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Worldwide Racial and Ethnic Distribution of ₁-Antitrypsin Deficiency^*

Summary of an Analysis of Published Genetic Epidemiologic Surveys

^* From the Laboratory of Toxicology, Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC.

Correspondence to: Frederick J. de Serres, PhD, 632 Rock Creek Rd, Chapel Hill, NC 27514-6716; e-mail: f.deserres{at}worldnet.att.net

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion Summary and Conclusions References

 
Study objectives: ₁-antitrypsin (AAT) deficiency is a genetic disease that is widely known in Europe as a disease of white individuals, who, along with their descendants in other parts of the world, are at the highest risk for liver and/or lung disease. There is a limited database of individuals affected by this disease worldwide. It has been estimated, for example, that there are 70,000 to 100,00 individuals affected in the United States, with comparable numbers in Europe.

Study design: Genetic epidemiologic studies in the peer-reviewed literature have been used in an exploratory study to estimate the number of carriers and the number of those individuals who are homozygous or heterozygous for the two most common defective alleles for AAT deficiency in 58 individual countries. The total country database of 373 control cohorts has been combined to estimate the numbers of carriers and deficiency allele combinations for PiS and PiZ in 11 geographic regions and worldwide. The study was designed to be illustrative rather than comprehensive, and more detailed publication of the enormous database developed in this exploratory study is planned.

Conclusions: The database presented indicates that in a total population of 4.4 billion in the countries surveyed worldwide, there are at least 116 million carriers (PiMS and PiMZ) and 3.4 million deficiency allele combinations (PiSS, PiSZ, and PiZZ). Furthermore, this database demonstrates that AAT deficiency is found in various populations of African blacks, Arabs and Jews in the Middle East, whites in Australia/New Zealand, Europe, and North America, central Asians, far east Asians, and southeast Asians. These data demonstrate that AAT deficiency is not just a disease of whites in Europe, but that it affects individuals in all racial subgroups worldwide. In addition, AAT deficiency may be one of the most common serious hereditary disorders in the world.

Key Words: ₁-antitrypsin deficiency • ₁-protease • ₁-protease inhibitor • genetic epidemiology • Pi subtypes • Pi phenotypes • population genetics

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion Summary and Conclusions References

 
Genetic epidemiologic survey data on the general population in countries worldwide have been used to determine the number of carriers and those homozygous or heterozygous for a given genetic disease. This approach has provided data on the prevalence of ₁-antitrypsin (AAT) deficiency that demonstrate that this disease may be one of the most common serious hereditary disorders in the world.

AAT is a serine protease inhibitor, the principal substrate of which is neutrophil elastase. This is an omnivorous protease that can result in "genetic emphysema" from damage, primarily, to the lower lobes of the lungs¹ as well as liver disease, expressed as neonatal cholestasis that may progress to juvenile cirrhosis and slowly progressive liver disease in the adult.² The AAT gene locus is located on the long arm of chromosome 14, has been mapped to chromosome 14q32.19,³ and consists of seven exons spanning 12 kilobases.⁴ The normal gene is designated PiM, and at least 75 deficiency alleles have been described.^{5 6} Gene-mapping studies have shown that the PiZ allele probably arose in Northern Europe.^{7 8} Age estimates of AAT variants based on microsatellite variation suggest that the Z deficiency allele appeared 107 to 135 generations ago and could have been spread in neolithic times. The PiS deficiency allele has an older 279-generation to 470-generation age, and from its high incidence on the Iberia peninsula it has been suggested that PiS could have originated in this region.⁸

It has been estimated that there are 70,000 to 100,00 individuals affected in the United States⁴ with comparable numbers in Europe.⁹ AAT deficiency is widely known as a disease of whites in Europe with individuals in that continent as well as their descendants in other parts of the world at the highest risk.¹⁰ Reviews published since 1989^{11 12 13} and a statement by the American Thoracic Society and the European Respiratory Society on alpha-1 antitrypsin deficiency (in preparation) indicate that individuals who are both carriers and who have deficiency allele combinations for the PiS and PiZ defective alleles are at risk for adverse health effects. Thus, the populations at risk in each country and the 11 geographic regions include all of the same five phenotypic classes as those that are at risk for adverse health effects.

The issues that were investigated in the present article are the following: What is the worldwide racial and ethnic distribution of AAT deficiency? How many individuals are there in individual countries and worldwide who either are carriers or have deficiency allele combinations for the most common defective alleles for this disease?

The present study utilizes data from genetic epidemiologic studies performed by others to determine the phenotypes of carriers and deficiency allele combinations for the two most common defective alleles for AAT deficiency, namely, PiS and PiZ, in the control cohorts of individual case studies. The data from these individual cohorts for a given country are combined to calculate the mean gene frequencies for PiM, PiS, and PiZ. These frequencies then are utilized to calculate the total numbers of individuals in each of the six major genotypic classes of interest (ie, PiMM, PiMS, PiMZ, PiSS, PiSZ, and PiZZ) in the total population. This approach has provided such data on 373 cohorts in 58 countries worldwide. This total individual country database has been combined to estimate the numbers of carriers and deficiency allele combinations for PiS and PiZ in 11 different geographic regions and worldwide.

The database on the 11 geographic regions demonstrates that AAT deficiency is found in some populations of African blacks, Arabs and Jews in the Middle East, whites in Australia/New Zealand, Europe, and North America, central Asians, far east Asians, and southeast Asians. In each of these racial groups, there are marked differences in the frequency of PiS and PiZ. In addition, the estimated occurrence of PiSS, PiSZ, or PiZZ is as follows: North Americans, 656,928; Africans, 689,124; Arabs and Jews in the Middle East, 68,542; central Asians, 84,601; southeast Asians, 93,028; and Europeans, 1.7 million. The summary of the total database of 373 cohorts in these 58 countries indicates that there are at least 116 million carriers (PiMS and PiMZ) and 3.4 million individuals with deficiency allele combinations (ie, PiSS, PiSZ, and PiZZ) worldwide.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion Summary and Conclusions References

 
Source of Data
The articles used in the present analysis were obtained through a variety of sources such as searches of the peer-reviewed literature on PubMed and the Web of Science in the Library of the National Institutes of Health. In addition, articles on genetic epidemiologic surveys for AAT deficiency in Europe⁹ and for the Middle East¹⁴ also were used.

Selection of Cohorts
Only the data on the phenotypes of the control group cohort in each article were used in the present study. These control cohorts (ie, blood donors, newborns, hospital patients, and high school or college students) were described in detail by Hutchison.⁹ The same criteria were used in the present study to select the control cohort data. In addition, care was taken to ensure that the most reliable method of analysis (ie, isoelectric focusing) was used for phenotyping. In addition, these databases usually consisted of the numbers of (control) subjects with each of the following phenotypes (PiMM, PiMS, PiMZ, PiSS, PiSZ, PiZZ, PiM-, and others). Articles that reported the total number of subjects in the control cohort as well as the gene frequencies of PiM, PiS, and PiZ also were used.

Source of Data on Total Populations and Numbers of Individuals in Different Ethnic Subgroups
The data on the number of individuals in the total populations and in different racial and ethnic subgroups in different countries worldwide were obtained from the following two sources: http://www.odci.gov/cia/publications/factbook/index.html; and http://cnn.countrywatch.com.

Data Processing of Genetic Epidemiologic Surveys for Serum Proteins in the General Population in Different Countries
Spreadsheets (Excel; Microsoft; Redmond, WA) were developed to record and process the data from genetic epidemiologic studies to determine Pi (types, subtypes, phenotypes, or genotypes) in control populations in each country. The data from surveys on a given racial or ethnic subgroup (ie, blacks, Asians, and whites) within a country were tabulated individually to determine the total numbers in each of eight different genotypic classes, namely, PiMM, PiMS, PiMZ, PiSS, PiSZ, PiZZ, PiM-, and others. The data in each article on the total number of subjects and the numbers in each of these eight phenotypic classes were used to calculate gene numbers for PiM, PiS, and PiZ, and gene frequencies for PiM, PiS, and PiZ for the entire country.

In the present study, formulas were developed and embedded into spreadsheet templates to process the original control cohort data in individual articles to calculate a derived database consisting of the numbers of genes as well as the mean gene frequencies for PiM, PiS, and PiZ. These formulas accomplish the following: (1) calculate the total number of cohorts, the total number of subjects in all cohorts, and the total numbers in each of the eight or more phenotypic classes; and (2) calculate the total gene numbers for PiM, PiS, and PiZ and their mean gene frequencies. The spreadsheet also was designed to then compare the numbers in the original and derived databases so that error messages would be generated to highlight any discrepancy between the original and derived numbers as well as to guard against accidental erroneous data entry for any given control cohort.

