Association Between C-Reactive Protein and Age-Related Macular Degeneration: Les Liaisons Dangereuses.
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ABSTRACT:
SUBMITTER: Keenan TD
PROVIDER: S-EPMC8336682 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Importance:C-reactive protein (CRP) is a circulating inflammatory marker associated with late age-related macular degeneration (AMD). It remains uncertain whether the association between CRP concentrations and AMD is causal. Objective:To assess whether CRP (OMIM 123260) single-nucleotide polymorphisms that influence circulating CRP concentrations are associated with late AMD. Design, Setting, and Participants:Participants in 2 UK, hospital-based, case-control studies (Cambridge AMD study and Moorfields Eye Hospital AMD study) and 1 pan-European, cross-sectional, population-based study (the European Eye [EUREYE] Study) were recruited between November 6, 2000, and April 30, 2007. Participants underwent dilated stereo-digital fundus photography graded according to the International Classification of Age-related Maculopathy and Macular Degeneration. There were 1727 cases of late AMD (1151 neovascular, 384 geographic atrophy, and 192 mixed [neovascular AMD and geographic atrophy]) and 1153 controls. Early AMD cases (n?=?574) were included only from the EUREYE Study. Data analysis was performed from August 1 to November 30, 2016. Four common single-nucleotide polymorphisms (rs1205, rs1130864, rs1800947, and rs3093077) were selected based on demonstrated influence on circulating CRP concentrations in the literature. In one study, genotyping of rs3093077 failed, and rs1800947 was typed in only 1 study. Main Outcomes and Measures:A genetic multiplicative model was used for the association of single-nucleotide polymorphisms with late AMD adjusted for age and sex. Results:Among the 1727 patients with late AMD, the mean (SD) age was 78.7 (7.4) years, and 668 (38.7%) were men. The mean (SD) age of the controls was 74.9 (7.0) years, and 510 (44.2%) were men. In the pooled results of all 3 studies, neither rs1205 (odds ratio [OR], 0.99; 95% CI, 0.86-1.14) nor rs1130864 (OR, 0.96; 95% CI, 0.83-1.11) was associated with late AMD. For geographic atrophy, rs1205 had an OR of 0.91 (95% CI, 0.74-1.13) and rs1130864 had an OR of 0.94 (95% CI, 0.76-1.16). For neovascular AMD, rs1205 had an OR of 1.01 (95% CI, 0.87-1.19) and rs1130864 had an OR of 0.99 (95% CI, 0.84-1.16). There was no association of rs3093077 and rs1800947 with late AMD or any late AMD phenotype. There were no significant findings for early AMD. Conclusions and Relevance:Our results do not support a causal association between CRP concentrations and AMD.
| S-EPMC5710541 | biostudies-literature
Project description:Age-related macular degeneration (AMD) is a devastating disease characterized by central vision loss in elderly individuals. Previous studies have suggested a link between elevated levels of total C-reactive protein (CRP) in the choroid, CFH genotype, and AMD status; however, the structural form of CRP present in the choroid, its relationship to CFH genotype, and its functional consequences have not been assessed. In this report, we studied genotyped human donor eyes (n = 60) and found that eyes homozygous for the high-risk CFH (Y402H) allele had elevated monomeric CRP (mCRP) within the choriocapillaris and Bruch's membrane, compared to those with the low-risk genotype. Treatment of choroidal endothelial cells in vitro with mCRP increased migration rate and monolayer permeability compared to treatment with pentameric CRP (pCRP) or medium alone. Organ cultures treated with mCRP exhibited dramatically altered expression of inflammatory genes as assessed by RNA sequencing, including ICAM-1 and CA4, both of which were confirmed at the protein level. Our data indicate that mCRP is the more abundant form of CRP in human choroid, and that mCRP levels are elevated in individuals with the high-risk CFH genotype. Moreover, pro-inflammatory mCRP significantly affects endothelial cell phenotypes in vitro and ex vivo, suggesting a role for mCRP in choroidal vascular dysfunction in AMD. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
| S-EPMC5527328 | biostudies-literature
Project description: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.
