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Intraocular Pressure Response to Topical β-Blockers Associated With an ADRB2 Single-Nucleotide Polymorphism
Catherine A. McCarty, PhD, MPH;
James K. Burmester, PhD;
Bickol N. Mukesh, PhD;
Richard B. Patchett, MD;
Russell A. Wilke, MD, PhD
Arch Ophthalmol. 2008;126(7):959-963.
ABSTRACT
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Objectives To determine whether candidate pharmacodynamic (β-adrenergic receptor) and pharmacokinetic (cytochrome P450 2D6) gene polymorphisms are associated with the intraocular pressure (IOP) response to topical β-blockers.
Methods Medical records of 18 773 adults in the Personalized Medicine Research Project were searched to extract all IOP measurements for subjects who had been prescribed a topical β-blocker. Five single-nucleotide polymorphisms in the β1-, β2-, and β3-adrenergic receptor genes and 6 polymorphisms in the CYP2D6 gene were genotyped.
Results A total of 58.1% of the subjects were female; the mean age was 63.8 years. Topical β-blockers were prescribed for 343 eyes of 215 subjects. An IOP reduction of 20% or more in 1 or both eyes was observed in 61.0% of subjects. Men were significantly more likely than women to have an IOP decrease of 20% or more (69.3% vs 54.9%, respectively;  2 = 4.48; P = .04). After adjusting for sex, family history of glaucoma, and use of systemic β-blockers, subjects with the CC genotype at coding single-nucleotide polymorphism rs1042714 in the ADRB2 gene were significantly more likely to experience an IOP decrease of 20% or more (odds ratio, 2.00; 95% confidence interval, 1.00-4.02).
Conclusion We found that a coding single-nucleotide polymorphism in ADRB2 is associated with an increased likelihood of a clinically meaningful IOP response to topical β-blockers.
Clinical Relevance Because topical β-blockers are the least expensive class of agents used to lower IOP, genotype-based drug prescribing could save health care dollars.
INTRODUCTION
Glaucoma is a progressive optic neuropathy1 with an estimated prevalence of 1.86% in the US population aged 40 years and older.2 Glaucoma has been called the "silent thief of sight," and previous research has shown that half of the glaucoma cases in the community are undiagnosed.3 Timely diagnosis and treatment of glaucoma are necessary to prevent irreversible degeneration of retinal ganglion cells and concomitant vision loss. The goal of glaucoma management is to lower intraocular pressure (IOP); treatment options include pharmacologic agents, laser treatment, and surgery.4 Lowering IOP has been shown in clinical trials to reduce the risk of visual loss5; however, compliance in clinical settings has been low.6-7 There has been a recent trend away from the use of β-blockers as first-line medical therapy and toward newer therapies such as prostaglandin analogues.8 The result has been a concomitant rise in the overall cost of glaucoma drugs.9
Genetic variability, compliance, environment, and eye and systemic disease are thought to contribute to the overall IOP response to glaucoma medications.10 β-Blockers are used to treat elevated blood pressure and elevated IOP. Cytochrome P450 2D6 metabolizes timolol in vivo, and CYP2D6 (GenBank AY545216) gene polymorphisms have been shown to be associated with timolol-related outcomes.11 Topical β-blockers have been shown to have systemic effects,12-15 and outcomes related to systemic absorption of timolol are related to the CYP2D6 genotype as well as antidepressants and other drugs known to inhibit CYP2D6.16-17On the pharmacodynamic side, β1- and β2-adrenergic receptor genes are likely candidate genes for IOP response because they transduce the cellular effects of endogenous β-adrenergic agonists (eg, epinephrine).18-19 Also, systemic β-blockers have been shown to be associated with blood pressure response and mortality outcome following the systemic administration of β-blockers.20
To determine whether candidate pharmacodynamic and pharmacokinetic gene polymorphisms are associated with IOP response to topical β-blockers, we genotyped 5 common, functionally relevant single-nucleotide polymorphisms (SNPs) in the β1-, β2-, and β3-adrenergic receptor genes and 6 common, functionally relevant polymorphisms in the CYP2D6 gene. We also genotyped 4 additional polymorphisms in 2 disease genes, optineurin and myocillin.