We assumed that if these formulas could successfully recreate the number of subjects in each of these eight phenotypic classes in the derived database, the derived gene frequencies for PiM, PiS and PiZ could be used with Hardy-Weinberg equilibrium statistics to estimate the total number of carriers (PiMS and PiMZ) and deficiency allele combinations (PiSS, PiSZ, and PiZZ) for each country. It is important to note that PiSS and PiZZ individuals are homoallelic homozygotes and that PiSZ individuals are heteroallelic heterozygotes, since both deficiency alleles (PiS and PiZ) result from different base-pair changes in the same gene.^{4 5}

Our approach is a step beyond the data that typically are published,^{9 14 15 16 17} in which these gene frequencies for PiM, PiS, and PiZ were calculated and reported for individual cohorts in individual cities or geographic regions.

Estimating the Total Number of Individuals in a Particular Racial or Ethnic Subgroup Within a Given Country
The data from individual epidemiologic surveys on a given racial or ethnic subgroup within a country were combined to determine the mean gene frequencies for PiM, PiS, and PiZ. Using the formulas discussed above and the total number of subjects in that subgroup, the total numbers of carriers and deficiency allele combinations for PiS and PiZ were calculated. Using the data from the population size of a particular racial or ethnic subgroup in a given country, we determined the total number of carriers and deficiency allele combinations for that subgroup. These total numbers for individual subgroups then were summarized to obtain the total numbers of carriers and deficiency allele combinations for PiS and PiZ for the entire population of a given country.

Estimating the Total Number of Carriers and Deficiency Allele Combinations for PiS and PiZ in Different Geographic Regions
Spreadsheets were designed to tabulate the total numbers of carriers (PiMS and PiMZ) and deficiency allele combinations (PiSS, PiSZ, and PiZZ) for all the countries within given geographic regions. These 11 geographic regions are arbitrary but were designed to attempt to collate the data on populations with similar anthropologic origins. Thus, the Arab population of the countries in the northern part of the African continent was collated with the Arab population in the Middle East rather than with the black populations in the remaining countries of the African continent.

These spreadsheets of the 11 geographic region were linked to each of the original country data sheets so that these numbers would change automatically with any new cohort entry into the individual country spreadsheet. The numbers are summarized in each geographic region spreadsheet to estimate the total numbers of carriers and deficiency allele combinations for PiS and PiZ.

Estimating the Total Number of Carriers and Deficiency Allele Combinations for PiS and PiZ in the World
In the final spreadsheet, the data from 11 of 12 geographic regions were used in a final spreadsheet to create a worldwide summary of the genetic epidemiologic studies in those countries where data have been generated and published in the peer-reviewed literature. The database from the 12th geographic region (South America) consists only of a group of four small cohorts of indigenous Indians located in Brazil, French Guiana, or Venezuela^{18 19 20} as well as a larger mixed population (Amerindian and Spanish).²¹ These groups were omitted from the present article since they are considered atypical of the more general populations of these three countries.

Publication of the Primary Database on the Alpha-1 Foundation Web Page
The primary database on the 58 individual countries in the present article is extensive and too large to be published in the present manuscript and will be published in other manuscripts for each of the 11 geographic regions (eg, southern Europe²² ).

Since it provides the supporting documentation for the geographic region and world summaries, the data also will be published on the Alpha-1 Foundation Web site (www.alphaone.org). It is the intention of the author to update this country database as new articles on such genetic epidemiologic surveys are published in countries already included as well as new countries as the data emerge. The summaries of the 11 geographic regions and the world also will be included on this Web site. This type of publication of the overall database on individual countries, the 11 geographic regions, and the world provides a mechanism to ensure that all data will be current.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion Summary and Conclusions References

 
Estimation of the Numbers of Carriers and Deficiency Allele Combinations for PiS and PiZ in Africa
The database for 11 countries in central and southern Africa is given in Table 1 . There are a total of 23 cohorts with a total cohort sample size of 3,886. The sample size of the different cohorts varies from 88 in Botswana to 1,354 in the Republic of South Africa. This tabulation demonstrates striking differences between the prevalence of carriers and deficiency allele combinations for PiS and PiZ within this part of the African continent. In the final tabulation, with an estimated population of 263,933,984 for these 10 countries, the total population at risk consists of 19,427,775 carriers and 689,124 deficiency allele combinations for PiS and PiZ.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion Summary and Conclusions References

The issue for AAT deficiency is whether carriers for the two major defective alleles (ie, PiS and PiZ) are at risk. In his 1989 review, Feld¹² reviewed data in the literature on susceptibility to emphysema, asthma, and liver disease in infants as well as adults, and rheumatoid arthritis, uveitis, and a variety of other diseases. He concludes that there is evidence that both carriers and those individuals with deficiency allele combinations for the PiS and PiZ alleles are at risk. However, based on the evidence on the prevalence of these alleles available in the late 1980s, he concluded that the increased susceptibility of carriers for PiS and PiZ did not warrant mass screening. The present data on prevalence of these two alleles worldwide mandate re-evaluation of this earlier conclusion.

