Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1987 Mar;40(3):267–277.

Does the PI polymorphism alone control alpha-1-antitrypsin expression?

N G Martin, P Clark, A F Ofulue, L J Eaves, L A Corey, W E Nance
PMCID: PMC1684104  PMID: 3495177

Abstract

Whether genetic factors other than the protease-inhibitor (PI) polymorphism itself contribute to variation in alpha-1-antitrypsin is of both theoretical and practical interest. We have measured the quantity of alpha-1-antitrypsin (by an immunoturbidometric assay) and its activity (by assaying elastase inhibitory capacity [EIC]) in 583 individuals from 114 twin kinships who were also typed for PI by isoelectric focusing. Models of variation were fitted directly to the raw observations by a maximum-likelihood method. Specification of phenotypic means led to highly significant improvements in fit over models including only individual environment variance and additive genetic variance. The 29 phenotype means could also be described as the appropriate additive combinations of the 12 allelic effects. Only small improvements in fit could then be obtained by addition of polygenic components of variance. We conclude that nearly all genetic variation in alpha-1-antitrypsin quantity and activity can be explained by detectable variation at the PI locus and that this variance is largely additive. Bivariate analysis of alpha-1-antitrypsin and EIC revealed marginal evidence for differences in specific activities of molecules coded by different PI alleles. The correlation between environmental deviations for the two measures was only .63, which may reflect, in part, the rather low reliability of the assays and account for the modest heritabilities (less than .5) of the two measures. An intriguing finding was the presence of significant differences in E1 variance for different PI types, suggesting that different phenotypes have differing capacities to react to environmental challenges.

Full text

PDF
267

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Beckman G., Beckman L. Serum levels of alpha-1-antitrypsin in individuals with different Pi M subtypes. Hum Hered. 1980;30(2):81–83. doi: 10.1159/000153106. [DOI] [PubMed] [Google Scholar]
  2. Bieth J., Spiess B., Wermuth C. G. The synthesis and analytical use of a highly sensitive and convenient substrate of elastase. Biochem Med. 1974 Dec;11(4):350–357. doi: 10.1016/0006-2944(74)90134-3. [DOI] [PubMed] [Google Scholar]
  3. Clark P., Martin N. G. An excess of the Pi S allele in dizygotic twins and their mothers. Hum Genet. 1982;61(2):171–174. doi: 10.1007/BF00274213. [DOI] [PubMed] [Google Scholar]
  4. Corey L. A., Eaves L. J., Mellen B. G., Nance W. E. Testing for developmental changes in gene expression on resemblance for quantitative traits in kinships of twins: application to height, weight, and blood pressure. Genet Epidemiol. 1986;3(2):73–83. doi: 10.1002/gepi.1370030203. [DOI] [PubMed] [Google Scholar]
  5. Cox D. W., Johnson A. M., Fagerhol M. K. Report of Nomenclature Meeting for alpha 1-antitrypsin, INSERM, Rouen/Bois-Guillaume-1978. Hum Genet. 1980;53(3):429–433. doi: 10.1007/BF00287070. [DOI] [PubMed] [Google Scholar]
  6. Cox D. W., Johnson A. M., Fagerhol M. K. Report of Nomenclature Meeting for alpha 1-antitrypsin, INSERM, Rouen/Bois-Guillaume-1978. Hum Genet. 1980;53(3):429–433. doi: 10.1007/BF00287070. [DOI] [PubMed] [Google Scholar]
  7. Eaves L. J., Last K. A., Young P. A., Martin N. G. Model-fitting approaches to the analysis of human behaviour. Heredity (Edinb) 1978 Dec;41(3):249–320. doi: 10.1038/hdy.1978.101. [DOI] [PubMed] [Google Scholar]
  8. Fagerhol M. K., Cox D. W. The Pi polymorphism: genetic, biochemical, and clinical aspects of human alpha 1-antitrypsin. Adv Hum Genet. 1981;11:1-62, 371-2. [PubMed] [Google Scholar]
  9. Gibson J. B., Martin N. G., Oakeshott J. G., Rowell D. M., Clark P. Lung function in an Australian population: contributions of polygenic factors and the Pi locus to individual differences in lung function in a sample of twins. Ann Hum Biol. 1983 Nov-Dec;10(6):547–556. doi: 10.1080/03014468300006771. [DOI] [PubMed] [Google Scholar]
  10. Hopper J. L., Mathews J. D. Extensions to multivariate normal models for pedigree analysis. Ann Hum Genet. 1982 Oct;46(Pt 4):373–383. doi: 10.1111/j.1469-1809.1982.tb01588.x. [DOI] [PubMed] [Google Scholar]
  11. Klasen E. C., Bos A., Simmelink H. D. PI (alpha 1-Antitrypsin) subtypes: frequency of PI*M4 in several populations. Hum Genet. 1982;62(2):139–141. doi: 10.1007/BF00282302. [DOI] [PubMed] [Google Scholar]
  12. Lange K., Boehnke M. Extensions to pedigree analysis. IV. Covariance components models for multivariate traits. Am J Med Genet. 1983 Mar;14(3):513–524. doi: 10.1002/ajmg.1320140315. [DOI] [PubMed] [Google Scholar]
  13. Lange K., Westlake J., Spence M. A. Extensions to pedigree analysis. III. Variance components by the scoring method. Ann Hum Genet. 1976 May;39(4):485–491. doi: 10.1111/j.1469-1809.1976.tb00156.x. [DOI] [PubMed] [Google Scholar]
  14. Martin N. G., Oakeshott J. G., Clark P., Carr A. Association between alpha-1-antitrypsin types and the common cold. Hum Hered. 1983;33(5):265–269. doi: 10.1159/000153389. [DOI] [PubMed] [Google Scholar]
  15. Martin N. G., Oakeshott J. G. Is Pi a selectively balanced polymorphism? Hum Hered. 1983;33(1):24–28. doi: 10.1159/000153342. [DOI] [PubMed] [Google Scholar]
  16. Oakeshott J. G., Muir A., Clark P., Martin N. G., Wilson S. R., Whitfield J. B. Effects of the protease inhibitor (Pi) polymorphism on alpha-1-antitrypsin concentration and elastase inhibitory capacity in human serum. Ann Hum Biol. 1985 Mar-Apr;12(2):149–160. doi: 10.1080/03014468500007641. [DOI] [PubMed] [Google Scholar]
  17. Rantala H., Finni K., Similä S. Alpha-1-antitrypsin: the PiM subtypes and serum concentrations in Finnish newborns. Hum Hered. 1982;32(3):228–232. doi: 10.1159/000153298. [DOI] [PubMed] [Google Scholar]
  18. Talamo R. C., Langley C. E., Reed C. E., Makino S. 1 -Antitrypsin deficiency: a variant with no detectable 1 -antitrypsin. Science. 1973 Jul 6;181(4094):70–71. doi: 10.1126/science.181.4094.70. [DOI] [PubMed] [Google Scholar]
  19. 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(3):203–211. doi: 10.1007/BF00200725. [DOI] [PubMed] [Google Scholar]
  20. Weidinger S., Jahn W., Cujnik F., Schwarzfischer F. Alpha-1-antitrypsin: evidence for a fifth PI M subtype and a new deficiency allele PI*Z augsburg. Hum Genet. 1985;71(1):27–29. doi: 10.1007/BF00295662. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES