MLIP genotype as a predictor of pharmacological response in primary open-angle glaucoma and ocular hypertension

Abstract

Predicting the therapeutic response to ocular hypotensive drugs is crucial for the clinical treatment and management of glaucoma. Our aim was to identify a possible genetic contribution to the response to current pharmacological treatments of choice in a white Mediterranean population with primary open-angle glaucoma (POAG) or ocular hypertension (OH). We conducted a prospective, controlled, randomized, partial crossover study that included 151 patients of both genders, aged 18 years and older, diagnosed with and requiring pharmacological treatment for POAG or OH in one or both eyes. We sought to identify copy number variants (CNVs) associated with differences in pharmacological response, using a DNA pooling strategy of carefully phenotyped treatment responders and non-responders, treated for a minimum of 6 weeks with a beta-blocker (timolol maleate) and/or prostaglandin analog (latanoprost). Diurnal intraocular pressure reduction and comparative genome wide CNVs were analyzed. Our finding that copy number alleles of an intronic portion of the MLIP gene is a predictor of pharmacological response to beta blockers and prostaglandin analogs could be used as a biomarker to guide first-tier POAG and OH treatment. Our finding improves understanding of the genetic factors modulating pharmacological response in POAG and OH, and represents an important contribution to the establishment of a personalized approach to the treatment of glaucoma.

Figure 1

Study flowchart, design and cohort.

Figure 2

Correlation between copy number of the MLIP locus and intraocular pressure (IOP) reduction response to timolol maleate (A) and to latanoprost (B). Boxplots in each panel shows the percentage distribution of IOP reductions for individuals (black dots) grouped according to their MLIP genotype (B: no copy; A: 1 copy). The horizontal red line marks a 25% IOP reduction that differentiates responders from non-responders. Panel A. IOP reduction in response to a beta-blocker (timolol maleate). More copy numbers (AA genotype) tend to be associated with a smaller percentage IOP reduction, while the median response is higher among individuals with 1 or no MLIP variant copy. Panel B. Individual responses to prostaglandins (latanoprost) and their genotypes. Individuals with fewer copy numbers show a lower median response to latanoprostf in terms of relative IOP reduction.

Figure 3

Response probabilities for timolol maleate and latanoprost. (A) Overall response probability for both therapeutic groups. (B) Response probability related to copy number variant (CNV) genotyping BB (no copy), AB (1 allelic copy), and AA (2 allelic copies) for the MLIP locus and the therapeutic groups.