Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

Abstract

Elevation of intraocular pressure (IOP) due to therapeutic use of glucocorticoids is called steroid-induced ocular hypertension (SIOH); this can lead to steroid-induced glaucoma (SIG). Glucocorticoids initiate signaling cascades ultimately affecting expression of hundreds of genes; this provides the potential for a highly personalized pharmacological response. Studies attempting to define genetic risk factors were undertaken early in the history of glucocorticoid use, however scientific tools available at that time were limited and progress stalled. In contrast, significant advances were made over the ensuing years in defining disease pathophysiology. As the genomics age emerged, it appeared the time was right to renew investigation into genetics. Pharmacogenomics is an unbiased discovery approach, not requiring an underlying hypothesis, and provides a way to pinpoint clinically significant genes and pathways that could not have been discovered any other way. Results of the first genome-wide association study to identify polymorphisms associated with SIOH, and follow-up on two novel genes linked to the disorder, GPR158 and HCG22, is discussed in the second half of the article. However, knowledge of genetic variants determining response to steroids in the eye also has value in its own right as a predictive and diagnostic tool. This article concludes with a discussion of how the Precision Medicine Initiative®, announced by U.S. President Obama in his 2015 State of the Union address, is beginning to touch the practice of ophthalmology. It is argued that SIOH/SIG may provide one of the next opportunities for effective application of precision medicine.

Keywords: Glaucoma; Glucocorticoid; Ocular hypertension; Ophthalmology; Pharmacogenomics; Precision medicine.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Cumulative probability of experiencing an IOP spike with glucocorticoid treatment

Kaplan-Meier analysis showing the cumulative probability of experiencing an IOP spike (defined as postoperative IOP ≥ 24 mm Hg or increased by ≥ 10 mm Hg over the baseline preoperative reading) when prednisolone acetate 1% ophthalmic suspension was dosed 4 times a day for 4 months then tapered over 2 to 3 months to once or twice daily dosing to prevent cornea transplant rejection. Patient data from (Vajaranant et al., 2009); the graphic has not been previously published.

Figure 2. Quantitative trait distribution for the Florida-1 cohort

A graphic distribution of ΔIOP values (y-axis) calculated for each of the research subjects comprising the Florida-1 cohort (x-axis) is shown. Patient data from (Gerzenstein et al., 2008); the graphic has not been previously published.

Figure 3. Predicted features of the protein encoded by GPR158

The schematic shown is based on sequence analysis of the conceptually translated product of GPR158. Three extracellular loops (ELs) and three intracellular loops (ILs) connect the seven TM (numbered I–VII). The arrow indicates putative PKC and PKA phosphorylation sites in the ILs. The cysteine residues in EL-1 and EL-2 involved in disulfide (S-S) bond formation are shown as a dotted grey double line. The eighth helix, bipartite NLS, c-Myc and PITX2 interaction motifs, and putative phosphorylation sites for kinases, such as CDK1, are indicated in the C-terminal tail. The leucine zipper domain, EGF like domain, N-glycosylation sites and putative CRD are shown in the N-terminal of GPR158. The conserved amino acid residues, KXXR and E, involved in G protein activation in class C GPCRs are marked in red color. CDK1, cyclin-dependent kinase 1; CRD, cysteine rich domain; EGF, epidermal growth factor; EL, extracellular loop; IL, intracellular loop; NLS, nuclear localization signal; PITX2, paired-like homeodomain transcription factor 2. From: GPR158, an orphan member of G protein-coupled receptor Family C: glucocorticoid-stimulated expression and novel nuclear role. Patel N et al. PLoS One. 2013;8(2):e57843. doi: 10.1371/journal.pone.0057843 CC-BY; used with permission from the publisher.

Figure 4. Regional Association Plot for lead SNP rs2523864 (marked as purple diamond) on Chr6

All SNPs shown as circles are plotted with their respective P values against their genomic location. The solid diamond indicates the top-ranked SNP rs2523864. The colored box at the right or left corner of each plot indicates the pairwise correlation (r2) between the top SNP and the other SNPs in the region. The grey circles indicate the imputed SNPs from the CEU population of the HapMap. Each plot was created using LocusZoom (http://csg.sph.umich.edu/locuszoom/) for the top-ranked SNP in each region with a 400-kb region surrounding it. SNPs are plotted at the top of the figure. The box underneath each plot shows the gene annotations in the region, with the arrow indicated the DNA strand for transcription. The lower LD plot was created using Haploview (http://www.broadinstitute.org/scientific-community/science/programs/medical-and-population-genetics/haploview/haploview). From: Identification of a Novel Mucin Gene HCG22 Associated With Steroid-Induced Ocular Hypertension. Jeong S, et al. Invest Ophthalmol Vis Sci. 2015 Apr;56(4):2737–48. doi: 10.1167/iovs.14-14803. Used with permission from the publisher. The authors acknowledge the Association for Research in Vision and Ophthalmology as the copyright holder.

Figure 5. Location and expression of genes surrounding the QTL in chromosomal region 6p21.32-33

(Top panel) Schematic of chromosomal region 6p21.32-33 from the NCBI Gene website depicting annotated genes surrounding the identified QTL (red arrow). (Bottom panel) Total RNA was purified from cultured primary HCE and TM-1 cells, and used for cDNA synthesis. RT-PCR using cDNA was performed using gene-specific primers from MUC21, MUC22 and HCG22, and the products were resolved on a 1.5% agarose gel. Primers for HCG22 were designed to detect only the coding transcript. Similar results were obtained using three primary TBM cell lines (not shown). RTase: reverse transcriptase; HCE: primary corneal epithelial cells obtained from corneal rims; TBM: cells of the TM-1 line. From: Identification of a Novel Mucin Gene HCG22 Associated With Steroid-Induced Ocular Hypertension. Jeong S, et al. Invest Ophthalmol Vis Sci. 2015 Apr;56(4):2737–48. doi: 10.1167/iovs.14-14803. Used with permission from the publisher. The authors acknowledge the Association for Research in Vision and Ophthalmology as the copyright holder.

Figure 6. Conceptual Translation of HCG22

(A) HCG22 deduced sequence. Genbank transcript AB560771 is 1,671 nucleotides in length. The deduced amino acid sequence is 251 amino acids. A signal peptide of 22 amino acids at the N-terminus is predicted (underlined). The yellow highlights mark the start of each mucin-type repeat, which could be O-glycosylated. No transmembrane domain is found, suggesting that the protein is secreted. (B) Prediction of glycosylation. N- and O-linked glycosylation patterns of HCG22 were predicted by analysis of coding regions using web-based software analysis (N-glycosylation: http://www.cbs.dtu.dk/services/NetNGlyc/; O-glycosylation: http://www.cbs.dtu.dk/services/NetOGlyc/). (C) Amino acid substitutions in the signal peptide. Signal peptide sequences deduced from GenBank transcript AB560771 and from cDNA prepared from human lung cell line BET1A are compared in the figure (relevant amino acids are in red and underlined). This graphic has not been previously published.