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(Chest. 2001;120:1493-1499.)
© 2001 American College of Chest Physicians

Polymorphism of the ß2-Adrenoceptor in COPD in Chinese Subjects*

Li-Ing Ho, MD, FCCP; Horng-Jyh Harn, MD, PhD; Cheng-Jueng Chen, MD and Nu-Man Tsai, MS

* From the Department of Respiratory Care (Dr. Ho), Veterans General Hospital-Taipei, Taipei, Taiwan; Department of Pathology (Dr. Harn), Tri-Service General Hospital, Taipei, Taiwan; Department of General Surgery (Dr. Chen), Tri-Service General Hospital, Taipei, Taiwan; and Graduate Institute of Medical Sciences (Ms. Tsai), National Defense Medical Center, Taipei, Taiwan.

Correspondence to: Li-Ing Ho, MD, FCCP, Department of Respiratory Care, Veterans General Hospital-Taipei, No. 201, Section 2, Shih-Pai Rd, Taipei, Taiwan; e-mail: liho{at}vghtpe.gov.tw


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To assess the frequencies of three polymorphisms at amino acid positions 16, 27, and 164 of the ß2-adrenoceptor (ß2-AR) gene and their effects on COPD patients.

Design: Prospective, case-control study

Patients: Sixty-five patients with COPD and 41 healthy subjects were included.

Measurements: Polymorphisms of the ß2-AR coding block were delineated using an allele-specific polymerase chain reaction (PCR) approach. The allele-specific PCR technique was verified by direct dideoxy sequencing of PCR products. Pulmonary function tests were performed in all patients.

Results: The Arg16 ß2-AR polymorphism was less prevalent in COPD patients than in healthy populations (p = 0.01). A significant correlation (p < 0.018) between the Gln27 ß2-AR polymorphism and FEV1 percent predicted value was found. Patients with the Gln27 polymorphism had a higher percentage of low FEV1 percent predicted than did patients with the GlnGlu and GluGlu variants.

Conclusions: The polymorphism of Gly16 may increase the patient’s susceptibility to the development of COPD. The Gln27 ß2-AR polymorphism may be associated with the severity of COPD in a Chinese population.

Key Words: allele-specific polymerase chain reaction • ß2-adrenoceptor polymorphism • COPD • dideoxy DNA sequencing


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Despite decades of intensive study, a satisfactory understanding of the epidemiology and natural history of COPD remains elusive. Tobacco smoking is the major risk factor for COPD; however, only approximately 15% of smokers develop clinically relevant airflow obstruction.1 2 This variation in the susceptibility to cigarette smoke in combination with the familiar aggregation of COPD suggests that there may be a genetic component to the development of COPD. Multiple studies in diverse populations have shown evidence for a large genetic contribution to the variability in pulmonary function and for the familial aggregation of COPD patients.3 4 5 6 7 8 As expected, segregation analysis suggests that multiple genes may be involved. At present, however, only a single gene, {alpha}1-antitrypsin, a potent inhibitor of inflammatory cell protease in the lung, has been unequivocally implicated in the development of COPD. The association between the ZZ type polymorphism of this gene and COPD has been established.9 10 Furthermore, the associations between COPD and polymorphisms in several other genes of potential importance to COPD pathogenesis also have been studied. These include {alpha}1-antichymotrypsin,11 12 microsomal epoxide hydrolase,13 vitamin D-binding protein,14 and tumor necrosis factor-{alpha}.15

ß2-adrenergic agonists are one of the most potent bronchodilators presently available for the treatment of both asthma and COPD.16 17 The gene encoding this G-protein-coupled receptor is located on the long arm of chromosome 5 (5q31–33) and was cloned in 1987.18 Nine different polymorphisms occurring in this intronless gene have been identified.19 Five of these polymorphisms are degenerative, but four are single-point mutations resulting in single amino acid substitution in the ß2-adrenoceptor (ß2-AR). However, only three loci have been found to alter the receptor function by site-directed mutagenesis and recombinant expression study.19 20 21 22 23 24 25 These polymorphisms consist of substitutions of glycine for arginine at amino acid position 16 (Arg16->Gly16), glutamic acid for glutamine at position 27 (Gln27->Glu27), and isoleucine for threonine at position 164 (Thr164->Ile164).

The polymorphisms at positions 16 and 27 of ß2-AR are relatively common both in asthma populations and healthy populations.22 26 27 Both in vitro and in vivo evidence suggest that these two polymorphisms are also functionally relevant.20 21 22 23 24 25 In vitro studies in transfected cell lines and primary cultures of human-airway smooth-muscle cells have shown that the ß2-agonist-promoted down-regulation of the receptor number is enhanced in Gly-16 compared with Arg-16 cells and is absent when Glu is at position 27.23 24 Clinical studies also have shown that these ß2-AR polymorphisms act as disease modifiers in subjects with asthma,20 22 28 but the possible role that these polymorphisms may play in COPD patients has not yet been investigated.

