Complement Factor H Y402H Research Articles

Association of the Complement Factor H Y402H Polymorphism and Response to Anti-Vascular Endothelial Growth Factor Treatment in Age-Related Macular Degeneration: An Updated Meta-Analysis.

Anti-vascular endothelial growth factor (anti-VEGF) agents have a variable effect on patients with age-related macular degeneration (AMD) that has been attributed to several causes, including genetic factors. We evaluated the effects of Complement Factor H (CFH) rs1061170/Y402H polymorphism on the response to anti-VEGF therapy among AMD patients. PubMed, Scopus, EMBASE, Web of Science, and Google Scholar were used for a literature search. Pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated to assess the effects of CFH Y402H polymorphism on the response to anti-VEGF therapy in AMD. I2 was used to present the amount of heterogeneity. We used STATA version 14.0 software. Twenty-five papers reporting data for 4,681 patients were included in this study. Better response to anti-VEGF therapy was seen in T over C (OR = 1.25, 95% CI = 1.04-1.50), TT over CC (OR = 1.60, 95% CI = 1.06-2.4), and TT + TC over CC (OR = 1.68, 95% CI = 1.23-2.28) genotypes. There was no significant difference in the three other genetic models (TT vs. TC, TT vs. TC + CC, TC vs. TT + CC). In Asians, no significant difference was observed in all six genetic models. Ranibizumab and bevacizumab had similar efficacy; however, conbercept was more effective in homozygous genotypes. The literature indicated that TT and TC genotypes and T allele were associated with a better functional response, while the CC genotype and C alleles had a better anatomical response. The combination of risk alleles in ARMS2 A69S (rs10490924), VEGF-A (rs699947), and VEGF-A (rs833069) with Y420H is a predictor of non-respondents. In patients with AMD, the CFH Y402H is a predictor of the response to anti-VEGF agents and should be considered in the treatment plan.

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.

Exogenous CFH Modulates Levels of Pro-Inflammatory Mediators to Prevent Oxidative Damage of Retinal Pigment Epithelial Cells with the At-Risk CFH Y402H Variant.

Age-related macular degeneration (AMD) is a complex, progressive degenerative retinal disease. Retinal pigment epithelial (RPE) cells play an important role in the immune defense of the eye and their dysfunction leads to the progressive irreversible degeneration of photoreceptors. Genetic factors, chronic inflammation, and oxidative stress have been implicated in AMD pathogenesis. Oxidative stress causes RPE injury, resulting in a chronic inflammatory response and cell death. The Y402H polymorphism in the complement factor H (CFH) protein is an important risk factor for AMD. However, the functional significance of CFH Y402H polymorphism remains unclear. In the present study, we investigated the role of CFH in the pro-inflammatory response using an in vitro model of oxidative stress in the RPE with the at-risk CFH Y402H variant. ARPE-19 cells with the at-risk CFH Y402H variant were highly susceptible to damage caused by oxidative stress, with increased levels of inflammatory mediators and pro-apoptotic factors that lead to cell death. Pretreatment of the ARPE-19 cell cultures with exogenous CFH prior to the induction of oxidative stress prevented damage and cell death. This protective effect may be related to the negative regulation of pro-inflammatory cytokines. CFH contributes to cell homeostasis and is required to modulate the pro-inflammatory cytokine response under oxidative stress in the ARPE-19 cells with the at-risk CFH Y402H variant.

Age-Related Maculopathy Susceptibility 2 and Complement Factor H Polymorphism and Intraocular Complement Activation in Neovascular Age-Related Macular Degeneration.

