Therapeutic Advances in Respiratory Disease

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1 457113TAR Therapeutic Advances in Respiratory DiseaseFJ de Serres and I Blanco 2012 Therapeutic Advances in Respiratory Disease Review Prevalence of α1-antitrypsin deficiency alleles PI*S and PI*Z worldwide and effective screening for each of the five phenotypic classes PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ: a comprehensive review Ther Adv Respir Dis (2012) 6(5) DOI: / The Author(s), Reprints and permissions: journalspermissions.nav Frederick J. de Serres and Ignacio Blanco Abstract: Genetic epidemiological studies on the prevalence and numbers of individuals with α1-antitrypsin deficiency in each of 97 countries worldwide were used to estimate the numbers in each of the five following phenotypic classes: PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ. These 97 countries were then grouped into 10 major geographic regions to make it possible to compare the numbers in each of these five phenotypic classes in immediately adjacent countries. Such groupings also make it possible to review the spread of the PI*S and PI*Z alleles from one major geographic grouping to another in the world as well as the spread of these two deficiency alleles within a major geographic region. The data in the 10 tables on the numbers in each of the five phenotypic classes in the countries in the same geographic region as well as the prevalence of the PI*S and PI*Z alleles in countries in the same geographic region provide a novel database for the identification of large numbers of individuals in a given phenotypic class. The database also provides useful information for the identification of countries with high numbers of PI*ZZ individuals for augmentation therapy within a given geographic region. Keywords: α1-antitrypsin deficiency, PI subtypes, PI phenotypes, genetic epidemiology, SERPINA1 Introduction α1-antitrypsin (AAT) deficiency is a recessive heritable metabolic disease that results in the synthesis and secretion of defective AAT. AAT is a 52 kda α1 glycoprotein, composed of 394-amino-acid residues and three asparagine-linked complex carbohydrate side chains. It is produced mainly by hepatocytes and secreted into the blood, where it acts as a circulating serine protease inhibitor whose principal substrate is neutrophil elastase [Brantly et al. 1988a]. About 100 genetic variants of AAT are recognizable. Protease inhibitor (PI) M (medium mobility) is the normal allele, and the two most frequent deficient alleles are PI*S and PI*Z. PI*ZZ phenotype results in very low AAT serum concentration (10 15%), and PI*SZ, PI*SS and PI*MZ phenotypes result in low intermediate serum AAT concentrations from 35% to 70%. The two most frequent deficiency alleles are PI*S (which expresses approximately 50 60% of AAT) and PI*Z (which expresses approximately 10 20% of AAT [Brantly et al. 1988b]. At least another 20 variants affect the amount and function of the AAT molecule. However, in clinical practice, most (96%) AAT deficiency related diseases are linked to the PI*ZZ type, and the remaining 4% to PI*SZ, and about another 30 rare or null phenotypes [Brantly et al. 1988; Stoller 2003a, 2003b]. Individuals who are homozygous for the PI*Z allele undergo significant intracellular polymerization of their AAT, showing a profound suppression of their Correspondence to: Frederick J. de Serres, PhD Center for the Evaluation of Risks to Human Reproduction, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC , USA deserres@bellsouth.net Ignacio Blanco, MD Biomedical Research Office (OIB-FICYT), Oviedo, Spain 277

