some Lappish and Finnish populations. Hum Hered 1969;19:360–364.[ISI][Medline] [Order article via Infotrieve]
  21. Arnaud P, Koistinen J, Wilson GB, Fudenberg HH. Alpha-1-antitrypsin (Pi) phenotypes in a Finnish population. Scand J Clin Lab Invest 1977;37:339–343.[ISI][Medline] [Order article via Infotrieve]
  22. Fagerhol MK, Gedde-Dahl T Jr. Genetics of the Pi serum types. Family studies of the inherited variants of serum alpha-1-antitrypsin. Hum Hered 1969;19:354–359.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  23. Sesböue R, Martin JP. Alpha-1-antitrypsin (PI) polymorphism in France, with special regard to the PI*Z allele. Hum Hered 1991;41:340–346.[ISI][Medline] [Order article via Infotrieve]
  24. Sesböue R, Charlionet R, Vercaigne D, Guimbretiere J, Martin JB. Genetic variants of serum alpha-1-antitrypsin (Pi types) in Bretons. Hum Hered 1978;28:280–284.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  25. Youinou P, Gueguen A, Martin JP, et al. Genetic variants of serum alpha-1-antitrypsin (Pi types) in a Breton population, the Bigoudens. Hum Hered 1984;34:114–119.[ISI][Medline] [Order article via Infotrieve]
  26. Arnaud P, Chapuis-Cellier C, Vittoz P, Creyssel R. Alpha-1-antitrypsin phenotypes in Lyon, France. Hum Genet 1977;39:63–68.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  27. Morcamp C, Charlionet R, Sesboue R, Lefevre F, Martin JP. Genetic variants of the Pi system in Normans: comparison with some European populations. Bull Eur Physiopathol Respir 1980;16: Suppl. 285–291.
  28. Robinet-Levy M, Rieunier M. [Method for the identification of Pi groups: 1st statistics from Languedoc]. Rev Franc Transfus 1972;15:61–72.[CrossRef]
  29. Weidinger S, Schwarzfischer F, Cleve H. Pi subtyping by isoelectric focusing: further genetic studies and application to paternity examinations. Z Rechtsmed 1980;86:1–7.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  30. Weidinger S, Cleve H, Patutschnick W. Alpha1-antitrypsin: evidence for a fourth PiM allele. Distribution of the PiM subtypes in Southern Germany. Z Rechtsmed 1982;88:203–211.[ISI][Medline] [Order article via Infotrieve]
  31. Genz T, Martin JP, Cleve H. Classification of alpha1-antitrypsin (Pi) phenotypes by isoelectrofocusing. Distinction of six subtypes of the PiM phenotype. Hum Genet 1977;38:325–332.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  32. Schmechta H, Geserick G. [Population genetic studies on alpha-1 antitrypsin polymorphism (Pi-system) in the population of Berlin]. Dtsch Gesundheitsw 1972;27:1089–1091.[Medline] [Order article via Infotrieve]
  33. Patzelt D, Schroder H. Genetic-polymorphism of alpha-1-antitrypsin (Pi system) – data on the formal and population-genetics of the Pi subtypes. Dtsch Gesundheitsw 1983;38:119–123.
  34. Goedde HW, Benkmann HG, Kriese L, et al. Genetic markers among three populations of Hungary. Gene Geogr 1987;1:109–120.[Medline] [Order article via Infotrieve]
  35. Pittschieler K, Massi G. Alpha-1-antitrypsin deficiency in two population groups in north Italy. Padiatr Padol 1988;23:307–311.[Medline] [Order article via Infotrieve]
  36. Seefried-Lehmann S-J, Walter H, Danker-Hopfe H, Ricjards O, De Stefano GF. Investigations on the variability of four genetic serum protein markers (HP; TF; CG and PI subtypes) in Italy. Z Morphol Anthropol 1992;79:215–231.[Medline] [Order article via Infotrieve]
  37. Massi G, Cotumaccio R, Auconi P. Alpha-1-antirypsin (alpha-1-AT) phenotypes and PiM subtypes in Italy. Evidence of considerable geographic variability. Hum Genet 1982;61:76–77.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  38. Piantelli M, Auconi P, Musiani P. Alpha-1-antitrypsin phenotypes in new-borns from Central and Southern Italy. Hum Hered 1978;28:468–473.[ISI][Medline] [Order article via Infotrieve]
  39. Pascali VL, De Mercurio D. Determination of alpha-1-antitrypsin subtypes in the population of Rome: a study in ultrathin-layer isoelectric focusing. Hum Hered 1981;31:296–298.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  40. Massi G, Fabiano A, Ragusa D, et al. Alpha-1-antitrypsin phenotypes and Pi M subtypes in Italy. Bull Eur Physiopathol Respir 1980;16: Suppl. 301–306.