Based on these clinical and biochemical studies, we investigated ß2-AR polymorphisms at amino acid positions 16, 27, and 164 in 65 COPD patients and 41 corresponding healthy control subjects, and we correlated the incidence of the polymorphisms with the pulmonary function of the patients and control subjects to evaluate the clinical significance of the polymorphism.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Subjects
From July 1997 to June 1998, we recruited 65 patients with COPD who were regularly followed-up in our outpatient department. The definition of COPD was consistent with that in the American Thoracic Society (ATS) consensus statement.29 The patients had a history of chronic or recurrent productive cough for > 2 years and decreased maximum expiratory flow that has been slowly progressive and irreversible. The presence of other lung or cardiac diseases as the cause of patient symptoms was excluded by clinical and radiographic examinations. The criteria of enrollment were as follows: (1) individuals with an FEV1 < 70% of predicted, an FEV1/FVC ratio of < 70%, and an increase in FEV1 of < 12% 15 min after the inhalation of 400 µg Fenoterol HBr MDI (Berotec; Boehringer Ingelheim; Ridgefield, CT); and (2) patient consent to participate in the study. Most of the patients were receiving oral methylxanthine, inhaled anticholinergic agents, and inhaled ß2-agonists as needed. The patient’s name, age, sex, family history, smoking habits, the number of cigarettes smoked, the duration of diseases, and chest radiographic findings were recorded. Pulmonary function testing (model SP-10; Schiller; Baar, Switzerland) was performed according to the ATS performance requirements. Forty-one unrelated, age-matched healthy subjects, who had no known medical illness or family disorders and were taking no medications, acted as control subjects.

ß2-AR Polymorphism Genotyping
Genomic DNA from peripheral whole blood was prepared by standard phenol/chloroform extraction procedures.30

Polymorphisms of the ß2-AR coding block were delineated using an allele-specific polymerase chain reaction (PCR) approach.20 Allele-specific PCR is based on the premise that under the appropriate conditions a match between the template and the primer at the most 3' nucleotide is necessary for the generation of a PCR product and that mismatches result in no product. For the current study, allele-specific PCR was performed to assess polymorphisms at nucleic acids 46, 79, and 491, which result in changes in the encoded amino acids at positions 16, 27, and 164 of the receptor protein. The genotypes are abbreviated as Arg16, Gly16, Gln27, Glu27, Thr164, and Ile164. Genomic DNA was isolated from 2 mL peripheral blood. PCR reactions were carried out in a volume of 50 µL using 100 ng genomic DNA. To delineate the two polymorphisms at nucleic acid 46, the primer pairs were 5'-CTTCTTGCTGGCACCCAATA-3' (sense) and 5'-CCAATTTAGGAGGATGTAAACTTC-3' (anti-sense) or the same antisense primer and 5'-CTTCTTGCTGGCACCCAATG-3' (sense). The generated PCR product size using these primers is 913 base pairs (bp). The primer pair for delineating the two polymorphisms at nucleic acid 79 were 5'-GGACCACGACGTCACGCAGC-3' (sense) and 5'-ACAATCCACACCATCAAGAAT-3' (antisense) or the same antisense primer and 5'-GGACCACGACGTCACGCAGG-3 (sense). Use of these primers resulted in a product with a molecular size of 442 bp. For the detection of polymorphisms at nucleic acid 491, the primer pairs were 5'-TGGATTGTGTCAGGCCTTAT-3' (sense) and 5'-CACAGCAGTTTATTTTCTTT-3' (antisense) or the same antisense primer and 5'-TGGATTGTGTCAGGCCTTAC-3' (sense). The PCR product size from these primers was 662 bp. In general, a 0.1-µg (2-µL) DNA template was added to 50 µL reaction mixtures containing 0.5 µL Takara Taq DNA polymerase (Takara Shuzo Co; Kyoto, Japan), 1 µL each primer, 1 µL dinucleoside 5'-triphosphate, 5 µL 10 x PCR reaction buffer, and 39.5 µL deionized water. The reaction consisted of an initial denaturation at 94°C for 5 min, followed denaturation at 94°C for 2 min, at 55°C for 1 min, and at 72°C for 1 min for 35 cycles and a final extension of 10 min at 72°C (DNA Thermal Cycler; Perkin-Elmer Co; Norwalk, CT). The allele-specific PCR technique was verified by direct dideoxy sequencing (PE Applied Biosystems; Foster City, CA) of PCR products that were generated using sequencing primers that were different from those used in the PCR.

