Received on December 31, 2007
Accepted on April 24, 2008

Molecular Diagnostics and Genetics

SERPINA1 Gene Variants in Individuals from the General Population with Reduced ₁-Antitrypsin Concentrations

¹ Center for Diagnosis of Severe Alpha1-antitrypsin Deficiency, Laboratory of Biochemistry and Genetics, Institute for Respiratory Disease and Unit of Statistics and Biometry, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy
² Pulmonary Division, University Hospital of Zurich, Switzerland
³ Pulmonary Division, University Hospital of Zurich, Switzerland, and Molecular Epidemiology/Cancer Registry, Institutes of Social and Preventive Medicine and Clinical Pathology, University of Zurich, Switzerland
⁴ Molecular Epidemiology/Cancer Registry, Institutes of Social and Preventive Medicine and Clinical Pathology, University of Zurich, Switzerland, and Institute of Clinical Chemistry, University Hospital of Zürich, Switzerland
⁵ Institute of Clinical Chemistry, University Hospital of Zürich, Switzerland
⁶ Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Switzerland
⁷ Zürcher Höhenklinik Wald, Switzerland
⁸ Division of Pulmonary Medicine, University Hospitals of Geneva, Geneva, Switzerland
⁹ Molecular Epidemiology/Cancer Registry, Institutes of Social and Preventive Medicine and Clinical Pathology, University of Zurich, Switzerland
¹⁰ Center for Diagnosis of Severe Alpha1-antitrypsin Deficiency, Laboratory of Biochemistry and Genetics, Institute for Respiratory Disease and Unit of Statistics and Biometry, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy, and Pulmonary Division, University Hospital of Zurich, Switzerland, and Molecular Epidemiology/Cancer Registry, Institutes of Social and Preventive Medicine and Clinical Pathology, University of Zurich, Switzerland, and Institute of Clinical Chemistry, University Hospital of Zürich, Switzerland, and Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Switzerland, and Zürcher Höhenklinik Wald, Switzerland, and Division of Pulmonary Medicine, University Hospitals of Geneva, Geneva, Switzerland

^* To whom correspondence should be addressed. E-mail: Nicole.Probst{at}usz.ch.

BACKGROUND: Individuals with severe deficiency in serum ₁-antitrypsin (AAT) concentrations are at high risk for developing chronic obstructive pulmonary disease (COPD), whereas those carrying the PI*MZ genotype are at slightly increased risk. Testing appropriate subgroups of the population for AAT deficiency (AATD) is therefore an important aspect of COPD prevention and timely treatment. We decided to perform an exhaustive investigation of SERPINA1 gene variants in individuals from the general population with a moderately reduced serum AAT concentration, because such information is currently unavailable.

METHODS: We determined the Z and S alleles of 1399 individuals enrolled in the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) with serum AAT concentrations <113 mg/dL and submitted 423 of these samples for complete exon 25 sequencing.

RESULTS: We found that 900 of 1399 samples (64%), carried the normal PI*MM genotype, whereas 499 samples (36%) carried at least 1 SERPINA1 deficiency variant. In the subpopulations in which AAT concentrations ranged from 103 to 113 and from 93 to 103 mg/dL, individuals with the PI*MM genotype represented the majority (86.5% and 53.8%, respectively). The PI*MS genotype was predominant (54.9%) in the AAT range of 83 to 93 mg/dL, whereas PI*MZ represented 76.4% in the AAT range of 73 to 83 mg/dL.

CONCLUSIONS: This analysis provided a detailed molecular definition of intermediate AATD, which would be helpful in the diagnostic setting.