METHODS
The electronic medical records of adults enrolled in the population-based Marshfield Clinic Personalized Medicine Research Project (PMRP)21 were searched from January 1960 to December 2005 to identify subjects with a diagnosis of ocular hypertension or glaucoma. The PMRP is a population-based biobank with stored DNA and serum samples for more than 19 000 subjects aged 18 years and older.22 All of the participants gave written, informed consent for the project, which includes access to Marshfield Clinic medical records for phenotyping. More than 95% of the residents within the geographic area selected for the PMRP use Marshfield Clinic for their health care, thus allowing for population-based epidemiologic research within the Marshfield Clinic system. Marshfield Clinic is an integrated regional health care system with 700 physicians in 41 locations serving approximately 360 000 patients throughout central and northern Wisconsin. All major medical specialties and subspecialties except whole-organ transplantation are covered within the clinic system. Except for the city of Marshfield, Marshfield Epidemiologic Study Area residents23 reside rurally or in small towns or villages. The overall project and this substudy were approved by the Marshfield Clinic Institutional Review Board.
The medical records were manually abstracted for all IOP measurements, glaucoma diagnoses, and operations for glaucoma. The medical records were also manually abstracted for the concomitant use of systemic medications known to interact with topical β-blockers (ie, systemic β-blockers or selective serotonin reuptake inhibitors). Glaucoma diagnosis was confirmed with medical record evidence of 2 or more of the following: (1) glaucomatous visual field defect; (2) elevated IOP (> 21 mm Hg); (3) optic disc cupping (cup-disc ratio  0.8); or (4) rim narrowing characteristic of glaucoma. For this study, glaucoma suspects had only 1 of the preceding characteristics. Ten percent of the records were abstracted twice for quality assurance purposes. The IOP prior to topical β-blocker prescription and the lowest IOP in the first 3 months after prescription of a topical β-blocker were used to classify case or control status. Subjects were classified as cases for this study if their IOP in the first 3 months after being prescribed a topical β-blocker decreased by less than 20%. Subjects with IOPs that decreased by 20% or more were classified as control subjects.
Stored DNA samples were genotyped from the subjects who had used topical β-blockers and had baseline and follow-up IOP measurements within the first 3 months. TaqMan assays (Applied Biosystems, Foster City, California) were used. Validated assays were used for CYP2D6 Cys188Thr, Gly1934Ala, and Cys2838Thr. Custom assays were designed by Applied Biosystems for the other 3 CYP2D6 polymorphisms, Gly17949Cys, Ala2637del, and Gly4268Cys, necessary to assign a common haplotype. The CYP2D6 genotypes were categorized functionally as extensive metabolizers (*1*1, *1*2, *2*2), intermediate metabolizers (*1*10, *1*3, *1*4, *2*10, *2*3, *2*4), and poor metabolizers (*3*4, *4*4).24-25
Premade assays (Applied Biosystems) were used for the β1-adrenergic receptor gene (ADRB1 Ser49Gly and Arg389Gly). Custom-made assays (Applied Biosystems) were used for the β2-adrenergic receptor gene (ADRB2 Gly16Arg and Gln27Glu) and the β3-adrenergic receptor gene (ADRB3 Trp64Arg). Combinations of minor alleles for genotypes in the ADRB1, ADRB2 and ADRB3 SNPs were also calculated as suggested in a review of the pharmacogenetics of human β-adrenergic receptors.26 For optineurin Glu50Lys and Met98Lys, assays from Applied Biosystems were used. Custom assays were developed for myocillin Gln368ter and –1000 Gly/Cys. Myocillin and optineurin were included because of their known genetic risk in certain forms of open-angle glaucoma. Test assays were set up; if there was a clear distinction between 11, 12, and 22 alleles, then the assay was run on all of the samples. The allele frequencies were compared with the known allele frequencies in dbSNP and were consistent with the known frequencies.
Data were entered twice and verified. For statistical analyses, SPSS version 15.0 statistical software (SPSS Inc, Chicago, Illinois) was used. To compare proportions, 2 analysis and Fisher exact test were used. Logistic regression was used to identify independent predictors of IOP response. The 95% confidence intervals (CIs) were calculated using the exact binomial distribution. P < .05 was considered statistically significant.