Statistical Analysis
The patient’s age and pulmonary function test data were expressed as the mean ± SD .The association of the ß2-AR polymorphism genotype between healthy subjects and COPD patients was examined by the Mantel-Haenszel {chi}2 test (Excel; Microsoft; Redmond, WA) on a personal computer.


   Results
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Discussion
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There were 60 male and 5 female patients with COPD. The mean age was 71.2 ± 8.8 years. The mean FEV1 was 1.05 ± 0.4 L (45.2 ± 17.8% predicted). The allele frequencies of Gly16 and Gln27 from other studies are shown in Table 1 for comparison.22 26 31 The allele frequencies of our population at positions 16 and 27 were different from those of a white population.


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  		Table 1.. ß2-AR Allele Frequencies in Different Studies

 
Figure 1 shows the results of allele-specific PCR from patients A, B, and C. The identification of polymorphisms occurred in nucleic acid 46 of the ß2-AR in lanes 1 and 2, in nucleic acid 79 of the ß2-AR in lanes 3 and 4, and in nucleic acid 491 of the ß2-AR in lanes 5 and 6.



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  		Figure 1.. The identification of polymorphisms in nucleic acids 46 (lanes 1 and 2), 79 (lanes 3 and 4), and 491 (lanes 5 and 6) of the ß2-AR in three patients. Heterozygotes for glycine 16 allele (ie, nucleic acid 46) are in lanes 1 and 2 (left, A), lanes 1 and 2 (middle, B), and lanes 1 and 2 (right, C). Homozygotes for the glutamic acid 27 allele (ie, nucleic acid 79) are in lanes 3 and 4 (left, A) and lanes 3 and 4 (middle, B), and heterozygotes are in lanes 3 and 4 (right, C). Homozygotes for the Thr 164 allele (ie, nucleic acid 491) are in lanes 5 and 6 (left, A), and heterozygotes are in lanes 5 and 6 (middle, B) and lanes 5 and 6 (right, C). M = molecular marker.

 
The distribution of Arg-Gly16, Gln-Glu27, and Thr-Ile164 ß2-AR polymorphisms within COPD patients and healthy control subjects is shown in Table 2 . There was a significant difference in the frequency of homologous Arg 16 between COPD patients and healthy control subjects (13.8% vs 36.6%, respectively; p = 0.01) but not at position 27 (Gln or Glu27) and position 164 (Thr or Ile164). When we compared the polymorphisms of Arg-Gly16 and Gln-Glu27 with the results of the patients’ pulmonary function tests, there was no significant difference (Table 3 and 4 ).


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  		Table 2.. Frequency of the Genotypes of the ß2-AR Polymorphism in Healthy Subjects and COPD Patients*

 

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  		Table 3.. Age and Pulmonary Function of Patients with ß2-AR Gln27/Glu27 Polymorphism*

 

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  		Table 4.. Age and Pulmonary Function Test Data for Patients With ß2-AR Arg16/Gly16 Polymorphism*

 
The patients were further divided into the following three groups by their FEV1 values according to the proposed staging system of the ATS for the severity of COPD29 : FEV1 < 35% of predicted (severe); FEV1 35 to 50% of predicted (moderate); and FEV1 > 50% of predicted (mild). The genotypic frequencies of these polymorphisms were compared in each group (Table 5). Only the polymorphism of position 27 showed a significant correlation (p < 0.018) with FEV1 percent predicted. There was a clustering of GlnGln27 in patients with severe COPD (12 of 38 patients [31.6%] had FEV1 values < 35% of predicted). Patients with GlnGlu27-type and GluGlu27-type variants were more likely to have moderate and mild COPD (5 of 20 patients [20%] with the GlnGlu27 variant and 1 of 7 patients [14%] with the GluGlu27 variant had FEV1 values < 35% of predicted). The carrying of the Gln27 allele (including both homozygous and heterozygous patients) was associated with an increased risk of more severe impairment of pulmonary function (ie, FEV1 < 35% of predicted; odds ratio, 2.5). There was no other significant correlation between the Gln27 polymorphism and other parameters measured in the pulmonary function test.


   Discussion
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 Abstract
 Introduction
 Materials and Methods
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References
 
The allele frequencies found in our Chinese population were 0.4 for Gly16 and 0.71 for Gln27. These data were different from those reported by Martinez and coworkers27 in the largest study of unrelated white subjects (Gly16 frequency, 0.62; Gln27 frequency, 0.61). However, the results were similar to those for 15 Asian asthmatic patients reported by Weir et al.31 They found that the allele frequencies among whites were significantly different from those of blacks and Asians. For whites, blacks, and Asians, the allele frequency of Gly16 was 0.61, 0.50, and 0.40, respectively, and the allele frequency of Gln27 was 0.57, 0.73, and 0.80, respectively. Our results confirmed the ethnic variability in allele frequencies of ß2-AR.