2 Therapeutic Advances in Respiratory Disease 6 (5) circulating plasma AAT levels. The retained AAT polymers in the endoplasmic reticulum of hepatocytes can cause liver damage with a variable clinical presentation, from neonatal hepatitis to liver cirrhosis and hepatocellular carcinoma in adults, whilst the lack of circulating protein may promote development of chronic obstructive pulmonary disease (COPD) [Lomas et al. 1992]. In an earlier paper we discussed the possibility that AAT deficiency is not a rare disorder but one that is rarely diagnosed [de Serres et al. 2003]. Since it was known as a disease of white people from Northern Europe [Hutchison, 1990, 1998], little thought was apparently given in the medical community that this disease might affect other racial subgroups. Using genetic epidemiology studies performed by others in the peer-reviewed medical literature, we started to collate data on the prevalence of the two most deleterious alleles, namely PI*S and PI*Z, outside of Northern Europe. In these papers we determined the number in each of the five phenotypic classes: PI*MS, PI*MZ, PI*SS, PI*SZ and PI*ZZ. with 95% confidence intervals on all estimates [Blanco et al. 2001a, 2001b, 2004, 2005; Blanco and Fernández, 2001; de Serres, 2002; de Serres et al. 2003a, 2003b, 2005a, 2005b, 2006a, 2006b, 2007]. These previous studies on the genetic epidemiology of AAT deficiency have demonstrated that this human genetic condition is widely distributed worldwide [Blanco et al. 2001a, 2001b, 2005a, 2005b, 2006, 2007; de Serres, 2002; de Serres et al. 2003a, 2003b]. In this paper, we have organized the overall database on the genetic epidemiology of AAT deficiency into 10 major geographic regions worldwide. The database comprises studies performed by others in the peer-reviewed medical literature on 97 of the 193 countries worldwide. Within each of these 10 major geographic regions, we have highlighted the database for the individual country, among those listed, that has the highest numbers in each of the following phenotypic classes: PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ. Materials and methods Estimates of the total population in each country Estimates of the total population of each country as of July 2011 were obtained from the Central Intelligence Agency site ( library/publications/the-world-factbook/index. html). Source of genetic epidemiological studies for PI*S and PI*Z and estimates of the prevalence for each of these two major deficiency alleles The articles used in this study were obtained through a variety of sources and our research strategy for selection of relevant genetic epidemiological studies has been discussed in earlier publications [de Serres, 2002; de Serres et al. 2003a, 2003b; Blanco et al. 2006]. In this study, the overall database has been increased from 69 countries in our most recent publication [de Serres et al. 2007] to 97 countries. The data reported by two valuable studies published in 2010 and 2011 were added to our original database [Spínola et al. 2009; Carroll et al. 2011]. These 97 countries are only those out of a possible 193 countries worldwide ( gov/library/publications/the-world-factbook/ index.html) where there are genetic epidemiological studies on AAT deficiency in the peerreviewed medical literature. For the present analysis, these countries were classified into eight geographic regions, namely, geographic region 1 North Africa, with the following countries in alphabetic order: Cameroon, Cape Verde, Gambia, Mali, Morocco, Nigeria, Somalia and Tunisia; geographic region 2 Central and South Africa, with the following countries: Angola, Botswana, Democratic Republic of the Congo, Mozambique, Namibia, Republic of the Congo and South Africa; geographic region 3 Northern Europe, with the following countries: European Russia, Denmark, Estonia, Finland, Iceland, Latvia, Lithuania, Norway, Poland and Sweden; geographic region 4 Eastern Europe, with the following countries: Albania, Austria, Bosnia- Herzegovina, Greece, Hungary, Macedonia, Romania and Serbia; geographic region 5 Western and South Europe, with the following countries: Belgium, England, France, Germany, Italy, Netherlands, Northern Ireland, Portugal, Republic of Ireland, Scotland, Spain and Switzerland; geographic region 6 North and Central Asia, with the following countries: Asian Russia, Afghanistan, India, Iran, Israel, Jordan, Kazakhstan, Nepal, Pakistan, Saudi Arabia and Tajikistan; geographic region 7 Southeast Asia, Australia and New Zealand, with the following 278

3 FJ de Serres and I Blanco countries: Australia, China, Indonesia, Japan, Malaysia, Mongolia and New Zealand; geographic region 8 North and Central America, with the following countries: Canada, Costa Rica, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama and the United States of America; geographic region 9 Caribbean, with the following countries: Cuba, Dominican Republic, Haiti, Jamaica, Puerto Rico and Trinidad & Tobago; geographic region 10 South America, with the following countries: Argentina, Brazil, Bolivia, Chile, Colombia, Ecuador, Guyana, Paraguay, Peru, Suriname, Uruguay and Venezuela. Estimating the numbers in each of five phenotypic classes (PI*MS, PI*MZ, PI*SS, PI*SZ and PI*ZZ) and gene frequencies of PI*S and PI*Z with 95% confidence intervals The formulas for developing estimates of the two deficiency allele frequencies and 95% confidence intervals were discussed in earlier articles [de Serres et al. 2003a; Blanco et al. 2004]. In addition, the most recent population estimates for each of these 97 countries obtained from the CIA website ( the-world-factbook/index.html) were used to make all calculations concerning the numbers (with 95% confidence intervals of each of five phenotypic classes: PI*MS, PI*MZ, PI*SS, PI*SZ and PI*ZZ) as well as the prevalence of the two deficiency alleles, namely PI*S and PI*Z. Results Figures 1 10 make it possible to compare the prevalence of the two major deficiency alleles PI*S and PI*Z in each of the 10 geographic regions. All prevalences are expressed as cases per 1000 population. Summaries of the numbers of each of the five PI phenotypes for carriers and deficiency alleles among countries included in these 10 geographic regions are given in Tables The country with the highest number in each of the five phenotypic classes is indicated in bold type. It is important to note that each estimate in bold type in these 10 tables could be as low as the lower confidence interval or as high as the upper 95% confidence interval. In Figure 1 North Africa Pi*S frequencies range from 0.0 in Mali to 63.8 in Nigeria, and PI*Z frequencies range from 0.0 in Tunisia, Gambia and Cameroon to 11.5 in Somalia. The highest numbers of deficiency genotypes of all classes are in Nigeria. Figure 1. Prevalences of the PI*S and PI*Z deficiency alleles in geographic region 1 North Africa. Prevalences are expressed as cases per 1000 population