RESULTS
As of December 31, 2005, 18 773 adults were enrolled in the PMRP; all were included in this study. The overall rate of definite glaucoma in subjects aged 50 years and older was 2.07% (95% CI, 1.20%-2.38%) and the rate of treated ocular hypertension was 1.42% (95% CI, 1.19%-1.69%). Topical β-blockers were prescribed for 343 eyes of 215 PMRP subjects. Of these, 5 subjects receiving selective serotonin reuptake inhibitor medications at the same time they were receiving topical β-blockers were excluded from the study. Hence, a total of 210 subjects available for genotyping were included in this study. The sex distribution was 58.1% female (n = 122) and 41.9% male (n = 88). Their mean (SD) age on December 31, 2005, was 63.8 (11.3) years, ranging from 33.8 to 85.4 years. Of the subjects, 90 (42.9%) reported a family history of glaucoma on the initial questionnaire administered at the time of enrollment into the PMRP. Fifteen subjects (7.1%) were receiving systemic β-blockers at the same time they were receiving topical β-blockers. All of the polymorphisms were found to be in Hardy-Weinberg equilibrium. The frequency of alleles defining the CYP2D6 haplotype were as follows: 40.1% for *1, 35.2% for *2, 3.3% for *3, 19.5% for *4, and 1.9% for *10, which is similar to what has been reported previously in white subjects.23-24 Of the 210 subjects genotyped, 28 (13.3%) had allele combinations that could not be assigned to common CYP2D6 haplotypes.
The mean (SD) IOP in the right eye was 24.9 (5.9) mm Hg at baseline and 19.1 (3.9) mm Hg at follow-up. The mean (SD) IOP in the left eye was 24.8 (5.9) mm Hg at baseline and 18.8 (3.6) mm Hg at follow-up. The greatest change in IOP in either eye in the first 3 months ranged from –70.8 mm Hg to +25.0 mm Hg (median change, –23.3 mm Hg). An IOP reduction of 20% or more in the first 3 months was observed for 91 right eyes (55.2%) and 92 left eyes (54.4%). An IOP reduction of 20% or more in the first 3 months in 1 or both eyes was observed in 128 subjects (61.0%). Subjects treated with β-blockers alone had significantly higher response rates than subjects treated with a combination of β-blockers and other IOP-lowering medications (70.3% vs 40.1%, respectively; 2 = 14.7; P < .001). In this drug-exposed study cohort (n = 210), neither age (t test = 1.48; P = .14) nor use of systemic β-blockers (2 = 0.01; P = .94) was related to IOP response. Men were significantly more likely than women to have either 1 or both eyes respond with an IOP decrease of 20% or more with topical β-blockers (69.3% vs 54.9%, respectively; 2 = 4.48; P = .04).
Tables 1, 2, and 3 display the comparison of genotype distribution for CYP2D6, ADRB, and glaucoma disease genes, respectively, between subjects who did or did not have an IOP decrease of 20% or more. Variables were created to combine genotypes. Neither predicted CYP2D6 phenotypes (Table 1) nor optineurin or myocillin gene polymorphisms (Table 3) were related to IOP response. Optineurin Glu50Lys was not polymorphic in this population. The ADRB-coding SNPs were not associated with IOP-lowering efficacy in univariate analyses (Table 2). Variables that combined the minor alleles for the 5 ADRB SNPs were created. None were found to be statistically significant (data not shown).
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Table 1. Unadjusted Comparison of CYP2D6 Functional Genotype Between Subjects Who Did and Did Not Have an Intraocular Pressure Decrease of 20% or More in Either Eye in the First 3 Months of Topical β-Blocker Use
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Table 2. Unadjusted Comparison of ADRB Genotypes Between Subjects Who Did and Did Not Have an Intraocular Pressure Decrease of 20% or More in Either Eye in the First 3 Months of Topical β-Blocker Use
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Table 3. Unadjusted Comparison of Putative Glaucoma Disease Genotypes Between Subjects Who Did and Did Not Have an Intraocular Pressure Decrease of 20% or More in Either Eye in the First 3 Months of Topical β-Blocker Use
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Table 4 shows the results of the logistic regression models for ADRB2, developed to predict an IOP decrease of 20% or more with β-blocker use and adjusted for sex, family history of glaucoma, and use of systemic β-blockers. For both ADRB1 and ADRB3, there were too few subjects homozygous for the minor allele to allow for multivariate logistic regression analyses. After adjusting for sex, family history of glaucoma, and use of systemic β-blockers, subjects with the homozygous major allele (CC) genotype for rs1042714 were significantly more likely than subjects with the heterozygous (CG) genotype to experience an IOP decrease of 20% or more (odds ratio, 2.00; 95% CI, 1.00-4.02).
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Table 4. Logistic Regression Models to Predict an Intraocular Pressure Decrease of 20% or More With Topical β-Blocker Use for the Individual ADRB2 Single-Nucleotide Polymorphismsa
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COMMENT
In this study, we found that candidate pharmacodynamic but not pharmacokinetic polymorphisms were associated with IOP response to topical β-blockers. Specifically, a coding SNP in the ADRB2 gene (Gln27Glu) was associated with 2-fold greater odds of a clinically meaningful reduction in IOP following treatment with a topical β-blocker.
The β-adrenergic receptor is a member of the adrenergic family of G-protein–coupled receptors. Epinephrine and norepinephrine are the primary endogenous agonists, but other endogenous catecholamines (eg, dopamine) can interact with these receptors as well. In the early 1990s, investigators characterized several ADRB2 polymorphisms with altered signaling properties.27-29 In 1999, the same group reported an ADRB1 polymorphism that altered the cytoplasmic tail near the seventh transmembrane-spanning segment.30 Using site-directed mutagenesis, these investigators were able to show that the resulting amino acid change (Gly389Arg) in ADRB1 was associated with differential adenylate cyclase activation in permanently transfected fibroblasts (CHW-1102 cells). Other investigators have linked this ADRB1 SNP to altered receptor expression.31 Two nonsynonymous coding SNPs in ADRB2 have also been associated with altered cellular receptor trafficking (in vitro).32 Importantly, these SNPs have also been associated (in vivo) with altered clinical outcomes, including asthma33 and acute coronary syndromes.20 Further, there appears to be marked linkage disequilibrium between these 2 ADRB2 SNPs,34 and future research may benefit from the consideration of diplotypes.
Three other studies have looked at the β2-adrenergic receptor gene in relation to glaucoma and IOP, with varying results. In a study35 of healthy volunteers, a single candidate β2-adrenergic receptor polymorphism was found to not be associated with IOP response to topical timolol. The differing results between our study and the previous study of the β2-adrenergic receptor gene and IOP could be owing to the differing study populations or a lack of statistical power in the previous study. In a study36 of 583 subjects, the β2-adrenergic receptor gene was not found to be a glaucoma susceptibility locus. In a study37 of 505 Japanese subjects, the IOP at glaucoma diagnosis was found to be significantly higher in patients carrying 27Glu. This coding SNP (C79G transversion) induces a nonconservative amino acid substitution (Gln27Glu) near the N terminus of the ADRB2 gene product.33 The result is an alteration in agonist-promoted downregulation of the receptor.28 In vitro studies have demonstrated that Gln27Glu affects receptor function.38 A 60-fold greater isoprenaline concentration was required to downregulate Glu27 to the same extent as Gln27.
One of the major strengths of this study is the population-based nature of the study cohort, which allows inferences to the entire population to be made. Limitations of the study include the fact that the potential effect of noncompliance on the study results cannot be determined and the fact that IOP data were not available for all of the subjects, limiting statistical power for some analyses. Prospectively collected data with a standardized protocol and a larger study cohort could lead to statistically significant results for some of the other SNPs that were of borderline significance.
In conclusion, we found that a coding SNP in the ADRB2 gene is associated with an increased likelihood of a clinically meaningful IOP response to topical β-blockers. Topical β-blockers are the least expensive agents used to treat glaucoma and ocular hypertension; therefore, the potential for genotype-based prescribing could save health care dollars. These findings need to be confirmed in other populations and evaluated prospectively.
AUTHOR INFORMATION
Correspondence: Catherine A. McCarty, PhD, MPH, Center for Human Genetics, Marshfield Clinic Research Foundation, 1000 N Oak Ave, Marshfield, WI 54449 (mccarty.catherine{at}mcrf.mfldclin.edu).
Submitted for Publication: November 1, 2007; final revision received December 19, 2007; accepted December 21, 2007.
Author Contributions: Dr McCarty had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Financial Disclosure: None reported.
Funding/Support: This study was funded in part by a grant from National Glaucoma Research, a program of the American Health Assistance Foundation.
Additional Contributions: Terrie Kitchner and William Hubbard, BS, provided medical record abstraction, Carla Rottscheit provided data management, and Kai Qi Zhang, BS, provided genotyping. Marshfield Clinic Research Foundation supported this work through the assistance of Linda Weis and Alice Stargardt in the preparation of the manuscript.