  41. Stakisaitis D, Benetis R. Does alpha-1-proteinase inhibitor play a protective role in coronary atherosclerosis? Med Sci Monit 2001;7:701–711.[Medline] [Order article via Infotrieve]
  42. Hoffman JJML, van den Broek WGM. Distribution of alpha-1-antitrypsin phenotypes in two Dutch population groups. Hum Genet 1976;32:43–48.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  43. Klasen EC, Biemond I, Weterman IT. Alpha 1-antitrypsin-levels and phenotypes in Crohn's disease in the Netherlands. Gut 1980;21:840–842.[Abstract/Free Full Text]
  44. Biedmond I, Shelby WS, Jewell DP. Alpha-1-antitrypsin serum concentration and phenotypes in ulcerative colitis. Digestion 1984;29:124–128.[ISI][Medline] [Order article via Infotrieve]
  45. Fagerhol MK, Gedde-Dahl T Jr. Serum Pi types in Norwegians. Acta Pathol Microbial Scand 1967;70:421–428.[ISI][Medline] [Order article via Infotrieve]
  46. Moller P, Fagerhol MK. Pi phenotypes in patients with ankylosing spondylitis, acute anterior uveitis, psoriasis and chronic prostatitis. Clin Genet 1984;26:339–341.[ISI][Medline] [Order article via Infotrieve]
  47. Gulsvik A, Fagerhol MK. Alpha-1-antitrypsin phenotypes and obstructive lung disease in the city of Oslo. Scand J Respir Dis 1979;60:267–274.[ISI][Medline] [Order article via Infotrieve]
  48. Titenko-Holland NV, Kowalska A. Alpha-1-antitrypsin (PI) subtypes in Russians and Poles. Hum Hered 1992;42:384–386.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  49. Szczeklik AB, Turowska B, Gzerniawska-Mysik B, Opolska B, Nizankowska E. Serum alpha-1 antitrypsin in bronchial asthma. Am Rev Respir Dis 1974;109:487–490.[ISI][Medline] [Order article via Infotrieve]
  50. Kowalska A, Rujner J, Titenko-Holland NV, Pitacik B. Alpha-1-antitrypsin subtypes in Polish newborns. Hum Hered 1995;45:351–354.[ISI][Medline] [Order article via Infotrieve]
  51. Walter H, Danker-Hopfe H, Lemmermann M, Lorenz M. Investigation on the variability of four genetic protein markers in Poland. Z Morphol Anthrop 1992;79:203–214.
  52. Pilacik B. Rare alpha 1-antirypsin phenotypes in the Polish population and the problems associated with their detection. Polski Tygodnik Lekarski (Warszawa) 1988;43:814–817.
  53. Kolwaska A, Rujner J. Polymorphism locus Pi (alpha-1-antitrypsin) of residents in the Poznan Province. Polski Tygodnik Lekarski (Warszawa) 1994;43:195–197.
  54. Geada HM, Pereira-Albino JA, Manso C. Polimorphism of alpha-1-antitrypsin in a Portuguese population. Hum Genet 1976;32:109–113.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  55. Martin JP, Seboue R, Charlionet R, Ropartz C, Pereira MT. Genetic variants of serum alpha-1-antitrypsin (Pi types) in Portuguese. Hum Hered 1976;26:310–314.[ISI][Medline] [Order article via Infotrieve]
  56. Santos-Rosa MA, Robalo-Cordeiro AJA. Alpha-1-proteinase inhibitor phenotypes in Portuguese population. Eur J Respir Dis 1986;69: Suppl. 146 167–173.