4 Therapeutic Advances in Respiratory Disease 6 (5) Figure 2. Prevalences of the PI*S and PI*Z deficiency alleles in geographic region 2 Central and South Africa. Prevalences are expressed as cases per 1000 population. In Figure 2 Central and South Africa Pi*S frequencies range from 0.0 in Republic of the Congo to 188 in Angola, and PI*Z frequencies are 0.0 in all these regions. The highest numbers of MS and SS genotypes were estimated for Angola, but remarkably, none of these African regions have MZ, SZ or ZZ genotypes. In Figure 3 Northern Europe Pi*S frequencies range from 7.3 in Finland to 31.3 in Latvia, and PI*Z frequencies range from 0.0 in Iceland to 45.1 in Latvia. Very high frequencies of PI*Z are also found in Denmark and Estonia (with 27.9 and 24.5 per 1000 respectively). The highest numbers of MS, MZ, SS and SZ genotypes are in European Russia, and the highest numbers of the ZZ phenotype are found in Latvia (4519) and in Denmark (4033). In Figure 4 Eastern Europe PI*S frequencies range from 0.0 in Albania and Bosnia-Herzegovina to over 21 in Austria and Greece, and PI*Z frequencies range from 0.0 in Albania to 13.3 in Austria. The highest numbers of MS and SS genotypes are in Greece, the highest numbers of MZ and ZZ are in Romania, and the highest number of SZ (almost 5000) is in Austria. In Figure 5 Central and Western Europe PI*S frequencies range from per 1000 in the Iberian Peninsula to 19 in Northern Ireland. PI*Z frequencies range from 7 in Switzerland to 30 in 280

5 FJ de Serres and I Blanco Figure 3. Prevalences of the PI*S and PI*Z deficiency alleles in geographic region 3 Northern Europe. Prevalences are expressed as cases per 1000 population. Figure 4. Prevalences of the PI*S and PI*Z deficiency alleles in geographic region 4 Eastern Europe. Prevalences are expressed as cases per 1000 population

6 Therapeutic Advances in Respiratory Disease 6 (5) Figure 5. Prevalences of the PI*S and PI*Z deficiency alleles in geographic region 5 Central and South Europe. Prevalences are expressed as cases per 1000 population. Figure 6. Prevalences of the PI*S and PI*Z deficiency alleles in geographic region 6 North and Central Asia. Prevalences are expressed as cases per 1000 population

7 FJ de Serres and I Blanco Figure 7. Prevalences of the PI*S and PI*Z deficiency alleles in geographic region 7 Southeast Asia; Australia and New Zealand. Prevalences are expressed as cases per 1000 population. Portugal. The highest number of PI*MS genotypes is in France. The highest numbers of PI*SS and PI*SZ are in Spain. Spain with around 12,000, England, France and Germany with around ,000 each have very high numbers of ZZ genotypes. Portugal with almost 5000 also shows an important number of PI*ZZ genotypes. In Figure 6 North and Central Asia PI*S frequencies range from 0.0 in Nepal and Kazakhstan to 31 in Saudi Arabia. PI*Z frequencies range from less than 1 in Nepal, India, Jordan and Israel to 15 in Saudi Arabia. India and Pakistan show the highest numbers of PI*MS (over 3.5 million each). Saudi Arabia and Pakistan show the highest numbers of PI*SS (over 20,000 each). Pakistan, with almost 4 million MZ, 36,000 SZ and 15,000 ZZ is the country with the highest numbers of deficient genotypes in this geographic area. In Figure 7 East Asia, Australia and New Zealand PI*S frequencies range from 0 1 per 1000 in Japan, Mongolia and China to in New Zealand and Australia. PI*Z frequencies range from 0 1 in Indonesia, China and Japan to per 1000 in Australia and New Zealand. The highest number of MS genotypes is in China with

8 Therapeutic Advances in Respiratory Disease 6 (5) Figure 8. Prevalences of the PI*S and PI*Z deficiency alleles in geographic region 8 North and Central America. Prevalences are expressed as cases per 1000 population. million. The highest numbers of MZ (about 500,000), SS (about 40,000) and SZ (about 22,000) genotypes are in Australia. Australia and New Zealand, with about 3000 ZZ each, are the countries with the highest numbers of this very deficient AAT genotype. The PI*ZZ genotype is rarely found in Malaysia and it is practically absent in China, Indonesia, Japan and Mongolia. In Figure 8 North and Central America PI*S frequencies range from 23 in the USA to in Central American states. PI*Z frequency ranges from 6 8 in Mexico and Central America to 10 and 13 in the USA and Canada respectively. The USA with almost 14 million MS, 6 million MZ, 160,000 SS, 150,000 SZ and 34,000 ZZ is the country with the highest number of AAT deficiency genotypes. In Figure 9 Caribbean PI*S frequencies range from 7 9 per 1000 in Jamaica, Haiti, and Trinidad & Tobago to around 40 per 1000 in Cuba, Puerto Rico and Dominican Republic. The highest number of AAT deficiency genotypes is in Cuba, with approximately 900,000 MS, 150,000 MZ, 20,000 SS, 7000 SZ and 500 ZZ. In Figure 10 South America the PI*S and PI*Z frequencies range from 30 and 50 for PI*S to 5 8 per 1000 for PI*Z in most populated countries (i.e. Brazil, Argentina, Colombia, Venezuela). The higher number of AAT deficiency genotypes is in 284

9 FJ de Serres and I Blanco Figure 9. Prevalences of the PI*S and PI*Z deficiency alleles in geographic region 9 Caribbean. Prevalences are expressed as cases per 1000 population. Brazil, with approximately 18 million MS, 2 million MZ, 500,000 SS, 100,000 SZ and 6000 ZZ. Population size summaries of the numbers in each of the five phenotypic classes of PI*S and PI*Z for all 97 countries in 10 geographic regions with data on the genetic epidemiology of alpha-1 antitrypsin deficiency (AATD) As shown in Table 11, in a total population of 5,264,150,044 in the 97 countries in 10 geographic regions with data on the genetic epidemiology of AAT deficiency there are a total of 190,574,275 AAT deficiency genotypes. Of these, 181,894 (0.1%) are PI*ZZ; 1,269,054 (0.7%) are PI*SZ; 4,017,900 (2.1%) are PI*SS; 42,564,136 (22.3%) are PI*MZ, and the remaining 142,541,291 (74.8%) are MS genotypes. Discussion In the last 49 years, following the report on AAT deficiency by Laurell and Eriksson [Laurell and Eriksson, 1963] in Malmöe, Sweden, a number of genetic epidemiology surveys have been performed, so that currently we have a global view of the AAT deficiency distribution worldwide. According to the present estimate there may be over 190 million deficiency genotypes in the 97 countries of the world, with data on the genetic epidemiology of AAT deficiency. However, 75% of them are only slightly deficient MS genotypes with no recognized risk of developing AAT deficiency related diseases; 24% are MZ and SS genotypes with a controversial but potential risk of developing AAT deficiency related diseases; 0.7% are SZ genotypes with increased risk for AAT deficiency related diseases; and 0.1% are ZZ genotypes, with a well established increased risk for development of AAT deficiency related diseases. According to the data from this study, 60% of all ZZ genotypes worldwide are in individuals living in Europe and North America, with Northern and Central Europe having over 74,000 of these subjects (41% of the total), and North America having over 44,000 of these ZZ subjects (24% of the total). In addition, 48% of all the SZ genotypes are also in Northern and Central Europe, 20% in North and Central America, and 16% in South America

10 Therapeutic Advances in Respiratory Disease 6 (5) Figure 10. Prevalences of the PI*S and PI*Z deficiency alleles in geographic region 10 South America. Prevalences are expressed as cases per 1000 population. We have found that one of the most striking features of the prevalence of PI*S and PI*Z deficiency alleles is that the highest or lowest prevalence is isolated to a given country and not shared with immediately adjacent countries in the same geographic populations. For example, in geographic region 3 Northern Europe, the highest prevalence of the PI*ZZ deficiency class is found in Latvia but not in the immediately adjacent countries: European Russia, Estonia or Lithuania. Thus, it may be that each country can be considered as isolated inbreeding populations where marriages occur between individuals in immediately adjacent villages, towns or cities rather than, in the main part, between individuals in other countries. However, we are aware that our calculations can have important limitations, most of them related to the method of selection of the cohorts and the sample size of the analyzed studies. In fact, the surveys on which we based our calculations included a wide variety of subjects, such as, blood donors, neonates, various groups of workers, students, laboratory or hospital staff, selected populations poorly representative of the 286

11 FJ de Serres and I Blanco Table 1. Summaries of the number of each of the five PI phenotypes for carriers and deficiency alleles in geographic region 1 North Africa. Country and total population PI*MS 95% CI PI*MZ 95% CI PI*SS 95% CI PI*SZ 95% CI PI*ZZ 95% CI Cameroon 216,376 55, ,294, , , Cape Verde 31,601 17, ,659 55,639 15, Gambia ,824, Mali ,865 45, , ,796, ,627 1,066, ,153 20,700 Morocco 286,197 48, ,197 48, , ,627,428 1,150,404 1,150,404 10,523 21,045 10,523 Nigeria 16,417,285 12,662, , , , ,671 68,908 17, ,217,341 21,102,935 2,558, , ,894 14,360 Somalia 339, , , , , ,112, , , , Tunisia 165,672 99, ,589, ,388 36, Region 1 totals 239,969,561 17,456,763 1,694, ,651 74, Table 2. Summaries of the number of each of the five PI phenotypes for carriers and deficiency alleles in geographic region 2 Central and South Africa. Country and total population P*MS 95% CI PI*MZ 95% CI PI*SS 95% CI PI*SZ 95% CI PI*ZZ 95% CI Angola 3,991,804 2,705, , , ,068,161 5,639, , , , Botswana 171,904 76, ,029, ,492 81,039 16, Democratic Republic of the 1,967,375 1,967,375 13,654 27,308 13,654 Congo 70,916,439 Mozambique 80,369 4, ,061, , , Namibia 532, , ,680 25, ,128, ,784 44,236 78, Republic of the 69,048 21, Congo 4,125, ,150 63, South Africa 3,012,450 2,432, ,052 34, ,109,107 3,716, ,902 77, Region 2 totals 7,857, , ,438,

