Genome-wide association study of the response of patients with diabetic macular edema to intravitreal Anti-VEGF injection

Abstract

Diabetic macular edema (DME), a complication of diabetes mellitus, is a leading cause of adult-onset blindness worldwide. Recently, intravitreal anti-VEGF injection has been used as a first-line treatment. This study analyzed the association between the genetic profile of patients with DME and their response to treatment. Intravitreal anti-VEGF injections were administered monthly for three months to Korean patients diagnosed with DME, who were classified into two groups depending on whether they responded to anti-VEGF therapy or showed recurrence within six months. Peripheral blood samples were used for genetic analyses. Genome-wide association analysis results sowed that the genes DIRC3 on chromosome 2 (rs16857280, p = 1.2 × 10^-6), SLCO3A1 on chromosome 15 (rs12899055, p = 2.5 × 10^-6), and RAB2A on chromosome 8 (rs2272620, p = 4.6 × 10^-6) were associated with treatment response to intravitreal anti-VEGF injection. SLC35F1, TMEM132D, KIAA0368, HPCAL1, IGF2BP3, SPN2S, COL23A1, and CREB5 were also related to treatment response (p < 5.0 × 10^-5). Using the KEGG pathway analysis, RAB2A and CREB5 were found to be associated with AMPK signaling related to VEGF (p = 0.018). The identified genetic biomarkers can elucidate the factors affecting patient response to intravitreal anti-VEGF injection and help select appropriate therapeutic strategy.

Figure 1

Changes in CST after intravitreal anti-VEGF injection. (A) Before, and (B) after 1 month. CST: central subfield thickness.

Figure 2

Genome-wide association analysis results of treatment response to intravitreal anti-VEGF injection to treat DME in Korean patients. Relatively significant loci are displayed with locus names (p < 5.0 × 10^–5).

Figure 3

Regional association plots for three high ranked SNPs: (A) DIRC3, (B) SLCO3A1, (C) RAB2A. Lead variants are indicated by blue-filled shapes and other variants are colored according to r² values with the lead variant in each SNPs.

Figure 4

Proposed scheme for AMPK signaling pathway. VEGF: vascular endothelial growth factor; AMPK: AMP-activated protein kinase; RAB2A: Ras-related protein 2A; CREB: CAMP responsive element binding protein 5; mTOR: mammalian target of rapamycin; eNOS: endothelial isoform of nitric-oxide synthase; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells.