Age-related Macular Degeneration Susceptibility Research Articles

Genome-wide Meta-analysis for Myopic Macular Neovascularization Identified a Novel Susceptibility Locus and Revealed a Shared Genetic Susceptibility with Age-Related Macular Degeneration

To identify the susceptibility loci for myopic macular neovascularization (mMNV) in patients with high myopia. A genome-wide association study (GWAS) meta-analysis (meta-GWAS). We included 2,783 highly myopic individuals, including 608 patients with mMNV and 2,175 control participants without mMNV. We performed a meta-analysis of three independent GWASs conducted according to genotyping platform (Illumina Asian Screening Array [ASA] dataset, Illumina Human610 BeadChip [610K] dataset, and whole genome sequencing [WGS] dataset), adjusted for age, sex, axial length and the first to third principal components. We used DeltaSVM to evaluate the binding affinity of transcription factors to DNA sequences around the susceptibility single nucleotide polymorphisms (SNPs). In addition, we evaluated the contribution of previously reported age-related macular degeneration (AMD) susceptibility loci. The association between SNPs and mMNV in patients with high myopia. The meta-GWAS identified rs56257842 at TEX29 -LINC02337 as a novel susceptibility SNP for mMNV (odds ratio [OR]meta = 0.62, Pmeta = 4.63 × 10-8, I2 = 0.00), which was consistently associated with mMNV in all datasets (ORASA = 0.59, PASA = 1.71 × 10-4; OR610K = 0.63, P610K = 5.53 × 10-4; ORWGS = 0.66, PWGS = 4.38 × 10-2). Transcription factor-wide analysis showed that the transcription factors ZNF740 and EGR1 lost their binding affinity to this locus when rs56257842 had the C allele (alternative allele), and the WNT signaling-related transcription factor ZBTB33 gained binding affinity when rs56257842 had the C allele. When we examined the associations of AMD susceptibility loci, rs12720922 at CETP showed a statistically significant association with mMNV (ORmeta = 0.52, Pmeta = 1.55 × 10-5), while rs61871745 near ARMS2 showed a marginal association (ORmeta = 1.25, Pmeta =7.79 × 10-3). Our study identified a novel locus associated with mMNV in high myopia. Subsequent analyses offered important insights into the molecular biology of mMNV, providing the potential therapeutic targets for mMNV. Furthermore, our findings imply shared genetic susceptibility between mMNV and AMD.

Relationship between CCL2 gene 2518A/G (rs1024611) polymorphism and age-related macular degeneration susceptibility: meta-analysis and trial sequential analysis.

This study aimed to investigate the association between the CC-cytokine ligand-2 (CCL2) 2518A/G (rs1024611) single nucleotide polymorphism (SNP) and susceptibility to age-related macular degeneration (AMD). PubMed, Embase, Web of Science, and other databases were searched for articles published before August 24, 2023. After searching, data extraction, and quality assessment, meta-analysis and trial sequential analysis were conducted using RevMan 5.4, Stata 17.0, and TSA 0.9.5.10 Beta software. Combined OR, P values, and 95% confidence intervals (CIs) were calculated. Sensitivity analysis, subgroup analysis and publication bias assessment were also performed. Six articles, comprising 1186 cases and 1124 controls, were included. No significant statistical difference was found in six main outcomes. However, due to observed heterogeneity and high sensitivity, subgroup analysis was performed, revealing statistically significant differences across different regions. No significant publication bias was observed. Trial sequential analysis suggested the need for additional follow-up case-control studies to further validate the findings. The CCL2 gene 2518A/G (rs1024611) polymorphism is associated with AMD susceptibility. Among Caucasian populations in West Asia and Europe, the G allele is protective against AMD, whereas in East and South Asia, it poses a risk factor.

Genetics in neovascular age-related macular degeneration susceptibility and treatment response to anti-VEGF intravitreal injection: A case series study.

To identify genotypes associated with neovascular age-related macular degeneration (nAMD) and investigate the associations between genotype variations and anti-vascular endothelial growth factor (VEGF) treatment response. This observational, retrospective, case series study enrolled patients diagnosed with nAMD who received anti-VEGF treatment in National Taiwan University Hospital with at least one-year follow-up between 2012 and 2020. A genome-wide association study (GWAS) was conducted on enrolled patients and controls. Correlations between the genotypes identified from GWAS and the treatment response of functional/anatomical biomarkers, including visual acuity (VA), presence of intraretinal or subretinal fluid (SRF), serous or fibrovascular pigmented epithelium detachment (PED), and disruption of the ellipsoid zone (EZ), were analysed. In total, 182 patients with nAMD and 1748 controls were enrolled. GWAS revealed 16 single nucleotide polymorphisms (SNPs) as risk loci for nAMD, including seven loci in CFH and ARMS2/HTRA1 and nine novel loci, including rs117517872 and rs79835234(COPB2-DT), rs7525578(RAP1A), rs2123738(LOC105376755), rs1374879(CNTN3), rs3812692(SAR1A), rs117501587(PRKCA), rs9965945(CNDP1), and rs189769231(MATK). Our study revealed rs800292(CFH), rs11200638(HTRA1), and rs2123738(LOC105376755) correlated with poor treatment response in VA (P = 0.005), SRF (P = 0.044), and fibrovascular PED (P = 0.007), respectively. Rs9965945(CNDP1) was correlated with poor response in disruption of EZ (P = 0.046) and serous PED (P = 0.049). Among the 16 SNPs found in the GWAS, four loci-CFH, ARMS2/HTRA1, and two novel loci-were correlated with the susceptibility of nAMD and anatomical/functional responses after anti-VEGF treatment.

Decreased Circulating Very Small Low-Density Lipoprotein is Likely Causal for Age-Related Macular Degeneration

Abnormal changes in metabolite levels in serum or plasma have been highlighted in several studies in age-related macular degeneration (AMD), the leading cause of irreversible vision loss. Specific changes in lipid profiles are associated with an increased risk of AMD. Metabolites could thus be used to investigate AMD disease mechanisms or incorporated into AMD risk prediction models. However, whether particular metabolites causally affect the disease has yet to be established. A 3-tiered analysis of blood metabolites in the United Kingdom (UK) Biobank cohort to identify metabolites that differ in AMD patients with evidence for a putatively causal role in AMD. A total of 72376 donors from the UK Biobank cohort including participants with AMD (N=1353) and non-AMD controls (N=71023). We analyzed 325 directly measured or derived blood metabolites from the UK Biobank for 72376 donors to identify AMD-associated metabolites. Genome-wide association studies for 325 metabolites in 98316 European participants from the UK Biobank were performed. The causal effects of these metabolites in AMD were tested using a 2-sample Mendelian randomization approach. The predictive value of these measurements together with sex and age was assessed by developing a machine learning classifier. Evaluating metabolic biomarkers associated with AMD susceptibility and investigating their potential causal contribution to the development of the disease. This study noted age to be the prominent risk factor associated with AMD development. While accounting for age and sex, we identified 84 metabolic markers as significantly (false discovery rate-adjusted P value < 0.05) associated with AMD. Lipoprotein subclasses comprised the majority of the AMD-associated metabolites (39%) followed by several lipoprotein to lipid ratios. Nineteen metabolites showed a likely causative role in AMD etiology. Of these, 6 lipoproteins contain very small, very low-density lipoprotein (VLDL), and phospholipids to total lipid ratio in medium VLDL. Based on this we postulate that depletion of circulating very small VLDLs is likely causal for AMD. The risk prediction model constructed from the metabolites, age and sex, identified age as the primary predictive factor with a much smaller contribution by metabolites to AMD risk prediction. This study underscores the pronounced role of lipids in AMD susceptibility and the likely causal contribution of particular subclasses of lipoproteins to AMD. Our study provides valuable insights into the metabopathological mechanisms of AMD disease development and progression.

Complement factor H Y402H polymorphism results in diminishing CD4+ T cells and increasing C-reactive protein in plasma

Age-related macular degeneration (AMD) is a common cause of visual loss among the elderly. Genetic variants in the gene encoding complement factor H (CFH) have been identified as an AMD susceptibility gene, however, the mechanistic link is debated. Here, we investigated the link between the CFH Y402H genotype and low-grade inflammation. We recruited 153 healthy individuals, 84 participants with dry stages of AMD, and 148 participants with neovascular AMD. All participants were subjected to detailed retinal examination, and interview regarding comorbidities and lifestyle. Blood samples were analyzed for level of C-Reactive Protein (CRP), white blood cell differential count, and stained with fluorescent antibodies to differentiate CD4+ and CD8+ T cells. CFH Y402H genotyping was performed using an allele-specific polymerase chain reaction genotyping assay. Splenocytes from young and aged wild type and Cfh null mutant C57BL/6J mice were examined for CD4+ and CD8+ T cells. Healthy individuals with the CFH Y402H at-risk polymorphism HH had higher levels of CRP and lower proportions of CD4+ T cells compared to persons with the YH or YY polymorphism (P = 0.037, Chi-square). Healthy individuals with the HH polymorphism displayed lower proportions of CD4+ T cells with ageing (P < 0.01, one-way ANOVA), whereas both young and aged Cfh null mutant mice displayed lower proportions of CD4+ T cells (P < 0.001 and P < 0.05; unpaired t test). Participants with dry AMD and the HH polymorphism had similarly lower proportions of CD4+ T cells (P = 0.024, one-way ANOVA), but no difference in CRP-levels. In the neovascular stage of AMD, there was no difference in proportion of CD4+ cells or CRP levels according to genotype. The risk-associated CFH genotype is associated with an age-related decrease in proportion of CD4+ T cells and increased levels of CRP in healthy individuals. This indicates that decreased complement regulation results in extensive changes in innate and adaptive immune compartments that precede development of AMD.

Relationship Between Retinal Layer Thickness and Genetic Susceptibility to Age-Related Macular Degeneration in Asian Populations

For OCT retinal thickness measurements to be used as a prodromal age-related macular degeneration (AMD) risk marker, the 3-dimensional (3D) topographic variation of the relationship between genetic susceptibility to AMD and retinal thickness needs to be assessed. We aimed to evaluate individual retinal layer thickness changes and topography at the macula that are associated with AMD genetic susceptibility. Genetic association study. A total of 1579 healthy participants (782 Chinese, 353 Malays, and 444 Indians) from the multiethnic Singapore Epidemiology of Eye Diseases study were included. Spectral-domain OCT and automatic segmentation of individual retinal layers were performed to produce 10 retinal layer thickness measurements at each ETDRS subfield, producing 3D topographic information. Age-related macular degeneration genetic susceptibility was represented via single nucleotide polymorphisms (SNPs) and aggregated via whole genome (overall) and pathway-specific age-related macular degeneration polygenic risk score (PRSAMD). Associations of individual SNPs, overall PRSAMD, and pathway-specific PRSAMD with retinal thickness were analyzed by individual retinal layer and ETDRS subfield. CFH rs10922109, ARMS2-HTRA1 rs3750846, and LIPC rs2043085 were the top AMD susceptibility SNPs associated with retinal thickness of individual layers (P<1.67×10-3), all at the central subfield. The overall PRSAMD was most associated with thinner L9 (outer segment photoreceptor/retinal pigment epithelium complex) thickness at the central subfield (β=-0.63 μm; P=5.45×10-9). Pathway-specific PRSAMD for the complement cascade (β=-0.53 μm; P=9.42×10-7) and lipoprotein metabolism (β=-0.05 μm; P=0.0061) were associated with thinner photoreceptor layers (L9 and L7 [photoreceptor inner/outer segments], respectively) at the central subfield. The mean PRSAMD score was larger among Indians compared with that of the Chinese and had the thinnest thickness at the L9 central subfield (β=-1.00 μm; P=2.91×10-7; R2=5.5%). Associations at other retinal layers and ETDRS regions were more heterogeneous. Overall genetic susceptibility to AMD and the aggregate effects of the complement cascade and lipoprotein metabolism pathway are associated most significantly with L7 and L9 photoreceptor thinning at the central macula in healthy individuals. Photoreceptor thinning has potential to be a prodromal AMD risk marker, and topographic variation should be considered. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Predicting late-stage age-related macular degeneration by integrating marginally weak SNPs in GWA studies.

Introduction: Age-related macular degeneration (AMD) is a progressive neurodegenerative disease and the leading cause of blindness in developed countries. Current genome-wide association studies (GWAS) for late-stage age-related macular degeneration are mainly single-marker-based approaches, which investigate one Single-Nucleotide Polymorphism (SNP) at a time and postpone the integration of inter-marker Linkage-disequilibrium (LD) information in the downstream fine mappings. Recent studies showed that directly incorporating inter-marker connection/correlation into variants detection can help discover novel marginally weak single-nucleotide polymorphisms, which are often missed in conventional genome-wide association studies, and can also help improve disease prediction accuracy. Methods: Single-marker analysis is performed first to detect marginally strong single-nucleotide polymorphisms. Then the whole-genome linkage-disequilibrium spectrum is explored and used to search for high-linkage-disequilibrium connected single-nucleotide polymorphism clusters for each strong single-nucleotide polymorphism detected. Marginally weak single-nucleotide polymorphisms are selected via a joint linear discriminant model with the detected single-nucleotide polymorphism clusters. Prediction is made based on the selected strong and weak single-nucleotide polymorphisms. Results: Several previously identified late-stage age-related macular degeneration susceptibility genes, for example, BTBD16, C3, CFH, CFHR3, HTARA1, are confirmed. Novel genes DENND1B, PLK5, ARHGAP45, and BAG6 are discovered as marginally weak signals. Overall prediction accuracy of 76.8% and 73.2% was achieved with and without the inclusion of the identified marginally weak signals, respectively. Conclusion: Marginally weak single-nucleotide polymorphisms, detected from integrating inter-marker linkage-disequilibrium information, may have strong predictive effects on age-related macular degeneration. Detecting and integrating such marginally weak signals can help with a better understanding of the underlying disease-development mechanisms for age-related macular degeneration and more accurate prognostics.

Vitronectin and Its Interaction with PAI-1 Suggests a Functional Link to Vascular Changes in AMD Pathobiology.

The pathogenesis of age-related macular degeneration (AMD), a frequent disorder of the central retina, is incompletely understood. Genome-wide association studies (GWAS) suggest a strong contribution of genomic variation in AMD susceptibility. Nevertheless, little is known about biological mechanisms of the disease. We reported previously that the AMD-associated polymorphism rs704C > T in the vitronectin (VTN) gene influences protein expression and functional aspects of encoded vitronectin, a human blood and extracellular matrix (ECM) protein. Here, we refined the association of rs704 with AMD in 16,144 cases and 17,832 controls and noted that rs704 is carried exclusively by the neovascular AMD subtype. Interaction studies demonstrate that rs704 affects the ability of vitronectin to bind the angiogenic regulator plasminogen activator inhibitor 1 (PAI-1) but has no influence on stabilizing its active state. Western blot analysis and confocal imaging reveal a strong enrichment of PAI-1 in the ECM of cultured endothelial cells and RPE cell line ARPE-19 exposed to vitronectin. Large-scale gene expression of VTN and PAI-1 showed positive correlations and a statistically significant increase in human retinal and blood tissues aged 60 years and older. Our results suggest a mechanism by which the AMD-associated rs704 variant in combination with ageing may contribute to the vascular complications in AMD.

Genome-wide Survival Analysis for Macular Neovascularization Development in Central Serous Chorioretinopathy Revealed Shared Genetic Susceptibility with Polypoidal Choroidal Vasculopathy

