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. 1995 Apr;95(4):1635–1641. doi: 10.1172/JCI117838

Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype.

J Turki 1, J Pak 1, S A Green 1, R J Martin 1, S B Liggett 1
PMCID: PMC295666  PMID: 7706471

Abstract

Nocturnal asthma represents a unique subset of patients with asthma who experience worsening symptoms and airflow obstruction at night. The basis for this phenotype of asthma is not known, but beta 2-adrenergic receptors (beta 2AR) are known to downregulate overnight in nocturnal asthmatics but not normal subjects or nonnocturnal asthmatics. We have recently delineated three polymorphic loci within the coding block of the beta 2AR which alter amino acids at positions 16, 27, and 164 and impart specific biochemical and pharmacologic phenotypes to the receptor. In site-directed mutagenesis/recombinant expression studies we have found that glycine at position 16 (Gly16) imparts an accelerated agonist-promoted downregulation of beta 2AR as compared to arginine at this position (Arg16). We hypothesized that Gly16 might be overrepresented in nocturnal asthmatics and thus determined the beta 2AR genotypes of two well-defined asthmatic cohorts: 23 nocturnal asthmatics with 34 +/- 2% nocturnal depression of peak expiratory flow rates, and 22 nonnocturnal asthmatics with virtually no such depression (2.3 +/- 0.8%). The frequency of the Gly16 allele was 80.4% in the nocturnal group as compared to 52.2% in the nonnocturnal group, while the Arg16 allele was present in 19.6 and 47.8%, respectively. This overrepresentation of the Gly16 allele in nocturnal asthma was significant at P = 0.007 with an odds ratio of having nocturnal asthma and the Gly16 polymorphism being 3.8. Comparisons of the two cohorts as to homozygosity for Gly16, homozygosity for Arg16, or heterozygosity were also consistent with segregation of Gly16 with nocturnal asthma. There was no difference in the frequency of polymorphisms at loci 27 (Gln27 or Glu27) and 164 (Thr164 or Ile164) between the two groups. Thus the Gly16 polymorphism of the beta 2AR, which imparts an enhanced downregulation of receptor number, is overrepresented in nocturnal asthma and appears to be an important genetic factor in the expression of this asthmatic phenotype.

