Lack of association between polymorphisms in the prostaglandin F2α receptor and solute carrier organic anion transporter family 2A1 genes and intraocular pressure response to prostaglandin analogs.

PURPOSE: To evaluate the association between variants in the prostaglandin F(α) receptor (PTGFR) and solute carrier organic anion transporter family 2A1 (SLCO2A1) genes and intraocular pressure (IOP) response to prostaglandin analogs. METHODS: The medical records of subjects with previously diagnosed open angle glaucoma or ocular hypertension were searched for intraocular pressure measurements before and after prescriptions of prostaglandin analogs. Stored DNA samples were genotyped for the following SNPs: rs3753380 (promoter region) and rs3766355 (intronic region) of the prostaglandin F(2α) receptor gene, and rs34550074 (Ala396Thr) of SLCO2A1. The mean change in IOP by genotype was measured. RESULTS: Prostaglandin analogs were prescribed to 267 subjects; 242 (204 right eyes, 205 left eyes) met the inclusion/exclusion criteria for the current study. There was no significant association between genotype and IOP response to prostaglandin analogs (p = 0.48, p = 0.54, p = 0.90). CONCLUSION: In summary, we found no indication for an association between SNPs in the prostaglandin F(2α) receptor gene or SLCO2A1 and IOP response to prostaglandin analogs in a population of European descent.

Intraocular pressure response to medication in a clinical setting: the Marshfield Clinic Personalized Medicine Research Project.

PURPOSE: To estimate glaucoma and ocular hypertension prevalence and to describe temporal trends in prescribing patterns and intraocular pressure (IOP) response to topical medications used in glaucoma and ocular hypertension. MATERIALS AND METHODS: The medical records of adult subjects enrolled in the population-based Marshfield Clinic Personalized Medicine Research Project were searched to identify participants who had been diagnosed with ocular hypertension or glaucoma and prescribed agent(s) to lower IOP. All IOPs before and after prescription of the IOP agents were recorded. RESULTS: As of December 31, 2005, 18,773 adults were enrolled in the Personalized Medicine Research Project, 57.1% were female, and their mean age was 50.3 years (range, 18 to 101 y). The overall rate of definite glaucoma in subjects aged 50 years and above was 2.1% (95% confidence interval=1.2, 2.4) and the rate of treated ocular hypertension was 1.4% (95% confidence interval=1.2, 1.7). Topical beta-blockers were the agents prescribed for the majority of subjects until the year 2000, when prostaglandins, first used in 1995, became the primary agent prescribed. In 2005, 75% of subjects used prostaglandin analogs and 46% used topical beta-blockers. The largest relative reduction in IOP in the first 3 months after prescription was observed for prostaglandin analogs (21.4% mean relative reduction), followed by beta-blockers (20.9% mean relative reduction). There has been a significant decrease over time in mean IOP before initiating medical therapy (linear regression beta coefficient=-0.30, P<0.0001, r=0.09). CONCLUSIONS: In this clinic-based setting, we found that treatment of glaucoma has changed over the past 20 years, with ophthalmologists more likely to begin treatment at lower baseline levels of IOP, and prostaglandin analogs the most commonly prescribed and agent to lower IOP.

Intraocular pressure response to topical beta-blockers associated with an ADRB2 single-nucleotide polymorphism.

OBJECTIVES: To determine whether candidate pharmacodynamic (beta-adrenergic receptor) and pharmacokinetic (cytochrome P450 2D6) gene polymorphisms are associated with the intraocular pressure (IOP) response to topical beta-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 beta-blocker. Five single-nucleotide polymorphisms in the beta(1)-, beta(2)-, and beta(3)-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 beta-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; chi(2) = 4.48; P = .04). After adjusting for sex, family history of glaucoma, and use of systemic beta-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 beta-blockers. Clinical Relevance Because topical beta-blockers are the least expensive class of agents used to lower IOP, genotype-based drug prescribing could save health care dollars.

Pharmacogenetics of ophthalmic topical beta-blockers.

Glaucoma is the second leading cause of blindness worldwide. The primary glaucoma risk factor is elevated intraocular pressure. Topical beta-blockers are affordable and widely used to lower intraocular pressure. Genetic variability has been postulated to contribute to interpersonal differences in efficacy and safety of topical beta-blockers. This review summarizes clinically significant polymorphisms that have been identified in the beta-adrenergic receptors (ADRB1, ADRB2 and ADRB3). The implications of polymorphisms in CYP2D6 are also discussed. Although the candidate-gene approach has facilitated significant progress in our understanding of the genetic basis of glaucoma treatment response, most drug responses involve a large number of genes, each containing multiple polymorphisms. Genome-wide association studies may yield a more comprehensive set of polymorphisms associated with glaucoma outcomes. An understanding of the genetic mechanisms associated with variability in individual responses to topical beta-blockers may advance individualized treatment at a lower cost.