| S-EPMC5916960 | biostudies-literature
Project description:The aim of the present study was to evaluate the association between statin use and the risk of age-related macular degeneration (AMD). A systematic search of the PubMed, EMBASE and ISI web of science databases was used to identify eligible published literatures without language restrictions up to April 2015. Summary relative ratios (RRs) and 95% CIs were estimated using a fixed-effect or random-effects model. A total of 14 studies met the inclusion criteria and were included in this meta-analysis. No significant association was observed between statin use and the risk of any AMD (RR, 0.95; 95% CI, 0.74-1.15); and stratified analysis showed that statins had a significantly different effects on early and late stages of AMD. For early AMD, statin use significantly reduced the risk approximately 17% (RR, 0.83; 95% CI, 0.66-0.99). At the late stage, we observed a significant protective association of statin use with exudative AMD (RR, 0.90; 95% CI, 0.80-0.99), in contrast with the absent association between statins and geographic atrophy (RR, 1.16; 95% CI, 0.77-1.56). These results demonstrated that statin use was protective for early and exudative AMD. Additional large prospective cohort studies and RCTs are required to determine the potential effect of statins on AMD prevention.
| S-EPMC4677306 | biostudies-other
Project description:CFH and HTRA1 genes are traditional markers of increased risk of age-related macular degeneration (AMD) across populations. Recent findings suggest that additional genes-for instance, in the dystrophin-associated protein complex-might be promising markers for AMD. Here, we performed a case-control study to assess the effect of SGCD single nucleotide polymorphisms (SNPs), a member of this protein family, on AMD diagnosis and phenotype. We performed a case-control study of an under-studied population from Hispanics in Mexico City, with 134 cases with 134 unpaired controls. Cases were 60 years or older (Clinical Age-Related Maculopathy Staging (CARMS) grade 4?5, as assessed by experienced ophthalmologists following the American Association of Ophthalmology (AAO) guidelines), without other retinal disease or history of vitreous-retinal surgery. Controls were outpatients aged 60 years or older, with no drusen or retinal pigment epithelium (RPE) changes on a fundus exam and a negative family history of AMD. We examined SNPs in the SGCD gene (rs931798, rs140617, rs140616, and rs970476) by sequencing and real-time PCR. Genotyping quality checks and univariate analyses were performed with PLINK v1.90b3.42. Furthermore, logistic regression models were done in SAS v.9.4 and haplotype configurations in R v.3.3.1. After adjusting for clinical covariates, the G/A genotype of the SGCD gene (rs931798) significantly increases the odds of being diagnosed with AMD in 81% of cases (1.81; 95% CI 1.06?3.14; p = 0.031), especially the geographic atrophy phenotype (1.82; 95% CI 1.03?3.21; p = 0.038) compared to the G/G homozygous genotype. Moreover, the GATT haplotype in this gene (rs931798, rs140617, rs140616, and rs970476) is associated with lower odds of AMD (adjusted odds ratio (OR) 0.13; 95% CI 0.02?0.91; p = 0.041). SGCD is a promising gene for AMD research. Further corroboration in other populations is warranted, especially among other Hispanic ethnicities.
| S-EPMC6210939 | biostudies-literature
Project description:ImportanceRecent reports suggest that cilioretinal arteries (CRAs) confer protection against developing advanced age-related macular degeneration (AMD).ObjectiveTo further characterize the association between the presence of a CRA and incidence of geographic atrophy (GA) or choroidal neovascularization (CNV).DesignThis cohort study constituted an ad hoc secondary analysis of data from the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and was performed at 44 clinical centers in the United States among participants in CATT with CNV in the study eye and without advanced AMD in the fellow eye at baseline. The presence of a CRA was determined by 2 graders, masked to clinical data, using color fundus photographs, red-free fundus photographs, and fluorescein angiography. The proportion with CRAs at baseline between the study eye with CNV and fellow eye without CNV was first compared. The association of a CRA with incidence of CNV or GA at 5 years among fellow eyes and with incidence of GA among study (treated) eyes was then assessed. In addition, the association of CRAs with the Age-Related Eye Disease Study severity scale among the fellow eyes at baseline was assessed. Data were collected from February 1, 2008, through April 30, 2015, and analyzed from July 1, 2018, through April 30, 2019.ExposuresPresence of a CRA.Main outcomes and measuresThe association between the presence of a CRA and incidence of CNV or GA at 5 years of follow-up.ResultsA total of 350 patients (700 eyes) (230 [65.7% women; mean [SD] age, 77 [7.2] years) were included in the analysis. Cilioretinal arteries were present in 67 of 345 (19.4%) fellow eyes without baseline CNV and 73 of 349 (20.9%) study eyes with baseline CNV (P = .60). Cilioretinal arteries in fellow eyes were not associated with incidence of CNV at 5 years (125 of 278 [45.0%] among eyes without CRAs and 30 of 67 [44.8%] among eyes with CRAs; P = .99) or with incidence of GA at 5 years (110 of 278 [39.6%] among eyes without CRAs and 25 of 67 [37.3%] among eyes with CRAs; P = .89). Cilioretinal arteries in study eyes were not associated with incidence of GA at 5 years (105 of 276 [38.0%] study eyes without CRAs and 26 of 73 [35.6%] study eyes with CRAs; P = .72).Conclusions and relevanceThe analysis did not find a protective association between CRAs and incidence of CNV or GA among CATT participants who had unilateral exudative AMD. Why these findings were different from those of previous publications is unclear but may be partially explained by the different techniques used to detect CRAs or by the baseline advanced disease in CATT participants.Trial registrationClinicalTrials.gov identifier: NCT00593450.