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Selected References

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  1. Barnes P. J. Beta-adrenoceptors on smooth muscle, nerves and inflammatory cells. Life Sci. 1993;52(26):2101–2109. doi: 10.1016/0024-3205(93)90725-i. [DOI] [PubMed] [Google Scholar]
  2. Barnes P., FitzGerald G., Brown M., Dollery C. Nocturnal asthma and changes in circulating epinephrine, histamine, and cortisol. N Engl J Med. 1980 Jul 31;303(5):263–267. doi: 10.1056/NEJM198007313030506. [DOI] [PubMed] [Google Scholar]
  3. Bates M. E., Clayton M., Calhoun W., Jarjour N., Schrader L., Geiger K., Schultz T., Sedgwick J., Swenson C., Busse W. Relationship of plasma epinephrine and circulating eosinophils to nocturnal asthma. Am J Respir Crit Care Med. 1994 Mar;149(3 Pt 1):667–672. doi: 10.1164/ajrccm.149.3.8118634. [DOI] [PubMed] [Google Scholar]
  4. Busse W. W. Pathogenesis and pathophysiology of nocturnal asthma. Am J Med. 1988 Jul 29;85(1B):24–29. doi: 10.1016/0002-9343(88)90238-0. [DOI] [PubMed] [Google Scholar]
  5. Cochrane G. M., Clark J. H. A survey of asthma mortality in patients between ages 35 and 64 in the Greater London hospitals in 1971. Thorax. 1975 Jun;30(3):300–305. doi: 10.1136/thx.30.3.300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Green S. A., Cole G., Jacinto M., Innis M., Liggett S. B. A polymorphism of the human beta 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J Biol Chem. 1993 Nov 5;268(31):23116–23121. [PubMed] [Google Scholar]
  7. Green S. A., Turki J., Innis M., Liggett S. B. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry. 1994 Aug 16;33(32):9414–9419. doi: 10.1021/bi00198a006. [DOI] [PubMed] [Google Scholar]
  8. Hetzel M. R., Clark T. J., Branthwaite M. A. Asthma: analysis of sudden deaths and ventilatory arrests in hospital. Br Med J. 1977 Mar 26;1(6064):808–811. doi: 10.1136/bmj.1.6064.808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Insel P. A., Wasserman S. I. Asthma: a disorder of adrenergic receptors? FASEB J. 1990 Jul;4(10):2732–2736. doi: 10.1096/fasebj.4.10.2197153. [DOI] [PubMed] [Google Scholar]
  10. JONES A. S. USE OF ALKYLTRIMETHYLAMMONIUM BROMIDES FOR THE ISOLATION OF RIBO- AND DESOXYRIBO-NUCLEIC ACIDS. Nature. 1963 Jul 20;199:280–282. doi: 10.1038/199280b0. [DOI] [PubMed] [Google Scholar]
  11. Kobilka B. K., Dixon R. A., Frielle T., Dohlman H. G., Bolanowski M. A., Sigal I. S., Yang-Feng T. L., Francke U., Caron M. G., Lefkowitz R. J. cDNA for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor. Proc Natl Acad Sci U S A. 1987 Jan;84(1):46–50. doi: 10.1073/pnas.84.1.46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Marsh D. G., Neely J. D., Breazeale D. R., Ghosh B., Freidhoff L. R., Ehrlich-Kautzky E., Schou C., Krishnaswamy G., Beaty T. H. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science. 1994 May 20;264(5162):1152–1156. doi: 10.1126/science.8178175. [DOI] [PubMed] [Google Scholar]
  13. Martin R. J., Cicutto L. C., Ballard R. D. Factors related to the nocturnal worsening of asthma. Am Rev Respir Dis. 1990 Jan;141(1):33–38. doi: 10.1164/ajrccm/141.1.33. [DOI] [PubMed] [Google Scholar]
  14. Martin R. J., Cicutto L. C., Smith H. R., Ballard R. D., Szefler S. J. Airways inflammation in nocturnal asthma. Am Rev Respir Dis. 1991 Feb;143(2):351–357. doi: 10.1164/ajrccm/143.2.351. [DOI] [PubMed] [Google Scholar]
  15. Martin R. J. Circadian rhythms, nocturnal asthma, and management. Ann Allergy. 1992 Sep;69(3):267–272. [PubMed] [Google Scholar]
  16. Meyers D. A., Postma D. S., Panhuysen C. I., Xu J., Amelung P. J., Levitt R. C., Bleecker E. R. Evidence for a locus regulating total serum IgE levels mapping to chromosome 5. Genomics. 1994 Sep 15;23(2):464–470. doi: 10.1006/geno.1994.1524. [DOI] [PubMed] [Google Scholar]
  17. Newton C. R., Graham A., Heptinstall L. E., Powell S. J., Summers C., Kalsheker N., Smith J. C., Markham A. F. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res. 1989 Apr 11;17(7):2503–2516. doi: 10.1093/nar/17.7.2503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Nijkamp F. P., Engels F., Henricks P. A., Van Oosterhout A. J. Mechanisms of beta-adrenergic receptor regulation in lungs and its implications for physiological responses. Physiol Rev. 1992 Apr;72(2):323–367. doi: 10.1152/physrev.1992.72.2.323. [DOI] [PubMed] [Google Scholar]
  19. Postma D. S., Keyzer J. J., Koëter G. H., Sluiter H. J., De Vries K. Influence of the parasympathetic and sympathetic nervous system on nocturnal bronchial obstruction. Clin Sci (Lond) 1985 Sep;69(3):251–258. doi: 10.1042/cs0690251. [DOI] [PubMed] [Google Scholar]
  20. REINBERG A., GHATA J., SIDI E. NOCTURNAL ASTHMA ATTACKS: THEIR RELATIONSHIP TO THE CIRCADIAN ADRENAL CYCLE. J Allergy. 1963 Jul-Aug;34:323–330. doi: 10.1016/0021-8707(63)90049-2. [DOI] [PubMed] [Google Scholar]
  21. Reihsaus E., Innis M., MacIntyre N., Liggett S. B. Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol. 1993 Mar;8(3):334–339. doi: 10.1165/ajrcmb/8.3.334. [DOI] [PubMed] [Google Scholar]
  22. Ryan G., Latimer K. M., Dolovich J., Hargreave F. E. Bronchial responsiveness to histamine: relationship to diurnal variation of peak flow rate, improvement after bronchodilator, and airway calibre. Thorax. 1982 Jun;37(6):423–429. doi: 10.1136/thx.37.6.423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Shirakawa T., Li A., Dubowitz M., Dekker J. W., Shaw A. E., Faux J. A., Ra C., Cookson W. O., Hopkin J. M. Association between atopy and variants of the beta subunit of the high-affinity immunoglobulin E receptor. Nat Genet. 1994 Jun;7(2):125–129. doi: 10.1038/ng0694-125. [DOI] [PubMed] [Google Scholar]
  24. Szefler S. J., Ando R., Cicutto L. C., Surs W., Hill M. R., Martin R. J. Plasma histamine, epinephrine, cortisol, and leukocyte beta-adrenergic receptors in nocturnal asthma. Clin Pharmacol Ther. 1991 Jan;49(1):59–68. doi: 10.1038/clpt.1991.11. [DOI] [PubMed] [Google Scholar]
  25. Turner-Warwick M. Epidemiology of nocturnal asthma. Am J Med. 1988 Jul 29;85(1B):6–8. doi: 10.1016/0002-9343(88)90231-8. [DOI] [PubMed] [Google Scholar]
  26. Young R. P., Sharp P. A., Lynch J. R., Faux J. A., Lathrop G. M., Cookson W. O., Hopkin J. M. Confirmation of genetic linkage between atopic IgE responses and chromosome 11q13. J Med Genet. 1992 Apr;29(4):236–238. doi: 10.1136/jmg.29.4.236. [DOI] [PMC free article] [PubMed] [Google Scholar]

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