To identify susceptibility genes for macular neovascularization (MNV) development in central serous chorioretinopathy (CSC). Genome-wide survival analysis using a longitudinal cohort study. We included 402 and 137 patients with CSC but without MNV at their first visit from the Kyoto CSC Cohort and Kobe CSC dataset, respectively. All patients underwent detailed ophthalmic examinations, including multimodal imaging, such as fundus autofluorescence, spectral-domain OCT, and fluorescein angiography/indocyanine green angiography or OCT angiography. We conducted a genome-wide survival analysis using the Kyoto CSC Cohort. We applied the Cox proportional hazard model to adjust for age, sex, and the first principal component. Single nucleotide polymorphisms (SNPs) with P values < 1.0× 10-5 were carried forward to the replication in the Kobe CSC dataset. Moreover, we evaluated the contribution of previously reported age-related macular degeneration (AMD) susceptibility loci. We used FUMA and ToppFun for the functional enrichment analysis. The association between SNPs and MNV development in patients with CSC. Rs370974631 near ARMS2 displayed a genome-wide significant association in the meta-analysis of discovery and replication result (hazard ratio [HR]meta, 3.63; Pmeta= 5.76× 10-9). Among previously reported AMD susceptibility loci, we additionally identified CFH rs800292 (HR, 0.39, P= 2.55× 10-4), COL4A3 rs4276018 (HR, 0.26, P= 1.56× 10-3), and B3GALTL rs9564692 (HR, 0.56, P= 8.30× 10-3) as susceptibility loci for MNV development in CSC. The functional enrichment analysis revealed significant enrichment of 8 pathways (GO:0051561, GO:0036444, GO:0008282, GO:1990246, GO:0015272, GO:0030955, GO:0031420, and GO:0005242) related to ion transport. ARMS2, CFH, COL4A3, and B3GALTL were identified as susceptibility genes for MNV development in CSC. These 4 genes are known as susceptibility genes for AMD, whereas COL4A3 and B3GALTL were previously reported to be polypoidal choroidal vasculopathy (PCV)-specific susceptibility genes. Our findings revealed the shared genetic susceptibility between PCV and MNV secondary to CSC.

Protective chromosome 1q32 haplotypes mitigate risk for age-related macular degeneration associated with the CFH-CFHR5 and ARMS2/HTRA1 loci

BackgroundSingle-variant associations with age-related macular degeneration (AMD), one of the most prevalent causes of irreversible vision loss worldwide, have been studied extensively. However, because of a lack of refinement of these associations, there remains considerable ambiguity regarding what constitutes genetic risk and/or protection for this disease, and how genetic combinations affect this risk. In this study, we consider the two most common and strongly AMD-associated loci, the CFH-CFHR5 region on chromosome 1q32 (Chr1 locus) and ARMS2/HTRA1 gene on chromosome 10q26 (Chr10 locus).ResultsBy refining associations within the CFH-CFHR5 locus, we show that all genetic protection against the development of AMD in this region is described by the combination of the amino acid-altering variant CFH I62V (rs800292) and genetic deletion of CFHR3/1. Haplotypes based on CFH I62V, a CFHR3/1 deletion tagging SNP and the risk variant CFH Y402H are associated with either risk, protection or neutrality for AMD and capture more than 99% of control- and case-associated chromosomes. We find that genetic combinations of CFH-CFHR5 haplotypes (diplotypes) strongly influence AMD susceptibility and that individuals with risk/protective diplotypes are substantially protected against the development of disease. Finally, we demonstrate that AMD risk in the ARMS2/HTRA1 locus is also mitigated by combinations of CFH-CFHR5 haplotypes, with Chr10 risk variants essentially neutralized by protective CFH-CFHR5 haplotypes.ConclusionsOur study highlights the importance of considering protective CFH-CFHR5 haplotypes when assessing genetic susceptibility for AMD. It establishes a framework that describes the full spectrum of AMD susceptibility using an optimal set of single-nucleotide polymorphisms with known functional consequences. It also indicates that protective or preventive complement-directed therapies targeting AMD driven by CFH-CFHR5 risk haplotypes may also be effective when AMD is driven by ARMS2/HTRA1 risk variants.

Interlink between Inflammation and Oxidative Stress in Age-Related Macular Degeneration: Role of Complement Factor H.

Age-related macular degeneration (AMD) heads the list of legal blindness among the elderly population in developed countries. Due to the complex nature of the retina and the variety of risk factors and mechanisms involved, the molecular pathways underlying AMD are not yet fully defined. Persistent low-grade inflammation and oxidative stress eventually lead to retinal pigment epithelium dysfunction and outer blood–retinal barrier (oBRB) breakdown. The identification of AMD susceptibility genes encoding complement factors, and the presence of inflammatory mediators in drusen, the hallmark deposits of AMD, supports the notion that immune-mediated processes are major drivers of AMD pathobiology. Complement factor H (FH), the main regulator of the alternative pathway of the complement system, may have a key contribution in the pathogenesis of AMD as it is able to regulate both inflammatory and oxidative stress responses in the oBRB. Indeed, genetic variants in the CFH gene account for the strongest genetic risk factors for AMD. In this review, we focus on the roles of inflammation and oxidative stress and their connection with FH and related proteins as regulators of both phenomena in the context of AMD.