Author Affiliations: Center for Human Genetics (Drs McCarty, Burmester, and Wilke) and Biomedical Informatics Research Center (Dr Mukesh), Marshfield Clinic Research Foundation, and Department of Ophthalmology, Marshfield Clinic (Dr Patchett), Marshfield, Wisconsin; and Department of Medicine and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee (Dr Wilke).
REFERENCES
| |
1. Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet. 2004;363(9422):1711-1720.
FULL TEXT
|
ISI
| PUBMED
2. Friedman DS, Wolfs RC, O’Colmain BJ; et al, Eye Diseases Prevalence Research Group. Prevalence of open-angle glaucoma among adults in the United States. Arch Ophthalmol. 2004;122(4):532-538.
FREE FULL TEXT
3. Wensor MD, McCarty CA, Stanislavsky YL, Livingston PM, Taylor HR. The prevalence of glaucoma in the Melbourne Visual Impairment Project. Ophthalmology. 1998;105(4):733-739.
FULL TEXT
|
ISI
| PUBMED
4. Khaw PT, Shah P, Elkington AR. Glaucoma, 2: treatment. BMJ. 2004;328(7432):156-158.
FREE FULL TEXT
5. Maier PC, Funk J, Schwarzer G, Antes G, Falck-Ytter YT. Treatment of ocular hypertension and open angle glaucoma: meta-analysis of randomised controlled trials. BMJ. 2005;331(7509):134.
FREE FULL TEXT
6. Gurwitz JH, Glynn RJ, Monane M; et al. Treatment for glaucoma: adherence by the elderly. Am J Public Health. 1993;83(5):711-716.
FREE FULL TEXT
7. Patel SC, Spaeth GL. Compliance in patients prescribed eyedrops for glaucoma. Ophthalmic Surg. 1995;26(3):233-236.
ISI
| PUBMED
8. Owen CG, Carey IM, De Wilde S, Whincup PH, Wormald R, Cook DG. The epidemiology of medical treatment for glaucoma and ocular hypertension in the United Kingdom: 1994 to 2003. Br J Ophthalmol. 2006;90(7):861-868.
FREE FULL TEXT
9. Knox FA, Barry M, McGowan B, O’Brien C. The rising cost of glaucoma drugs in Ireland 1996-2003. Br J Ophthalmol. 2006;90(2):162-165.
FREE FULL TEXT
10. McLaren NC, Moroi SE. Clinical implications of pharmacogenetics for glaucoma therapeutics. Pharmacogenomics J. 2003;3(4):197-201.
FULL TEXT
|
ISI
| PUBMED
11. McGourty JC, Silas JH, Fleming JJ, McBurney A, Ward JW. Pharmacokinetics and beta-blocking effects of timolol in poor and extensive metabolizers of debrisoquin. Clin Pharmacol Ther. 1985;38(4):409-413.
ISI
| PUBMED
12. Coleman AL, Diehl DL, Jampel HD, Bachorik PS, Quigley HA. Topical timolol decreases plasma high-density lipoprotein cholesterol level. Arch Ophthalmol. 1990;108(9):1260-1263.
FREE FULL TEXT
13. Huupponen R, Kaila T, Lahdes K, Salminen L, Iisalo E. Systemic absorption of ocular timolol in poor and extensive metabolizers of debrisoquine. J Ocul Pharmacol. 1991;7(2):183-187.
ISI
| PUBMED
14. Edeki TI, He H, Wood AJ. Pharmacogenetic explanation for excessive beta-blockade following timolol eye drops: potential for oral-ophthalmic drug interaction. JAMA. 1995;274(20):1611-1613.
FREE FULL TEXT
15. Stewart WC, Garrison PM. Beta-blocker-induced complications and the patient with glaucoma: newer treatments to help reduce systemic adverse events. Arch Intern Med. 1998;158(3):221-226.
FREE FULL TEXT
16. Jin Y, Desta Z, Stearns V; et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005;97(1):30-39.
FREE FULL TEXT
17. Nieminen T, Uusitalo H, Mäenpää J; et al. Polymorphisms of genes CYP2D6, ADRB1 and GNAS1 in pharmacokinetics and systemic effects of ophthalmic timolol: a pilot study. Eur J Clin Pharmacol. 2005;61(11):811-819.
