The recent revolution in age-related macular degeneration (AMD) genetics has demonstrated that genetic alterations affecting the alternative pathway of the complement cascade have a major influence on AMD risk. One of the two most important genetic loci is on chromosome 1 and contains genes encoding complement factor H (CFH). CFH is a blood-borne glycoprotein that is also produced locally by the RPE. This 155-kDa serum glycoprotein is composed of 20 complement control protein (CCP) domains, such that different regions of CFH recognize different ligands (Langford-Smith et al. 2014). CFH acts as a complement regulator and conveyor of host protection in two primary ways. CFH inhibits the formation of the alternative pathway C3 convertase by competing with factor B binding to C3b [or C3(H₂O)] via its CCP1–4 region; CFH also promotes the decay of existing C3 convertase by displacing factor Bb. In macular tissue, especially Bruch’s membrane, relatively high levels of a truncated splice variant of CFH called factor H-like protein 1 (FHL-1) are present. There is an age-related loss of heparan sulfate from Bruch’s membrane resulting in less available binding sites for FHL-1 (or CFH) to anchor to Bruch’s membrane. This is compounded by the Y402H polymorphism in which CFH binds HS poorly. This ultimately results in complement activation and inflammation and thereby predisposes to AMD. Evidently supplementation with recombinant CFH has been proposed as a therapeutic strategy for AMD (Clark and Bishop 2014). The Y402H polymorphism in the complement regulatory protein factor H (CFH) can confer a >5-fold increased risk of developing AMD (Kelly et al. 2010). The importance of CFH single nucleotide polymorphisms (SNP) in predicting the ARMD progression and anti-VEGF therapeutic response has been shown in a number of pharmacogenomics clinical studies shown in Table 4.2.

Intravitreal route of administration minimizes the systemic side effects of glucocorticoids such as triamcinolone acetonide. Dexamethasone implants and fluocinolone acetonide are the alternatives available for intravitreal anti-VEGF therapy in ocular neovascular conditions. Corticosteroid treatments have emerged as an alternative therapy to conventional laser photocoagulation and other modalities for persistent diabetic macular edema.

Glucocorticoids are the most potent anti-inflammatory agents; however, a major factor limiting their clinical use is the wide variation in responsiveness to therapy. Five percent of the population are high steroid responders and develop an intraocular pressure (IOP) elevation of more than 15 mmHg above baseline (Razeghinejad and Katz 2012).

A meta-analysis reported that 32 % of individuals developed ocular hypertension (OHT) following 4-mg intravitreal triamcinolone, 66 and 79 % following 0.59 and 2.1 mg fluocinolone implant, respectively, and 11 and 15 % following 0.35 and 0.7 mg dexamethasone implant, respectively. The common risk factors included preexisting glaucoma, higher baseline intraocular pressure (IOP), younger age, OHT following previous injection, uveitis, higher steroid dosage, and fluocinolone implant (Kiddee et al. 2013).

Glucocorticoid receptor polymorphisms (ER22/23EK, N363S, BclI, N766N, and single nucleotide polymorphisms (SNPs) within introns 3 and 4) were assessed in 52 patients (56 eyes) who underwent treatment with intravitreal triamcinolone acetonide (IVTA) for various retinal diseases. After removing the patients, those who are nonpolymorphic for ER22/23EK, N363S, and the intron 3 SNP, in the test population, the remaining were subjected for analysis for BclI, N766N, and intron 4 SNP. However, the small population did not record any statistically significant relationship between glucocorticoid receptor polymorphisms and IOP elevation following IVTA (Gerzenstein et al. 2008).