The second finding was that the distribution of genotype frequency of the Arg16 polymorphism in COPD patients was significantly different from that of the healthy population, whereas no association was found for the Gln27 and Ile164 polymorphisms between healthy and COPD patients. Several studies11 12 13 14 15 have suggested that genetic factors, including {alpha}1-antitrypsin, may be involved in susceptibility to the development of COPD. It is presumed that the endogenous risk factors that influence susceptibility to COPD are genetically mediated.6 7 8 It also has been reported that Gly16 is associated with increased agonist-promoted down-regulation of the ß2-AR compared with Arg16.23 24 Turki et al20 reported that the Gly16 allele was found more frequently among patients with nocturnal asthma than among patients with non-nocturnal asthma. A clinical study by Reihsaus et al19 also showed that the Gly16 variant was associated with a more severe form of asthma. So far as we know, no relationship between ß2-AR polymorphisms and asthma prevalence has yet been reported,19 20 27 31 but the Gly16 variant apparently was associated with some specific forms for asthma (steroid-dependent asthma and nocturnal asthma).19 20 Unlike in the asthma patients reported, the homozygous Arg16 is less prevalent in our COPD patients than in the healthy population. The findings suggested that our COPD patients were more likely to have at least one Gly16 allele. The presence of the Gly16 allele might be one of the genetic factors that make these patients more susceptible to the risk of COPD development than healthy control subjects. Does susceptibility occur through the down-regulation effect of ß2-AR by Gly16 or by other mechanisms? More studies are needed to answer this question.

Finally, a significant association between the Gln27 ß2-AR polymorphism and the severity of COPD, which was represented by values for FEV1 percent predicted, was observed. There is considerable epidemiologic evidence that genetic mechanisms influence both the spirometric measures of pulmonary function and the risk of COPD development.3 4 The estimated heritability was around FEV1 42 to 45% of predicted in several studies26 27 31 and was even higher (71% of predicted) in monozygote twins.32 A large study4 33 of COPD in families was performed at Johns Hopkins University (Baltimore, MD). A familial aggregation of airflow obstruction was demonstrated when, after adjusting for age, sex, race, and smoking history, a reduced FEV1/FVC ratio was found in 28% of the first-degree relatives of COPD patients.34 The variance component analysis of their data suggested a significant genetic contribution to FEV1 percent predicted and FEV1/FVC ratio values. Segregation analysis of their data provided support for the existence of a major gene influencing FEV1 values in families with COPD.35 36 37 38 A series of clinical studies21 39 of genotype-phenotype associations have shown that the Gln27 allele was associated with enhanced airway hyperresponsiveness among asthma patients, whereas the Glu27 allele was relatively resistant to ß2-AR down-regulation enhanced by the Gly16 allele. Although airway hyperresponsiveness to a variety of stimuli is one of the defining features of asthma, many subjects with COPD also have this feature.40 41 Our study showed that patients with low FEV1 values are more likely to have the Gln27 allele of the ß2-AR. The possible explanation for this is that the receptors with the Glu27 form down-regulate to a lesser extent than the Gln27 polymorphism, hence it is conceivable that individuals with the Gln27 allele may have chronically down-regulated airway ß2-ARs that result from long-term exposure to endogenous catecholamines. This could result in increased airway sensitivity to proinflammatory stimuli, thus leading to a higher degree of airway inflammation and a consequently greater degree of impairment of pulmonary function. This result not only suggested that the Gln27 type of ß2-AR polymorphism may portend a different clinical profile for COPD but also implicated that it may represent one of the genetic variables in the determination of FEV1.

In conclusion, the distributions of ß2-AR polymorphisms are different between different ethnic groups. These polymorphisms are important in the phenotypic modulation of COPD and in the determination of the severity of COPD. They may not only contribute to the risk of some individuals for developing COPD, but may also determine disease severity to a certain extent in affected individuals in the adult Chinese population.


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  		Table 5.. Distribution of Gln27/Glu27 ß2-AR Polymorphism Stratified by FEV1

 

   Footnotes
 
Abbreviations: ATS = American Thoracic Society; ß2-AR = ß2-adrenoceptor; bp = base pairs; PCR = polymerase chain reaction

Supported by grant No.170, 1999, from the Veterans General Hospital, Taipei, Taiwan, Republic of China.

Received for publication December 1, 2000. Accepted for publication May 22, 2001.


   References
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 Abstract
 Introduction
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 References
 

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