12 Therapeutic Advances in Respiratory Disease 6 (5) Table 3. Summaries of the number of each of the five PI phenotypes for carriers and deficiency alleles in geographic region 3 Northern Europe. Country and total population European Russia 100,000,000 Denmark 5,515,575 Estonia 1,291,170 Finland 5,255,068 Iceland 308,910 Latvia 2,217,969 Lithuania 3,545,319 Norway 4,676,305 Poland 38,463,689 Sweden 9,074,055 Region 3 totals 170,348,060 PI*MS 95% CI PI*MZ 95% CI PI*SS 95% CI PI*SZ 95% CI PI*ZZ 95% CI 1,676,996 1,374, , , ,042,943 1,201,439 10,728 12, , , , , , , ,770 23,033 60,514 48, ,553 75, ,057 52,396 68,696 46, , , , ,040 11, ,034 76, , , , , , ,276 89, ,232 79, , , , , , , , , ,113, , , , ,254, ,453 10, , , , , , , ,943,763 2,360,998 28,882 38,968 16,872 Table 4. Summaries of the numbers of each of the five PI phenotypes for carriers and deficiency alleles in geographic region 4 Eastern Europe. Country and total population Albania 3,659,616 Austria 8,214,160 Bosnia- Herzegovina 4,621,598 Greece 10,749,943 Hungary 9,880,059 Macedonia 2,072,086 Romania 22,181,287 Serbia 7,344,847 Region 4 totals 68,723,604 PI*MS 95% CI PI*MZ 95% CI PI*SS 95% CI PI*SZ 95% CI PI*ZZ 95% CI ,855 44, , , , , , , , ,216 29, ,959 68, , ,668 41, , ,887 12, ,126 85,813 56, , , ,500 27,323 33,409 14, ,184 72, ,035 76, , , , , ,108 11,286 95,131 53, , , , , ,390,728 1,049,474 11,673 10,

13 FJ de Serres and I Blanco Table 5. Summaries of the numbers of each of the five PI phenotypes for carriers and deficiency alleles in geographic region 5 Central and Western Europe. Country and total population PI*MS 95% CI PI*MZ 95% CI PI*SS 95% CI PI*SZ 95% CI PI*ZZ 95% CI Belgium 1,046, , , ,564 30,705 22,209 18,928 11, ,423,493 1,240, ,564 42,281 29, England 4,379,898 3,902,983 1,405,388 1,146, ,095 86,166 68,728 50,624 11, ,307,005 4,908,816 1,719, ,916 93,097 16,302 France 8,901,425 8,430,235 1,443,805 1,263, , , , , ,057,792 9,394,982 1,649, , ,323 12,666 Germany 3,391,943 3,004,409 1,556,160 1,300,035 37,243 29,410 34,173 25, ,282,988 3,826,383 1,860,359 47,114 45,813 11,137 Italy 3,378,063 3,135, , ,346 53,062 45,945 27,182 21, ,090,681 3,638,407 1,002,334 61,257 33, Netherlands 1,006, , , ,110 17,102 12,850 12, ,783,092 1,166, ,387 22,714 18, Northern 64,146 53,366 30,769 23, Ireland 1,775,000 76,956 40, Portugal 3,067,865 2,813, , , , , , , ,735,765 3,338, , , ,940 13,747 Republic of 424, ,91 171, ,363 12, , Ireland 4,250, ,50 230,918 17,731 15, Scotland 351, ,712 60,354 43,146 11, ,168, ,477 83,971 14, Spain 7,418,886 6,751,390 1,232, , , , , ,110 12, ,548,753 8,138,934 1,543, , , Switzerland 553, , ,337 74,386 11, ,623, , ,234 14, Region 5 totals 33,984, ,460, ,430 57, ,046,180 Table 6. Summaries of the numbers of each of the five PI phenotypes for carriers and deficiency alleles in geographic region 6 North and Central Asia. Country and total population PI*MS 95% CI PI*MZ 95% CI PI*SS 95% CI PI*SZ 95% CI PI*ZZ 95% CI Asian Russia 303, , ,225 56, ,390, , , Afghanistan 437, , , , ,121, , , India 3,443,764 1,503, , , ,173,108,018 7,455,372 3,977,831 12,128 12, (Continued) 289