| S-EPMC6743058 | biostudies-literature
Project description:AimTo investigate the association between SERPING1 rs2511989 (G>A) polymorphism and age-related macular degeneration (AMD).MethodsA number of electronic databases (up to July 15, 2014) were searched independently by two investigators. A Meta-analysis was performed on the association between SERPING1 rs2511989 polymorphism and AMD. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated.ResultsEight studies with 16 cohorts consisting of 9163 cases and 6813 controls were included in this Meta-analysis. There was no significant association between rs2511989 polymorphism and AMD under all genetic models in overall estimates (A vs G: OR= 0.938, 95%CI =0.858-1.025; AA vs GG:OR =0.871, 95%CI =0.719-1.056; AG vs GG: OR =0.944, 95%CI =0.845-1.054; AA+AG vs GG: OR =0.927, 95% CI =0.823-1.044; AA vs AG+GG: OR =0.890, 95%CI =0.780-1.034). Cumulative Meta-analyses also showed a trend of no association between rs2511989 polymorphism and AMD as information accumulated by year. Subgroup analysis and Meta-regression analysis indicated that age-matching status was the main source of heterogeneity. Sensitivity analysis found the results in overall comparisons and subgroup comparisons of white subjects under the allele model were found to have significantly statistical differences after studies deviating from Hardy-Weinberg equilibrium (HWE) were excluded (overall: OR=0.918, 95%CI = 0.844-0.999, P =0.049; whites: OR =0.901, 95%CI = 0.817-0.994, P =0.038). However, the results were not sufficiently robust for further sensitivity analysis and statistical differences disappeared on applying Bonferroni correction (with a significance level set at 0.05/25).ConclusionThis Meta-analysis indicates that SERPING1 rs2511989 polymorphism and AMD tend to have no association with each other. Age matching status is a big confounding factor, and more studies with subtle designs are warranted in future.
| S-EPMC4413591 | biostudies-literature
Project description:BACKGROUND We assessed the potential association between monocyte chemotactic protein 1 (MCP-1) variants (rs1024611 and rs3760396) and age-related macular degeneration (AMD) susceptibility among Chinese Han people. MATERIAL AND METHODS Our research included 129 AMD patients and 131 healthy controls. Genotyping for MCP-1 variants was performed in the 2 groups, and genotype and allele distributions were checked between groups by χ² analysis. Odds ratio (OR) and 95% confidence interval (CI) reflected the potential association between MCP-1 variants and AMD risk. The linkage disequilibrium of polymorphisms was detected using Haploview. RESULTS Significant differences in rs1024611 genotype distributions were detected between the 2 groups, and homozygous carriers with GG genotype had higher AMD incidence (P<0.05, OR=2.650, 95% CI=1.127-6.231). The rs1024611 G allele frequency was significantly higher in AMD patients, suggesting that the G allele promotes AMD onset (P<0.05, OR=1.447, 95% CI=1.013-2.068). Strong linkage disequilibrium was found between rs1024611 and rs3760396, and haplotype Ars1024611-Crs3760396 was significantly associated with decreased risk of AMD (P=0.001, OR=0.502, 95% CI=0.335-0.752). CONCLUSIONS MCP-1 rs1024611 variant appears to contribute to risk of AMD in the Chinese Han population, and the interaction of MCP-1 polymorphisms may also influence individual susceptibility to AMD.