Additional evidence for a risk for adverse health effects can be found in a statement by the American Thoracic Society and the European Respiratory Society on alpha-1 antitrypsin deficiency (in preparation) and in a more recent review.²³ The risk of COPD between PiSZ and PiZZ subjects was investigated by the ₁-Antitrypsin Deficiency Registry Study Group.²³ This study group found that airflow obstruction was less common and milder among PiSZ than PiZZ subjects. They also concluded that the PiSZ phenotype in smokers confers a significant risk for the development of COPD.

More recently, the adverse health effects for carriers of the PiZ defective allele have been reviewed in a statement by the American Thoracic Society and the European Respiratory Society on alpha-1 antitrypsin deficiency (in preparation). The influence of the PiMZ phenotype on respiratory disease appears to be established with an increased risk of COPD. From the available studies, the concept of a multifactorial interaction of genetic, smoking, and environmental factors has been established for PiMZ patients. The usual PiMZ individual who smokes has mild spirometric abnormalities that manifest later in life. A more substantial risk for symptomatic COPD may occur during the stresses of environmental challenge in heavy cigarette smokers, particularly in relatives of patients with obstructive lung disease.

The adverse health effects of carriers for AAT deficiency was first suggested as a predisposing factor for lung disease in 1969^{24 25} and has been the subject of considerable controversy ever since.²⁶ The adverse health effects associated with being a carrier of the PiS defective allele were reviewed in 1989,¹³ and they included cirrhosis,^{27 28} multiple sclerosis,²⁹ chronic cryptogenic liver disease,³⁰ and malignant hepatoma.³⁰ In addition, there are more recent reports that the PiMS phenotype can be associated with hepatic dysfunction during the first 6 months of life,^{31 32} with cryptogenic cirrhosis between the ages of 1 month and 18 years,³³ and with intracranial arterial dissections.³⁴ In other publications, PiMZ carriers were found to be more prone to the development of COPD³⁵ and of chronic liver failure in adults.³⁶ In addition, carriers for both defective alleles have been found to be at risk for the development of asthma³⁷ and of alcoholic toxic cirrhosis.³⁸

These reviews permit us to conclude that all five phenotypes of PiS and PiZ (carriers as well as deficiency allele combinations) are at risk for a wide variety of adverse health effects.

Limitations in the Present Database
The data on individual control cohorts for each of the 58 countries have been selected according to the criteria developed by Hutchison,⁹ but the database for some countries is limited both in the number of cohorts and their size. The data for such countries as Iceland and Vietnam have been included in the overall database, but caution must be exercised with regard to the presence and/or absence of the PiS and PiZ alleles in these two countries. They have been included to illustrate the need for further genetic epidemiologic studies in these countries as well as others in some of the 11 geographic regions listed. Another issue is the consistency of the database on control cohorts in those countries with more than one cohort and in countries where a high prevalence for PiS and/or PiZ has not been previously reported. Such consistency has been found for such countries in central and southern Africa, central Asia, southeast Asia, and far east Asia where high gene frequencies of PiS and PiZ have not been reported previously. Detailed presentation of the entire database on all 58 countries is in preparation.²²

Implications of the Gene Frequencies of PiS and PiZ Reported for Each of the 11 Geographic Regions
As stated above, age estimates of AAT variants based on microsatellite variation suggest that the Z deficiency allele appeared 107 to 135 generations ago and could have been spread in neolithic times. The PiS deficiency allele is older, 279 to 470 generations, and its high frequency on the Iberian peninsula suggests that PiS could have originated in this region.⁸ The primary issue resulting from the present analysis is whether the high incidence of these two alleles in other geographic regions worldwide is the result of the spread of these two original mutations from ancient European cultures to other cultures worldwide. Alternatively, are the high incidences reported in non-European geographic regions in the present report due to the occurrence of independent spontaneous mutations at the same sites in the AAT locus that gave rise to the original PiS and PiZ alleles?

