CCL2, CCR2 Gene Variants and CCL2, CCR2 Serum Levels Association with Age-Related Macular Degeneration

Abstract

Background: Age-related macular degeneration (AMD) is the most common cause of progressive and irreversible blindness in developed countries. Although the pathogenesis is not fully understood, AMD is a multifactorial pathology with an accumulation of inflammatory components and macrophages and a strong genetic predisposition. Our purpose was to investigate the association between early AMD and CCL2 (rs1024611, rs4586, rs2857656) and CCR2 (rs1799865) single nucleotide polymorphisms (SNPs) and CCL2, CCR2 serum levels in a Lithuanian population.

Methods: The study included 310 patients with early AMD and 384 healthy subjects. Genotyping of CCL2 rs1024611, rs4586, rs2857656, and CCR2 rs1799865 was performed using a real-time polymerase chain reaction method, while CCL2 and CCR2 chemokines serum concentrations were analyzed using an enzyme-linked immunosorbent assay.

Results: We found that the G allele at CCL2 rs1024611 was more prevalent in the early AMD group than in controls (29.2% vs. 24.1%, p = 0.032). Similarly, the C allele in CCL2 rs2857656 is more common in the early AMD group than in controls (29.2% vs. 24.2%, p = 0.037). Binomial logistic regression revealed that each G allele in rs1024611 was associated with 1.3-fold increased odds of developing early AMD under the additive model (OR = 1.322; 95% CI: 1.032-1.697, p = 0.027) as was each C allele in rs2857656 under the additive model (OR = 1.314; 95% CI: 1.025-1.684, p = 0.031). Haplotype analysis revealed that the C-A-G haplotype of CCL2 SNPs was associated with 35% decreased odds of early AMD development. Further analysis showed elevated CCL2 serum levels in the group with early AMD compared to controls (median (IQR): 1181.6 (522.6) pg/mL vs. 879.9 (494.4) pg/mL, p = 0.013); however, there were no differences between CCR2 serum levels within groups.

Conclusions: We found the associations between minor alleles at CCL2 rs1024611 and rs2857656, elevated CCL2 serum levels, and early AMD development.

Keywords: AMD; CCL2 (rs1024611, rs4586, rs2857656); CCL2 and CCR2 serum level; CCR2 rs1799865.

Figure 1

Fundus images and SS-OCT findings of normal (A) and early AMD (B) eyes. Patients were categorized according to the AREDS classification of AMD as follows: A—stage I, no or a few small drusen (<63 μm in diameter); B—stage II, multiple tiny drusen or a few intermediate drusen (63–124 μm in diameter) or changes in RPE. AMD, age-related macular degeneration; RPE, retinal pigment epithelium; SS-OCT, Swept-source optical coherence tomography.

Figure 2

Serum levels of CCL2 in patients with early AMD and control group. AMD: age-related macular degeneration; CCL2: chemokine (C-C motif) ligand 2. * Significant values are presented as median and IQR.

Figure 3

Serum levels of CCR2 in patients with early AMD and control group. AMD: age-related macular degeneration; CCR2: C-C chemokine receptor type 2. Values are presented as median and IQR.