14 Therapeutic Advances in Respiratory Disease 6 (5) Table 6. (Continued) Country and total population PI*MS 95% CI PI*MZ 95% CI PI*SS 95% CI PI*SZ 95% CI PI*ZZ 95% CI Iran 1,075, , , , ,037,517 1,618,645 1,411,944 10,221 17, Israel 133,557 98, ,353, ,977 27, Jordan 104,904 45, ,407, ,316 55, Kazakhstan ,706 12, ,460, , , Nepal ,951, , , Pakistan 3,873,278 1,549,938 3,227,732 1,169,403 22, , , ,276,594 8,897,669 8,014, , ,525 92,557 Saudi Arabia 1,711,646 1,269, , ,879 28,452 16,107 27,313 13, ,207,277 2,289,429 1,252,053 49,729 54,392 14,873 Tajikistan 55, , , ,487, , , Region 6 totals 11,139,101 6,877,323 61,140 78,652 29,582 1,580,801,804 Table 7. Summaries of the numbers of each of the five PI phenotypes for carriers and deficiency phenotypes in geographic region 7 East Asia, Australia and New Zealand. Country and total population PI*MS 95% CI PI*MZ 95% CI PI*SS 95% CI PI*SZ 95% CI PI*ZZ 95% CI Australia 1,735,653 1,588, , ,063 39,186 33,109 22,392 17, ,515,754 1,895, ,755 46,341 28, China 2,536,203 1,396, ,330,141,295 4,500, , Indonesia ,968,342 1,226,310 1,226, Japan 63,107 16,279 42, ,804, , , Malaysia 1,223, ,221 67,221 24,596 15,226 10, ,160,256 1,512, ,420 23, Mongolia ,086,918 22,506 22, New Zealand 263, , , , ,252, , , , Region 7 totals 5,821, ,033 60,263 31, ,754,929,

15 FJ de Serres and I Blanco Table 8. Summaries of the numbers of each of the five PI phenotypes for carriers and deficiency phenotypes in geographic region 8 North and Central America. Country and total population PI*MS 95% CI PI*MZ 95% CI PI*SS 95% CI PI*SZ 95% CI PI*ZZ 95% CI Canada 2,499,586 2,268, , ,898 51,474 42,799 33,931 26, ,759,742 2,751, ,131 61,852 43, Costa Rica 387, ,303 65,579 48, ,516, ,607 88,659 11, El Salvador 457, ,878 76,955 55, ,052, , ,312 12, Guatemala 859, , , ,343 14,756 11, ,550, , ,562 19, Honduras 565, ,931 96,814 69,113 10, ,989, , ,859 14, Mexico 7,485,572 6,652,033 1,293, , , ,286 47,912 29, ,468,855 8,792,429 1,818, ,169 76, Nicaragua 426, ,650 72,645 51, ,995, , ,193 10, Panama 226, ,840 39,264 27, ,410, ,026 55, United States of America 310,232,863 Region 8 totals 497,976,203 13,848,656 13,093,718 6,293,810 5,791, , , , ,134 34,395 29,223 14,644,776 6,837, , ,348 40,470 26,757,978 8,910, , ,599 45,689 Table 9. Summaries of the numbers of each of the five PI phenotypes for carriers and deficiency alleles in geographic region 9 Caribbean. Country and total population PI*MS 95% CI PI*MZ 95% CI PI*SS 95% CI PI*SZ 95% CI PI*ZZ 95% CI Cuba 906, , , ,974 19,767 15, ,477,459 1,030, ,590 25,284 10, Dominican 693, , ,687 84,728 13,409 10, Republic 9,794, , ,328 17, Haiti 126,810 92,707 26,542 12, ,203, ,612 52, Jamaica 42,324 31, ,847,232 57,208 16, Puerto Rico 342, ,605 57,748 42, ,977, ,571 78,073 10, Trinidad & Tobago 1,228,691 Region 9 totals 38,528,633 21,479 16, , ,133, ,386 42,125 14,

16 Therapeutic Advances in Respiratory Disease 6 (5) Table 10. Summaries of the numbers of each of the five PI phenotypes for carriers and deficiency alleles in geographic region 10 South America. Country and total population PI MS 95% CI PI MZ 95% CI PI SS 95% CI PI SZ 95% CI PI ZZ 95% CI Argentina 2,617,275 2,265, , ,415 45,650 34,586 16,807 10, ,343,201 3,018, ,976 60,133 26, Brazil 18,450,393 16,353,936 2,155,716 1,507, , , ,540 69, ,103,330 20,784,505 3,062, , ,882 12,886 Bolivia 305, ,946 52,080 30, ,947, ,671 86, Chile 1,180,405 1,028, , ,894 22,720 17, ,746,491 1,352, ,722 29,529 12, Colombia 3,210,100 2,802, , ,719 63,832 49,231 21,837 13, ,205,293 3,671, ,634 82,610 34, Ecuador 997, , , ,351 18,291 13, ,790,608 1,146, ,209 23, Guyana 16,009 12, ,486 20, Paraguay 476, ,876 81,115 58, ,375, , ,055 12, Peru 1,915,710 1,657, , ,915 33,230 25,158 11, ,907,003 2,210, ,474 43,804 18, Suriname 10, ,618 13, Uruguay 221, ,513 40,489 28, ,510, ,905 56, Venezuela 2,653,754 2,360, , ,183 73,140 58,676 22,107 14, ,223,228 2,978, ,647 91,020 33, Region 10 32,056,062 4,474, , ,575 14,250 totals 396,387,912 Table 11. Estimates of the numbers in each of five genotypic classes based on the genetic epidemiology of AATD in 98 of the 193 countries worldwide. Geographic region Total population PI*MS PI*MZ PI*SS PI*SZ PI*ZZ Region 1 North Africa 239,969,561 17,456,763 1,694, ,651 74, Region 2 Central and 163,438,852 7,857, , South Africa Region 3 Northern 170,348,060 3,943,763 2,360,998 28,882 38,968 16,872 Europe Region 4 Eastern 68,723,604 1,390,728 1,049,474 11,673 10, Europe Region 5 Central and 353,046,170 33,984,368 8,061,106 1,460, ,430 57,188 Western Europe Region 6 North and 1,580,801,804 11,139,101 6,877,323 61,140 78,652 29,582 Central Asia Region 7 East Asia, 1,754,929,275 5,821, ,033 60,263 31, Australia and New Zealand Region 8 North and 497,976,203 26,757,978 8,910, , ,599 45,689 Central America Region 9 Caribbean 38,528,615 2,133, ,386 42,125 14, Region 10 South 396,387,912 32,056,062 4,474, , ,575 14,250 America Worldwide totals 5,264,150, ,541,291 42,564,136 4,017,900 1,269, ,

17 FJ de Serres and I Blanco general population (so-called natives ), and only a few randomly selected unrelated healthy individuals from the general population. In addition, our approach using PI*M, PI*S and PI*Z gene frequency with the Hardy Weinberg equilibrium formula to estimate the total number of subjects with deficiency variant combinations in a given country or geographic region, taking into account the overall population, undoubtedly has potential biases, especially in regions with different ethnic or racial groups. Therefore the results should be considered with caution. However, our analysis has not taken into account the rare (which are called rare due to their low prevalence) and null AAT deficiency variants, due to the lack of available studies. Prevalence of the rare variants may be higher than was previously believed because they can be mistaken for the PI*Z variant and thus misdiagnosed. A recent revision of 3511 AAT deficiency determinations performed at the Spanish Registry Laboratory, from 1998 to 2010, detected 1.6% of cases with rare AAT alleles, a rate similar to those reported in other European studies [Rodriguez-Frias et al. 2012]. Hence, the so-called rare AAT alleles may not be as rare as assumed. It has even been suspected that rare AAT deficiency variants could be more frequent in those countries in which the gene frequency of PI*Z is lower, such as in some Mediterranean and North African countries [Denden et al. 2009]. Therefore, despite these caveats, the overall estimates of carriers and severe AAT deficiency subjects worldwide appear impressive, suggesting that AAT deficiency is probably one of the most common hereditary under-recognized disorders in the world, with only a small minority of subjects currently detected. The results of the present analysis support the concept of targeted screening for AAT deficiency in countries with large populations of white patients with COPD [de Serres et al. 2006]. The availability of AAT replacement therapy for individuals with pulmonary emphysema associated with AAT deficiency encouraged the scientific community to establish and reinforce AAT deficiency screening programs even in countries not previously considered to have a high prevalence of the disorder, and to implement national registries [Stoller et al. 2003]. In the future, with the publication of case studies on health problems associated with the PI*MS, PI*MZ, PI*SS or PI*SZ alleles, the data presented in the 10 tables can be utilized to identify larger numbers of individuals with a given phenotype in particular countries in each of these 10 geographic regions. Conclusion The overall data on the numbers of individuals in the countries in each geographic region and the prevalence of the PI*S and PI*Z deficiency alleles demonstrate the spread of these two alleles to many different countries worldwide from those countries where they arose generations ago. It appears that as a result of this spread by migrating populations, inbreeding populations have been established within given countries with prevalences not necessarily shared by immediately adjacent countries within a given geographic region. The genetic epidemiological data on the prevalence of the two most common deficiency alleles PI*S and PI*Z have shown that they exist in many countries worldwide where there are genetic epidemiological studies in the peerreviewed medical literature. In most countries, individuals with phenotypes that put them at risk of various environmental exposures have not been identified. Regarding AAT deficiency, questions exist as to whether there is an increased risk for adverse health effects when such individuals with AAT deficiency are exposed to toxic environmental agents [Mayer et al. 2000; Sigsgaard et al. 2000; de Serres, 2003]. Occupational exposures of concern may include a variety of situations that expose workers with AAT deficiency to hazardous agents. Such agents (and worker groups exposed) could include chemical substances (beauticians, chemical plant workers, fumigators, gas station attendants, painters and welders), toxic fumes (airport personnel, bus, cab and truck drivers, dry cleaners, factory workers, industrial and household cleaners, and manicurists), and organic wastes or particulates (agricultural workers, dental workers, farmers, miners and textile workers). Those at risk also may work in professions regularly exposed to pathogens and other readily transmissible diseases (doctors, school teachers, nurses and other healthcare professionals, sales personnel, and restaurant and hotel waiting staff). Thus, we can conclude that collection of detailed information on occupation is critical for the effective management of individuals with AAT deficiency [de Serres, 2003]. There are cost-effective, targeted screening approaches that could be used in the USA, for example, to detect AAT deficiency in patients with COPD [de Serres et al. 2006]

