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Editorials |
1-Antitrypsin Deficiency: The Promise of Early Diagnosis and Intervention
University of Florida, Alpha-1-Antitrypsin, Genetics Laboratory, Gainesville, FL, Fax 352-392-7088, E-mail brantml{at}medicine.ufl.edu
Abnormal human genes are rarely absolute predictors of the development of disease. With a few notable exceptions, abnormal genes predict risk of disease, and this risk is modified by environmental factors. When these environmental risk factors are known and minimized, early identification may translate into substantial health benefits. One of the best examples of the potential of this paradigm is 
1-antitrypsin deficiency.
1-Antitrypsin (AAT) deficiency is most often caused by inheritance of the so-called PI*Z allele (1)(2). "PI" is the former nomenclature for the SERPINA1 [serpin peptidase inhibitor, clade A (1 antiproteinase, antitrypsin), member 1] gene locus and stands for protease inhibitor. While the number of AAT variants is >100, 
95% of all AAT-deficient individuals are homozygous for the Z allele. The PI*Z allele is the result of a guanine-to-adenine base substitution, which in turn changes glutamic acid to lysine at position 342 of the mature AAT protein. This amino acid change alters the net charge of the protein and is the basis of its identification in isoelectric focusing gels. Inheritance of this allele increases the risk of developing chronic obstructive lung disease (COPD) and liver disease (1)(2). The diagnosis of AAT deficiency is based exclusively on laboratory assays (3).
Risk ratios for COPD range from 1.5–12-fold, depending on whether the Z allele is present in heterozygous or homozygous combinations (4)(5)(6)(7)(8). Among normal individuals only 1 in 100 have a Z allele. Nearly 97% of the population is homozygous for the normal PI*M allele. However, among individuals with COPD, up to 10% have a Z allele, 10 times the frequency of the normal population. Based on NHLBI data that 15 million individuals have COPD in the US, it is estimated that there are 1.5 million individuals who have at least one PI*Z allele. Thus, PI*Z is the most common known inherited risk factor for COPD.
Environmental risk factors for progression of lung disease among individuals with a Z allele include personal smoking, passive smoke exposure especially as a child, and mineral dust exposure (9)(10)(11). Personal smoking has the most dramatic effect on health status of PI ZZ individuals. PI ZZ individuals who smoke cigarettes die 20 years earlier than PI-ZZ nonsmokers (12).
Recent studies have demonstrated that significant positive effects are associated with the identification of AAT-deficient individuals. Importantly, these effects include an increased willingness to stop cigarette smoking in 75% of the study participants (13).
In this context there are compelling reasons to identify individuals with a Z allele, which in turn provides the opportunity to decrease environmental risk factors associated with progression to disease. Unfortunately, testing for AAT deficiency is rarely performed despite the fact that it is the major known genetic risk factor for the 4th leading cause of death in the US. Based on the gene frequency of the Z allele, it is estimated that there are at least 100 000 PI ZZ individuals in the US. To date, only 6000 of these individuals have been identified.
The guidelines of the American Thoracic Society and the European Respiratory Society strongly recommend testing for AAT deficiency in individuals with fixed airway obstruction, and they believe it is prudent to recommend testing for family members of AAT-deficient individuals (14). Why then are healthcare providers not following testing guidelines for a genetic condition that is common and for which intervention may substantially improve the lives of their patients and families? One reason may be that recommendations by experts in AAT deficiency have been slow to advocate allele identification over AAT concentration assays that typically miss most heterozygous individuals. There are likely more general reasons for not following the recommendation of these societies, including the lack of training in genetic diseases in most US residency programs. These deficiencies in training are currently being addressed by training oversight committees, and increased attention to genetics in medical practice will be forthcoming. Additionally, new online resources, such as GeneReviews funded by the NIH, are now available to healthcare providers. As these tools are incorporated into medical practice there should be a more rapid incorporation of genetics in general clinical medicine.
As AAT deficiency awareness increases, large numbers of individuals within the COPD population and their families will request testing. There is little doubt that existing testing facilities based on gold standard assays will not be able to cope with the increased need.