Rs10490924 surrounding HTRA1/ARMS2 regulates the susceptibility of age-related macular degeneration

Multiple studies have assessed the contribution of rs10490924 on chromosome 10q26 surrounding HTRA1/ARMS2 gene to age-related macular degeneration (AMD) risk. However, the causal allele at this locus is still inconclusive. In this meta-analysis, we systematically characterized the potential association between rs10490924 polymorphism and AMD risk. Data available from 12 case-control studies, including a total of 5244 cases and 2755 controls in three different ethnic populations, were used to evaluate the correlation between rs10490924 G/T polymorphism (Ala69Ser) and AMD risk. In overall populations, the results indicated the Ala69Ser polymorphism was significantly associated with AMD under allelic (OR = 0.35, 95% CI = 0.30–0.40), homozygous (OR = 0.12, 95%CI = 0.09–0.17), dominant (OR = 0.18, 95%CI = 0.14–0.24), recessive (OR = 0.33, 95%CI = 0.28–0.39), and heterozygous genetic models (OR = 0.26, 95% CI = 0.21–0.33). Similar results were observed in subgroup analysis. This meta-analysis suggests that rs10490924 (Ala69Ser) polymorphism was significantly associated with the susceptibility of AMD in all ethnicities, Ala69 carriers are resistant to AMD risk.

Family-based exome sequencing identifies rare coding variants in age-related macular degeneration

Genome-wide association studies (GWAS) have identified 52 independent variants at 34 genetic loci that are associated with age-related macular degeneration (AMD), the most common cause of incurable vision loss in the elderly worldwide. However, causal genes at the majority of these loci remain unknown. In this study, we performed whole exome sequencing of 264 individuals from 63 multiplex families with AMD and analyzed the data for rare protein-altering variants in candidate target genes at AMD-associated loci. Rare coding variants were identified in the CFH, PUS7, RXFP2, PHF12 and TACC2 genes in three or more families. In addition, we detected rare coding variants in the C9, SPEF2 and BCAR1 genes, which were previously suggested as likely causative genes at respective AMD susceptibility loci. Identification of rare variants in the CFH and C9 genes in our study validated previous reports of rare variants in complement pathway genes in AMD. We then extended our exome-wide analysis and identified rare protein-altering variants in 13 genes outside the AMD-GWAS loci in three or more families. Two of these genes, SCN10A and KIR2DL4, are of interest because variants in these genes also showed association with AMD in case-control cohorts, albeit not at the level of genome-wide significance. Our study presents the first large-scale, exome-wide analysis of rare variants in AMD. Further independent replications and molecular investigation of candidate target genes, reported here, would assist in gaining novel insights into mechanisms underlying AMD pathogenesis.

Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes (CFHR1-5) are major determinants of AMD susceptibility, but their molecular consequences remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. We show that systemic FHR-4 levels are elevated in AMD (P-value = 7.1 × 10−6), whereas no difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch’s membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant rs10922109 has the highest association with reduced FHR-4 levels (P-value = 2.2 × 10−56), independently of the AMD-protective CFHR1–3 deletion, and even in those individuals that carry the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player contributing to complement dysregulation in AMD.

Evaluation of the association of C5 with neovascular age-related macular degeneration and polypoidal choroidal vasculopathy

BackgroundNeovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are sight-threatening maculopathies with both environmental and genetic risk factors. We have previously shown relative risks posed by genes of the complement pathways to neovascular AMD and PCV.MethodsIn this study, we investigated the haplotype-tagging single nucleotide polymorphisms (SNPs) in the complement component 5 (C5) gene in 708 unrelated Chinese individuals: 200 neovascular AMD patients, 233 PCV patients and 275 controls. Six tagging SNPs in C5 were genotyped. Univariate single SNP association analysis, haplotype-based association analysis and gene-gene interaction analysis between C5 and other AMD-associated genes were performed.ResultsThe results revealed none of the six tagging SNPs of the C5 gene had a significant association with neovascular AMD or PCV (P > 0.05). We also found insignificant haplotype-based association, and no significant SNP-SNP interaction between C5 and other genes (including C2-CFB-RDBP-SKIV2L, SERPING1, CETP, ABCG1, PGF, ANGPT2, CFH and HTRA1) for neovascular AMD and PCV.ConclusionsThis study showed no statistical significance in the genetic association of C5 with neovascular AMD or PCV in a Hong Kong Chinese population. Further studies in large samples from different populations are warranted to elucidate the role of C5 in the genetic susceptibility of AMD and PCV.