| S-EPMC7291784 | biostudies-literature
Project description:Deficient 25-hydroxyvitamin D (25[OH]D) concentrations have been associated with increased odds of age-related macular degeneration (AMD).To examine whether this association is modified by genetic risk for AMD and whether there is an association between AMD and single-nucleotide polymorphisms of genes involved in vitamin D transport, metabolism, and genomic function.Postmenopausal women (N?=?913) who were participants of the Carotenoids in Age-Related Eye Disease Study (CAREDS) (aged 54 to <75 years) with available serum 25(OH)D concentrations (assessed October 1, 1993, to December 31, 1998), genetic data, and measures of AMD (n?=?142) assessed at CAREDS baseline from May 14, 2001, through January 31, 2004, were studied.Prevalent early or late AMD was determined from graded, stereoscopic fundus photographs. Logistic regression was used to estimate odds ratios (ORs) and 95% CIs for AMD by the joint effects of 25(OH)D (<12, ?12 to <20, ?20 to <30, and ?30 ng/mL) and risk genotype (noncarrier, 1 risk allele, or 2 risk alleles). The referent group was noncarriers with adequate vitamin D status (?30 ng/mL). Joint effect ORs were adjusted for age, smoking, iris pigmentation, self-reported cardiovascular disease, self-reported diabetes status, and hormone use. Additive and multiplicative interactions were assessed using the synergy index (SI) and an interaction term, respectively. To examine the association between AMD and variants in vitamin D-related genes, age-adjusted ORs and 95% CIs were estimated using logistic regression.Among the 913 women, 550 had adequate levels of vitamin D (?20 ng/mL), 275 had inadequate levels (?12 to <20 mg/mL), and 88 had deficient levels (<12 ng/mL). A 6.7-fold increased odds of AMD (95% CI,?1.6-28.2) was observed among women with deficient vitamin D status (25[OH]D <12 ng/mL) and 2 risk alleles for CFH Y402H (SI for additive interaction,?1.4; 95% CI,?1.1-1.7; P for multiplicative interaction?=?.25). Significant additive (SI,?1.4; 95% CI,?1.1-1.7) and multiplicative interactions (P?=?.02) were observed for deficient women with 2 high-risk CFI (rs10033900) alleles (OR,?6.3; 95% CI,?1.6-24.2). The odds of AMD did not differ by genotype of candidate vitamin D genes.In this study, the odds of AMD were highest in those with deficient vitamin D status and 2 risk alleles for the CFH and CFI genotypes, suggesting a synergistic effect between vitamin D status and complement cascade protein function. Limited sample size led to wide CIs. Findings may be due to chance or explained by residual confounding.
| S-EPMC4841267 | biostudies-literature
Project description:OBJECTIVE:Pigment epithelium-derived factor (PEDF) strongly inhibits angiogenesis, and plays an important role in retinoblastoma cells. In this study we detect the association of PEDF gene polymorphisms (rs1136287 and rs12150053) and age-related macular degeneration (AMD) risk. METHODS:This is a case-control study including 118 AMD patients and 121 healthy controls. PEDF gene polymorphisms were genotyped by TaqMan method. Hardy-Weinberg equilibrium (HWE) was used to detect the representativeness of the cases and controls. Differences of genotype and allele distributions of PEDF polymorphisms were calculated by Chi-square test. Odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were used to present the relative risk of AMD. RESULTS:Genotype and allele distributions in controls were in accordance with HWE. Genotype and allele distributions of rs1136287 had no significant association with the susceptibility of AMD under five contrast models (P<0.05). CC genotype and C allele of rs12150053 were higher in cases than that in controls, and rs12150053 was obviously related to the risk of AMD under T vs. C model (P=0.044, OR=1.499, 95% CI=1.009-2.226). CONCLUSION:In this study, there was no obvious association between PEDF gene rs1136287 polymorphism and AMD susceptibility, and rs12150053T might act as a susceptible allele in the occurrence of AMD.
| S-EPMC6966057 | biostudies-literature