There are technical hurdles to the introduction of AAT deficiency testing in routine hospital laboratories. Although AAT plasma/serum concentration assays are offered commonly by hospital laboratories, these assays are insufficient to identify carriers of the Z allele. More advanced testing for abnormal AAT variants is performed in only a dozen or so laboratories in the US. The reason for the limited number of laboratories offering specific testing for abnormal AAT variants is based on the fact that the gold standard for identification of these alleles is isoelectric focusing of plasma or serum in narrow-pH-gradient (pH 4–5), thin-layer gels (often called phenotyping or Pi typing) (3). Performance of this assay is technically challenging and requires highly skilled technicians. Furthermore, interpretation of the gels is challenging because of the complex microheterogeneity of AAT and the large number of variants.
While there have been substantial advances that make the molecular diagnosis of AAT deficiency less challenging, these advances have not been incorporated into most diagnostic laboratories. Separately, protein and DNA based assays have weaknesses in accurately establishing the presence of the Z or the minor deficiency allele S. In this issue of Clinical Chemistry, Synder et al. (15) validate an efficient and accurate algorithm for the diagnosis of AAT deficiency using a combination of assays.
Synder et al. present evidence that the use of a PCR-based assay system that identifies the Z and S alleles coupled with a measurement of serum or plasma AAT concentration accurately identifies 96% of all subjects when compared with the gold standard of isoelectric focusing-based phenotyping. In individuals in whom there was discordance between the AAT concentration and the genotype, reflex phenotyping was performed.
The strength of this approach is that genotyping is straightforward and provides unequivocal identification of the most common alleles associated with AAT deficiency. The addition of AAT concentration determination identifies those samples with rare deficiency alleles not recognized by genotyping for the S and Z alleles. These samples would prompt the use of phenotyping as a reflex test.
While this approach will not identify the rare normal AAT variants, these variants are not germane to clinical care. Rare AAT deficiency variants not readily recognized by phenotyping would be referred for more advanced diagnostic methods such as DNA sequencing.
The systematic and less complex approaches to the laboratory diagnosis of AAT deficiency should provide for greater penetration of AAT genetic testing into the hospital laboratory settings and clinics. When coupled with increased awareness of this disorder, perhaps the early diagnosis of AAT deficiency alleles will allow clinicians to prevent rather than treat a disease.
Acknowledgments
M.B. is supported by NIH grant HL-4456 and by the Alpha-1 Foundation.
References
-1-antitrypsin deficiency. Am J Med 1988;84:13-31.[Web of Science][Medline]
[Order article via Infotrieve]-1-antitrypsin deficiency. Crystal R eds. In Alpha-1-Antitrypsin Deficiency 1995:45-60 Marcel Dekker New York. .(1)-antitrypsin deficiency: MZ individuals with chronic obstructive pulmonary disease may have lower lung function than MM individuals. Clin Chem 2001;47:56-62.(1)-antitrypsin heterozygote schoolchildren. Thorax 2003;58:237-241.(1)-antitrypsin deficiency. Am J Respir Crit Care Med 2000;162:553-558.-1 antitrypsin deficiency]. Pneumologie 2005;59:36-68.[CrossRef][Medline]
[Order article via Infotrieve]-1-antitrypsin deficiency: an algorithm of quantitation, genotyping, and phenotyping. Clin Chem 2006;12:2236-2242.The following articles in journals at HighWire Press have cited this article:
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  E. K. Silverman and R. A. Sandhaus Alpha1-Antitrypsin Deficiency N. Engl. J. Med., June 25, 2009; 360(26): 2749 - 2757. [Full Text] [PDF]
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 M. Dahl Commentary Clin. Chem., August 1, 2008; 54(8): 1398 - 1399. [Full Text] [PDF]
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J. Prins, B. B. van der Meijden, R. J. Kraaijenhagen, and J. P.M. Wielders Inherited Chronic Obstructive Pulmonary Disease: New Selective-Sequencing Workup for {alpha}1-Antitrypsin Deficiency Identifies 2 Previously Unidentified Null Alleles Clin. Chem., January 1, 2008; 54(1): 101 - 107. [Abstract] [Full Text] [PDF]
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