FULL TEXT
|
ISI
| PUBMED
18. Johnson JA, Zineh I, Puckett BJ, McGorray SP, Yarandi HN, Pauly DF. Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol. Clin Pharmacol Ther. 2003;74(1):44-52.
FULL TEXT
|
ISI
| PUBMED
19. Schwartz SG, Puckett BJ, Allen RC, Castillo IG, Leffler CT. Beta1-adrenergic receptor polymorphisms and clinical efficacy of betaxolol hydrochloride in normal volunteers. Ophthalmology. 2005;112(12):2131-2136.
FULL TEXT
|
ISI
| PUBMED
20. Lanfear DE, Jones PG, Marsh S, Cresci S, McLeod HL, Spertus JA. Beta2-adrenergic receptor genotype and survival among patients receiving beta-blocker therapy after an acute coronary syndrome. JAMA. 2005;294(12):1526-1533.
FREE FULL TEXT
21. McCarty CA, Mukesh BN, Kitchner TE; et al. Intraocular pressure response to medication in a clinical setting: the Marshfield Clinic Personalized Medicine Research Project. J Glaucoma. In press.22. McCarty CA, Wilke RA, Giampietro PF, Wesbrook SD, Caldwell MD. Marshfield Clinic Personalized Medicine Research Project (PMRP): design, methods and recruitment for a large population-based biobank. Personalized Med. 2005;2(1):49-79.
FULL TEXT
23. DeStefano F, Eaker ED, Broste SK; et al. Epidemiologic research in an integrated regional medical care system: the Marshfield Epidemiologic Study Area. J Clin Epidemiol. 1996;49(6):643-652.
FULL TEXT
|
ISI
| PUBMED
24. Sachse C, Brockmöller J, Bauer S, Roots I. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet. 1997;60(2):284-295.
ISI
| PUBMED
25. Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics. 2002;3(2):229-243.
FULL TEXT
|
ISI
| PUBMED
26. Taylor MR. Pharmacogenetics of the human beta-adrenergic receptors. Pharmacogenomics J. 2007;7(1):29-37.
FULL TEXT
|
ISI
| PUBMED
27. Green SA, Cole G, Jacinto M, Innis M, Liggett SB. 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;268(31):23116-23121.
FREE FULL TEXT
28. Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry. 1994;33(32):9414-9419.
FULL TEXT
| PUBMED
29. Green SA, Turki J, Bejarano P, Hall IP, Liggett SB. Influence of beta 2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol. 1995;13(1):25-33.
ABSTRACT
30. Mason DA, Moore JD, Green SA, Liggett SB. A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J Biol Chem. 1999;274(18):12670-12674.
FREE FULL TEXT
31. Levin MC, Marullo S, Muntaner O, Andersson B, Magnusson Y. The myocardium-protective Gly-49 variant of the beta 1-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation. J Biol Chem. 2002;277(34):30429-30435.
FREE FULL TEXT
32. Dishy V, Sofowora GG, Xie HG; et al. The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization. N Engl J Med. 2001;345(14):1030-1035.
FREE FULL TEXT
33. Drysdale CM, McGraw DW, Stack CB; et al. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci U S A. 2000;97(19):10483-10488.
FREE FULL TEXT
34. Xie HG, Stein CM, Kim RB; et al. Frequency of functionally important beta-2 adrenoceptor polymorphisms varies markedly among African-American, Caucasian and Chinese individuals. Pharmacogenetics. 1999;9(4):511-516.
ISI
| PUBMED
35. Fuchsjager-Mayrl G, Markovic O, Losert D; et al. Polymorphism of the beta-2 adrenoceptor and IOP lowering potency of topical timolol in healthy subjects. Mol Vis. 2005;11:811-815.
ISI
| PUBMED
36. McLaren N, Reed DM, Musch DC; et al. Evaluation of the beta2-adrenergic receptor gene as a candidate glaucoma gene in 2 ancestral populations. Arch Ophthalmol. 2007;125(1):105-111.
FREE FULL TEXT
37. Inagaki Y, Mashima Y, Fuse N; et al. Polymorphism of beta-adrenergic receptors and susceptibility to open-angle glaucoma. Mol Vis. 2006;12:673-680.
ISI
| PUBMED
38. Brodde OE, Leineweber K. Beta2-adrenoceptor gene polymorphisms. Pharmacogenet Genomics. 2005;15(5):267-275.
ISI
| PUBMED
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