Associations of TLR4 gene polymorphisms with the risk of age-related macular degeneration in a Chinese Han population.

The study was designed to reveal the relationship of toll-like receptor 4 (TLR4, rs1927914 and rs1927907) polymorphisms with risk of age-related macular degeneration (AMD), as well as the adjustment of this association by some environmental and lifestyle factors in Chinese Han population.TLR4 polymorphisms were genotyped by polymerase chain reaction-restricted fragment length polymorphisms and direct sequencing method in 138 AMD patients and 146 healthy controls. Genotype distribution in the control group was checked with Hardy–Weinberg equilibrium. Association of TLR4 polymorphisms and AMD risk was evaluated by χ2 test and adjusted by age and sex, smoking and drinking. Odds ratio (OR) with 95% confidence interval (95% CI) was used to represent the association strength. Logistic regressive analysis was used to calculate the adjusted OR values.CC genotype of rs1927914 had significantly lower frequency in AMD patients (P = .010), indicated a negative association with AMD risk (crude: OR = 0.358, 95% CI = 0.162–0.791; adjusted: OR = 0.355, 95% CI = 0.160–0.789). C allele of rs1927914 might decrease the susceptibility of AMD (crude: OR = 0.698, 95% CI = 0.497–0.982; adjusted: OR = 0.698, 95% CI = 0.495–0.984). No significant association has been discovered between TLR4 rs1927907 polymorphism and AMD susceptibility. Strong linkage disequilibrium existed between rs1927914 and rs1927907 polymorphisms. C-C haplotype was negatively associated with AMD risk (OR = 0.242, 95% CI = 0.121–0.485; OR = 0.242, 95% CI = 0.120–0.488).CC genotype and C allele of rs1927914 were significantly associated with the decreased AMD susceptibility.

Complement factor B gene polymorphisms and risk of age-related macular degeneration: A meta-analysis.

To investigate the potential correlation between complement factor B polymorphisms and age-related macular degeneration. We retrieved relevant articles systematically by searching PubMed and Web of Science databases. The pooled odds ratios and 95% confidence intervals were calculated for five complement factor B polymorphism rs641153, rs4151667, rs1048709, rs2072633, and rs12614 using data from included articles in both random effects and fixed effect models. Subgroup meta-analysis based on age-related macular degeneration type, choroidal neovascular disease (rs641153 and rs4151667), geographic atrophy (rs641153 and rs4151667), and races was also performed. In the overall comparison, we observed that the distribution of rs641153 and the risk of age-related macular degeneration were significantly correlated (p < 0.00001). Similar results were obtained in subgroup analysis based on race (Caucasians, p < 0.00001; Asians, p = 0.003) and age-related macular degeneration type (choroidal neovascular disease, p < 0.00001; geographic atrophy, p = 0.04). As for complement factor B rs4151667, the genotypic effects were also demonstrated statistically significant in overall analysis (p < 0.00001) and only in Caucasians diagnosed with choroidal neovascular disease (p = 0.004), but not in Asians. Moreover, no statistically significant correlations between the complement factor B polymorphisms rs1048709 (p = 0.63), rs2072633 (p = 0.72), rs12614 (p = 0.98) and susceptibility to age-related macular degeneration were detected in either overall or subgroup analysis. Collectively, we demonstrated that the complement factor B genes rs641153 and rs4151667, but not rs1048709, rs2072633, rs12614, were associated with the susceptibility of age-related macular degeneration and might play predictive roles in future age-related macular degeneration diagnosis. More studies are needed to verify these findings.