  57. Kravchuk OI, Spitsyn VA, Ginter EK, Makarov SV. Population genetic characteristics of Highland and Meadow Mari: genetic markers. Hum Genet 1996;32:570–575.
  58. Anatonov MP, Petrukhin IS, Voitova TV, Portenko GM. Distribution of Pi phenotypes in normal subjects and subjects with diseases of the respiratory tract. Lab Delo 1988;3:23–27.
  59. Shurkhal AV, Podogas AV, Altukhov YP. Genetic polymorphism and rare variants of alpha-1-antitrypsin in the population of Moscow. Genetika 1984;20:2066–2069.[ISI][Medline] [Order article via Infotrieve]
  60. Shurkhal AV, Podogas AV, Dementeva GM, et al. Rare variants of alpha 1 antitrypsin in a group of families with developmental disorders in newborns. Genetika 1987;23:1692–1698.[ISI][Medline] [Order article via Infotrieve]
  61. Kucher AN, Puzyrev VP, Ivanova OF, Xu JJ, Oz RF. Subtypes of serum proteins among Russian inhabitants of the Tomsk region. Genetika 1993;29:845–852.[ISI][Medline] [Order article via Infotrieve]
  62. Jelic-Ivanovic Z, Spasojevic-Kalimanovska V, Topic A, Spasic S, Petrovic V. Alpha-1-antitrypsin (Pi) polymorphism in Serbia: deviation of Pi M subtype distribution from the Hardy-Weinberg equilibrium. Gene Geogr 1994;8:129–135.[ISI][Medline] [Order article via Infotrieve]
  63. Blanco I, Fernández E, Rodríguez MC, Fernández A. [Allelic frequency of the gene of alpha-1-antitrypsin in the general population in a county in Asturias]. Med Clin (Barcelona) 1999;133:366–370.
  64. Vidal R, Miravitlles M, Jardí R, et al. [Study of the frequency of different phenotypes of alpha-1-antitrypsin in a population of Barcelona]. Med Clin (Barcelona) 1996;107:211–214.[Medline] [Order article via Infotrieve]
  65. Puertas MJA, Arranz-Peña ML. Valoración de fenotipos de alfa-1-antitripsina en Castilla-León: estudio en una población de recién nacidos [Evaluation of phenotypes of alpha-1-antitrypsin in Castilla-Leon: study in a population of newborns]. Rev Clín Esp 1989;184:106–108.[ISI][Medline] [Order article via Infotrieve]
  66. Moral P. Estudio antropogenético de diversos polimorfismos hematológicos en la isla de Menorca [Anthropogenetic study of various haematological polymorphisms on Menorca island]. PhD thesis. University of Barcelona, Barcelona, Spain, 1986
  67. Hjalmarsson K. Distribution of alpha-1-antitrypsin phenotypes in Sweden. Hum Hered 1988;38:27–30.[ISI][Medline] [Order article via Infotrieve]
  68. Bar W, Kratzer A. Polymorphism of alpha-1-antitrypsin (Pi) in the Swiss population determined by isoelectric focusing with an immobilized pH gradient. Hum Hered 1988;38:106–110.[ISI][Medline] [Order article via Infotrieve]
  69. Arnaud P, Galbraith RM, Faulk WP, Black C. Pi phenotypes of alpha1-antitrypsin in Southern England: identification of M subtypes and implications for genetic studies. Clin Genet 1979;15:406–410.[ISI][Medline] [Order article via Infotrieve]
  70. Phillips C, Whitehouse D. A rapid high resolution separator IEF technique for phenotyping alpha-1 antrypsin. Adv Foren Haemogen 1990;8:274–276.
  71. Blundell G, Frazer A. Alpha1 antitrypsin phenotypes in Northern Ireland. Ann Hum Genet 1975;38:289–294.[ISI][Medline] [Order article via Infotrieve]



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