The database in the present report demonstrates that both deficiency alleles (PiS and PiZ) are found in all seven of the northern European counties listed in Table 8 . If the S allele arose on the Iberian peninsula, we need to account for its spread into the other European countries listed in Tables 4 , 8 , 10 , and 11 . The spread of the Z allele may be attributed in part to the voyages of the Viking marauders in their longboats to various countries in ninth century Europe, and to their later voyages to those countries bordering on the Mediterranean Sea.³⁹ These travels, along with the later travels of the Crusaders from England and France to the Middle East in the 10th and 11th centuries, could account for the spread of both these deficiency alleles into other European, middle eastern, and North African cultures. In addition, we must consider the movement of armies of various European countries throughout Europe and the Mediterranean in the numerous wars of the Catholic Popes between the 9th and the 16th centuries.⁴⁰

There is no historical record of any of these groups going into the countries of central and southern Africa to account for the prevalence of these two deficiency alleles, for example, in some of the indigenous black tribes in Nigeria or in South Africa. Nor is their any evidence to support the spread of these two deficiency alleles into central, southeast, or far east Asia by the Vikings, the Crusaders, the Papal armies, or their opponents. These and other issues must be resolved in the future because of the existence of these two deficiency alleles in all 11 geographic regions.

Future Expansion of the Country, Geographic Region, and World Databases
The present report is intended to be illustrative rather than comprehensive. There are many countries where the number of subjects in the control cohorts is small, and some of the estimates are based on control cohort numbers that should be larger. However, the development of the present database demonstrates that there is a significantly larger number of individuals at risk for adverse health effects than is given in the World Health Organization report on AAT deficiency¹⁰ or in any other follow-up publication.

New cohorts will be added to the overall database, as was discussed in the "Materials and Methods" section. This will require more thorough searches for articles that may have been missed in the initial PubMed and Web of Science searches. In addition, this effort will include the addition of control cohorts in new countries as they are published in the peer-reviewed literature.

The overall database for the 58 countries also contains information on the gene frequencies of PiM, PiS, and PiZ in different geographic regions and/or cities, as given in the reports of Hutchison,⁹ Nevo,¹⁴ and Blanco and coworkers.^{15 16 17} In addition, these data have been summarized to develop mean gene frequencies for PiM, PiS, and PiZ for individual countries and the 11 present geographic regions.

It is important to note, however, that this expansion of the present database should only serve to reinforce the present observations and to expand our conclusions to other countries and geographic regions. We do not anticipate that this expansion will affect the overall summary and conclusion of the present analysis.

	Summary and Conclusions

TOP Abstract Introduction Materials and Methods Results Discussion Summary and Conclusions References

 
The major finding in the present study is that AAT deficiency affects all major racial subgroups worldwide. The data presented in Table 12 indicate that there are at least 116 million carriers (PiMS and PiMZ) and 3.4 million deficiency allele combinations (PiSS, PiSZ, and PiZZ) worldwide. Furthermore, this database demonstrates that AAT deficiency is found in African blacks, Arabs and Jews in the Middle East, whites worldwide, central Asians, far east Asians, and southeast Asians. We conclude that AAT deficiency is not just a disease of whites in Europe but affects individuals in all racial subgroups worldwide.

The database in the present article demonstrates that AAT deficiency is one of the most common serious hereditary disorders in the world and is not just a disease of Europeans, but affects individuals in all racial subgroups worldwide. It also permits the conclusion that AAT deficiency may be one of the most common serious hereditary disorders in the world.

	Acknowledgements

 
The author is indebted to Mr. Eric Steele of National Institute of Environmental Health Sciences contractor OAO Corporation (Greenbelt, MD) for help in the original design of the spreadsheets used in data processing. The author also is indebted to Drs. Ignacio Blanco and Enrique Bustillo for their help in the preparation of new spreadsheet templates with embedded formulas for Hardy-Weinberg equilibrium statistics and 95% confidence limits. The author also is indebted to Drs. Jack Lieberman, Friedrich Kueppers, Edwin Silverman, and Gerard M. Turino for their review and useful comments for the revision of the draft manuscript.

	Footnotes

 
Abbreviation: AAT = ₁-antitrypsin

This research was supported by a Bridge Grant from the Alpha-1 Foundation, Miami, FL.

Received for publication January 15, 2002. Accepted for publication April 26, 2002.

	References

TOP Abstract Introduction Materials and Methods Results Discussion Summary and Conclusions References

 

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