18 Therapeutic Advances in Respiratory Disease 6 (5) In summary, identification of individuals with AAT deficiency worldwide is critical for management and education. More effective healthcare management and lifestyle changes, such as smoking cessation, can be undertaken in individuals with AAT deficiency to prevent the development of lung disease. Acknowledgements This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the United States government. The authors are indebted to Ms Suzan Edelstein of the DHHS/ NIH/NIEHS Arts and Photography Department for her creativity in displaying a very complex database both in worldwide maps and figures to facilitate comparisons of the prevalences of the P*S and PI*Z alleles in each of the 97 countries. The authors are also indebted to Professor Enrique Fernandez-Bustillo for development of a method for statistical analysis used to obtain the numbers in each of the five phenotypic classes as well as the prevalences of PI*S and PI*Z. Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors. Conflict of interest statement The authors declare that they have no competing interests. References Blanco, I., Bustillo, E.F. and Rodriguez, M. C. (2001a) Distribution of alpha1-antitrypsin PI S and PI Z frequencies in countries outside Europe: a meta-analysis. Clin Genet 60: Blanco, I., Fernandez, E. and Bustillo, E.F. (2001b) Alpha-1-antitrypsin PI phenotypes S and Z in Europe: an analysis of the published surveys. Clin Genet 60: Blanco, I., de Serres, F.J., Bustillo, E.F., Rodriguez, C. (2004) Cálculo estimativo del número de sujetos con déficit congénito de Alfa-1-antitripsina en España (alelos PIS y PIZ) y su distribución por fenotipos. Med Clin (Barc) 123 (20): Blanco, I. and Fernández. E. (2006) Estimated numbers and prevalence of PI*S and PI*Z alleles of alpha1-antitrypsin deficiency in European countries. Eur Respir J 27: Blanco, I. and Fernández, E. (2001) Alpha1- antitrypsin Pi phenotypes S and Z in Spain: an analysis of the published surveys. Respir Med 95: Brantly, M., Nukiwa, T. and Crystal, R.G. (1988a) Molecular basis of alpha-1-antitrypsin deficiency. Am J Med 84: Brantly, M. Paul, L.D., Miller, B.H., Falk, R.T., Wu, M., Crystal, R.G. et al. (1988b) Clinical features and history of the destructive lung disease associated with alpha-1-antitrypsin deficiency of adults with pulmonary symptoms. Am Rev Respir Dis 138: Carroll, T.P., O Connor, C. A., Floyd, O., McPartlin, J., Kelleher, D. P., O Brien, G. et al. (2011) The prevalence of alpha-1 antitrypsin deficiency in Ireland. Respir Res 12: 91. Denden, S., Zorzetto, M., Amri, F., Knani, J., Ottaviani, S., Scabini, R. et al. (2009) Screening for alpha 1 antitrypsin deficiency in Tunisian subjects with obstructive lung disease: a feasibility report. Orphanet J Rare Dis 4: 12. de Serres, F. (2002) Worldwide racial and ethnic distribution of alpha(1)-antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys. Chest 122: de Serres, F. (2003) Alpha-1 antitrypsin deficiency is not a rare disease, but a disease that is rarely diagnosed. Environ Health Perspect 111: de Serres, F., Blanco, I. and Fernandez-Bustillo, E. (2003a) Genetic epidemiology of alpha-1 antitrypsin deficiency in North America and Australia/New Zealand: Australia, Canada, New Zealand and the United States of America. Clin Genet 64: de Serres, F., Blanco, I. and Fernandez-Bustillo, E. et al. (2003b) Genetic epidemiology of alpha-1 antitrypsin deficiency in southern Europe: France, Italy, Portugal and Spain. Clin Genet 63: de Serres, F., Blanco, I. and Fernandez-Bustillo, E. (2005a) Health implications of alpha(1)-antitrypsin deficiency in Sub-Sahara African countries and their emigrants in Europe and the New World. Genet Med 7: de Serres, F., Luisetti, M., Ferrarotti, I., Blanco, I. and Fernandez-Bustillo, E. (2005b) Alpha-1 antitrypsin deficiency in Italy: regional differences of the PIS and PIZ deficiency alleles of alpha-1 antitrypsin deficiency in Italy. Monaldi Arch Chest Dis 63: de Serres, F., Blanco, I. and Fernandez-Bustillo, E. (2006a) Estimated numbers and prevalence of PI*S 294

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