CFH and VIPR2 as susceptibility loci in choroidal thickness and pachychoroid disease central serous chorioretinopathy

Central serous chorioretinopathy (CSC) is a common disease affecting younger people and may lead to vision loss. CSC shares phenotypic overlap with age-related macular degeneration (AMD). As recent studies have revealed a characteristic increase of choroidal thickness in CSC, we conducted a genome-wide association study on choroidal thickness in 3,418 individuals followed by TaqMan assays in 2,692 subjects, and we identified two susceptibility loci: CFH rs800292, an established AMD susceptibility polymorphism, and VIPR2 rs3793217 (P = 2.05 × 10-10 and 6.75 × 10-8, respectively). Case-control studies using patients with CSC confirmed associations between both polymorphisms and CSC (P = 5.27 × 10-5 and 5.14 × 10-5, respectively). The CFH rs800292 G allele is reportedly a risk allele for AMD, whereas the A allele conferred risk for thicker choroid and CSC development. This study not only shows that susceptibility genes for CSC could be discovered using choroidal thickness as a defining variable but also, deepens the understanding of differences between CSC and AMD pathophysiology.

C-Reactive Protein as a Therapeutic Target in Age-Related Macular Degeneration

Age-related macular degeneration (AMD), a retinal degenerative disease, is the leading cause of central vision loss among the elderly population in developed countries and an increasing global burden. The major risk is aging, compounded by other environmental factors and association with genetic variants for risk of progression. Although the etiology of AMD is not yet clearly understood, several pathogenic pathways have been proposed, including dysfunction of the retinal pigment epithelium, inflammation, and oxidative stress. The identification of AMD susceptibility genes encoding complement factors and the presence of complement and other inflammatory mediators in drusen, the hallmark deposits of AMD, support the concept that local inflammation and immune-mediated processes play a key role in AMD pathogenesis that may be accelerated through systemic immune activation. In this regard, increased levels of circulating C-reactive protein (CRP) have been associated with higher risk of AMD. Besides being a risk marker for AMD, CRP may also play a role in the progression of the disease as it has been identified in drusen, and we have recently found that its monomeric form (mCRP) induces blood retinal barrier disruption in vitro. In this review, we will address recent evidence that links CRP and AMD pathogenesis, which may open new therapeutic opportunities to prevent the progression of AMD.

Polymorphisms in Selected Genes and Their Association with Age-Related Macular Degeneration in a Chinese Population

BackgroundIncreasing evidence shows that polymorphisms in a number of genes can influence age-related macular degeneration (AMD) risk. This study aimed to investigate the association of CX3CR1 839C/T, CX3CR1 745G/A, PLEKHA1 958A/G, VEGFA +674C/T, and VEGFA +936C/T polymorphisms with AMD risk among Chinese.Material/MethodsThe polymorphisms were genotyped on 827 AMD patients and 827 controls, and the odds ratios (ORs) were calculated under allele, additive, recessive, and dominant genetic models. Logistic regression analysis was performed to control for potential confounders (age, sex, and smoking status).ResultsWe showed that all the 5 polymorphisms showed a significant association with AMD risk under the additive model (for homozygous mutant genotype) and at least 1 other genetic model, both before and after adjustment for the potential confounders. PLEKHA1 958A/G polymorphism was associated with a decreased AMD risk (additive model: aOR=0.722, 95% CI=0.450–0.979, P=0.019; allele model: aOR=0.883, 95% CI=0.736–0.992, P=0.014), while all other polymorphisms were associated with an increased AMD risk (CX3CR1 839C/T, additive model: aOR=2.682, 95% CI=1.119–5.709, P=0.022, recessive model: aOR=2.729, 95% CI=1.141–6.048, P=0.010; CX3CR1 745G/A, additive model: aOR=2.614, 95% CI=1.231–6.012, P=0.020, recessive model: aOR=2.340, 95% CI=1.227–5.993, P=0.011; VEGFA +674C/T, additive model: aOR=1.601, 95% CI=1.253–2.179, P<0.001, dominant model: aOR=1.287, 95% CI=1.058–1.570, P<0.001, allele model: OR=1.220, 95% CI=1.118–1.427, P<0.001; VEGFA +936C/T, additive model: aOR=1.509, 95% CI=1.105–2.311, P<0.001, recessive model: aOR=1.432, 95% CI=1.027–2.192, P=0.009, dominant model: aOR=1.207, 95% CI=1.031–1.514, P0.001, allele model: aOR=1.216, 95% CI=1.062–1.408, P<0.001).ConclusionsWe conclude that the 5 polymorphisms could serve as biomarkers for AMD susceptibility.