PurposeTo investigate the association of risk alleles in complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) with complement activation products in the aqueous humor in eyes with neovascular age-related macular degeneration (nAMD) including polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), and pachychoroid neovasculopathy (PNV).DesignProspective, comparative, observational study.ParticipantsTreatment-naïve patients with nAMD and cataract patients as controls.MethodsThe study included 236 eyes of 236 patients with nAMD and 49 control eyes of 49 patients. Aqueous humor samples were collected from 67 eyes with drusen-associated nAMD, 72 eyes with PCV, 26 eyes with RAP, and 71 eyes with PNV before intravitreal anti-VEGF injection and cataract surgery in the 49 control eyes. Clinical samples were measured for complement component 3a (C3a), C4a, and C5a using a bead-based immunoassay. Genotyping of the ARMS2 A69S (rs10490924), CFH I62V (rs800292), and CFH Y402H (rs1061170) was performed using TaqMan genotyping.Main Outcome MeasuresThe levels of complement activation products (C3a, C4a, and C5a) in the aqueous humor in each genotype of ARMS2 and CFH.ResultsThe C3a level in the aqueous humor was significantly elevated (P = 0.006) in patients with nAMD and the ARMS2 A69S risk allele, whereas the levels of the complement activation products were not associated with CFH I62V and Y402H genotypes. Among the control eyes, no significant differences were seen in any complement activation products for all genetic polymorphisms. The levels of the complement activation products in the aqueous humor of eyes with the nAMD subtypes for each genetic polymorphism did not show significant differences.ConclusionsThe C3a concentration in the aqueous humor was significantly higher in Japanese nAMD patients with the ARMS2 A69S risk allele, whereas it was not elevated in the patients with CFH I62V. Age-related maculopathy susceptibility 2 A69S polymorphism is strongly associated with local complement activation in nAMD patients.

Role of complement factor B rs4151667 (L9H) polymorphisms and its interactional role with CFH Y402H and C3 rs2230199 (R102G) risk variants in age-related macular degeneration: a case control study

BackgroundAge-related Macular Degeneration (AMD) is a complex eye disease, which is genetically associated with different susceptibility loci. We planned to investigate the possible association of Complement Factor B (CFB) rs4151667 (L9H) variants and their possible interaction with Complement Factor H (CFH) Y402H and Complement factor 3 (C3) rs2230199 (R102G) in AMD.MethodsThis case-control association study included 216 advanced type AMD patients and 191 healthy individuals for evaluation. Extracted-DNA samples were genotyped for the polymorphic regions of CFB rs4151667 (L9H), CFH Y402H and C3 rs2230199 (R102G).ResultsThe distribution of CFB rs4151667 (L9H) genotypes was not significantly different in the AMD patients compared to that of controls (P = 0.18). The AT genotype frequencies for CFB was non significantly lower in AMD group (6.5% vs. 13.1%, AOR = 0.49, CI = 0.23–1.04, P = 0.064(. The A allele of CFB rs4151667 (L9H) was found to be non-significantly lower in AMD patients. CFB rs4151667 (L9H) had no protective interactional effect against CFH (Y402H) and C3 (R102G) risk variants.ConclusionsThis study showed that the protective role of CFB rs4151667 (L9H) in AMD is not significant and it has no significant protective interactional effect against CFH (Y402H) and C3 (R102G) risk variants.

Association of Complement Factor H (CFH) Y402H Gene Polymorphism and Serum CFH with Risk of Age Related Macular Degeneration in Egyptian Patients

AbstractBackground: Age related Macular Degeneration (AMD) is stated as the most common cause of irreversible blindness among aging populations. It has been reported that both Complement Factor H (CFH) Y402H polymorphism and serum CFH concentration are linked to AMD.Aim of Study: To determine whether Y402H polymorphism and serum level of CFH are associated with AMD in the Egyptian population.Material and Methods: Eighty subjects were recruited; 40 AMD patients and 40 matched healthy individuals as control. Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) was performed for the analysis of CFH Y402H gene polymorphism. Serum CFH concentration was measured using Enzyme Linked-Imm-unosorbent Assay (ELISA).Results: Susceptibility to AMD in Egyptian population was not associated with CFH Y402H polymorphism and the presence of C allele is not considered risky; Odds Ratio (OR): 0.545, 95% CI (0.291-1.022). No significant association between CFH genotypes and AMD. Serum CFH concentration showed no statistically significant difference between cases & controls (p=0.706). In controls, there was a statistically significant decrease in serum CFH level in CC genotype compared to both CT genotype (p=0.038) and TT genotype (p=0.007), while in AMD group, no statistically significant difference in serum CFH concentration between different genotypes.Conclusion: CFH Y402H polymorphism does not confer risk of AMD in Egyptian patients. Further larger scaled studies are needed to confirm CFH role in AMD.

Incidence of and Risk Factors Associated With Age-Related Macular Degeneration

While the prevalence of age-related macular degeneration (AMD) differs according to continents and races/ethnicities, its incidence in the European continent has been scarcely documented. To describe the incidence and associated risk factors of AMD in elderly French individuals. This population-based cohort study of 963 residents of Bordeaux, France, who were 73 years or older at baseline and participated in the Antioxydants, Lipides Essentiels, Nutrition et Maladies Oculaires (ALIENOR) Study between October 2, 2006, and December 21, 2012. Of 829 participants at risk for incident AMD, 659 (79.5%) were observed for a mean (SD) duration of 3.8 (1.1) years. Data were analyzed from August 2016 to March 2017. Age-related macular degeneration was graded from retinal photographs and spectral-domain optical coherence tomography into 5 exclusive stages: no AMD, early AMD1, early AMD2, late atrophic AMD, and late neovascular AMD. Of the 659 eligible participants, 413 (62.7%) were women, and the mean (SD; range) age was 79.7 (4.4; 73-94) years. A total of 120 incident cases of early AMD and 45 incident cases of advanced AMD were recorded. Incidence rates of early and advanced AMD were 79.9 (95% CI, 66.8-95.5) per 1000 person-years and 18.6 (95% CI, 13.9-24.9) per 1000 person-years, respectively, corresponding to 5-year risks of 32.9% and 8.9%. Incidence of advanced AMD per 1000 eye-years was 1.5 in eyes without any AMD at baseline, 42.4 in those with early AMD1, and 85.1 in those with early AMD2. In multivariate analysis without correction for multiple testing, progression from early to advanced AMD was associated with AMD grade in the fellow eye (hazard ratio [HR] according to grade, 13.0 [95% CI, 2.8-61.2] to 22.5 [95% CI, 2.6-195.9]), having smoked at least 20 pack-years (calculated as number of smoking years × mean number of cigarettes per day / 20; HR, 3.0; 95% CI, 1.4-6.5), and complement factor H (CFH) Y402H genotype (CC genotype: HR, 2.3; 95% CI, 1.0-5.3; TC genotype: HR, 1.5; 95% CI, 0.6-3.7). Incidence of early AMD was associated with early AMD in the fellow eye (early AMD1: HR, 2.6; 95% CI, 1.6-4.2; early AMD2: HR, 5.6; 95% CI, 3.3-9.4) and high plasma high-density lipoprotein cholesterol levels (HR, 1.2; 95% CI, 1.0-1.4). In this cohort, AMD incidence rates were similar to those observed in other European populations. This study suggests a high risk for incident early AMD in individuals with high plasma high-density lipoprotein cholesterol levels while confirming the high risk for progression from early to advanced AMD in heavy smokers and carriers of CFH Y402H at-risk genotypes.

Prevalence of age-related macular degeneration associated genetic risk factors and 4-year progression data in the Irish population

Background/aimsAge-related macular degeneration (AMD) is estimated to affect 196 million people >50 years old globally. Prevalence of AMD-associated genetic risk factors and rate of disease progression are unknown in Ireland.MethodsPrevalence...

Complement factor H in AMD: Bridging genetic associations and pathobiology.

Age-Related Macular Degeneration (AMD) is a complex multifactorial disease characterized in its early stages by lipoprotein accumulations in Bruch's Membrane (BrM), seen on fundoscopic exam as drusen, and in its late forms by neovascularization ("wet") or geographic atrophy of the Retinal Pigmented Epithelial (RPE) cell layer ("dry"). Genetic studies have strongly supported a relationship between the alternative complement cascade, in particular the common H402 variant in Complement Factor H (CFH) and development of AMD. However, the functional significance of the CFH Y402H polymorphism remains elusive. In this article, we critically review the literature surrounding the functional significance of this polymorphism. Furthermore, based on our group's studies we propose a model in which CFH H402 affects CFH binding to heparan sulfate proteoglycans leading to accelerated lipoprotein accumulation in BrM and drusen progression. We also review the literature on the role of other complement components in AMD pathobiologies, including C3a, C5a and the membrane attack complex (MAC), and on transgenic mouse models developed to interrogate invivo the effects of the CFH Y402H polymorphism.

Association of the CFH Y402H Polymorphism with the 1-Year Response of Exudative AMD to Intravitreal Anti-VEGF Treatment in the Brazilian Population

Aim: Evidence of the relationship between the polymorphism of the complement factor H (CFH) gene at position 402 (Y402H) and the response to the treatment of wet AMD is controversial. The aim of this study was to compare the functional and morphological 1-year evolution of patients with exudative AMD treated with antivascular endothelial growth factor (VEGF) drugs with the CFH Y402H polymorphism in the Brazilian population. Methods: Forty-six patients treated for wet AMD with bevacizumab or ranibizumab in a pro re nata regimen were included. The evolution of best-corrected visual acuity (BCVA) and central retinal thickness (CRT), and the number of injections over 1 year of follow-up were correlated with CFH genotypes. Results: The analysis of variance for the difference between the BCVA denoted as log_MAR (logarithm of the minimum angle of resolution) values showed an improvement at 1 year when compared to baseline (p = 0.039). Profile contrast analysis showed that this difference was significant only in the group without the C allele (p = 0.049), without significance in patients presenting with the risk allele (p = 0.241). CRT showed a mean reduction at 1 year compared to baseline (p < 0.001). Significant differences in the profile contrast test were found in the group without the C allele (p < 0.001) and in patients with the risk allele (p = 0.002). No difference was found in the number of injections among the different groups (p = 0.787). Conclusions: The presence of the risk allele of the Y402H polymorphism in the CFH gene was related to a less favorable evolution over 1 year in this sample of the Brazilian population with exudative AMD who were being treated with anti-VEGF drugs. In agreement with similar previous studies, this study concludes that the CFH risk genotypes may affect the disease response to treatment.

Influence of CFH gene on symptom severity of schizophrenia.

ObjectiveRecent advances have provided compelling evidence for the role of excessive complement activity in the pathophysiology of schizophrenia. In this study, we aimed to detect the association of the gene encoding complement factor H (CFH), a regulator in complement activation, with schizophrenia.Materials and methodsA sample of 1783 individuals with or without schizophrenia was recruited for genetic analysis. Genomic DNA samples were extracted from peripheral blood cells using multiplex polymerase chain reaction and the SNaPshot assay. A Database for Schizophrenia Genetic Research (SZDB) was used to detect the association of brain CFH expression with schizophrenia. Next, we performed a genotype–phenotype analysis to identify the relationship between CFH Y402H polymorphism and clinical features of schizophrenia.ResultsThere was a significant association of hippocampal CFH expression with schizophrenia (P=0.017), whereas this significance did not survive after adjusting for false discovery rate (P=0.105). Comparing the genotype and allele frequencies of the genotyped single-nucleotide polymorphisms between case and control groups showed no significant difference. There were significant differences in the scores of negative symptoms and delayed memory between the patients with C allele and those without C allele (P<0.01 and P=0.04 after Bonferroni correction, respectively). Furthermore, we observed a marginally significant association between the Y402H polymorphism and CFH expression in the hippocampus (P=0.051); however, this significance was lost after multiple testing correction (P=0.51, after Bonferroni correction).ConclusionOur findings provide suggestive evidence for the role of CFH in the development of negative symptoms and cognitive dysfunction in schizophrenia.

The pharmacogenomics of CFH Y402H and wet age-related macular degeneration

Age-related macular degeneration(AMD) is one of the main leading causes of irreversible vision damage in patients over 50 years old. Genetic factors play an important role in the occurrence and development of AMD. Since the significant correlation between complement factor H (CFH) gene and AMD was found, the pharmacogenomics of CFH polymorphism was paid close attention by academic circles. Among which, studies concerning CFH Y402H were more deeply. Studies have found CFH Y402H genotypes might lead to differences toward the outcome of PDT and anti-VEGF treatment. In this article, we review the researches on the pharmacogenomics of CFH Y402H in wet AMD treatment. (Chin J Ophthalmol, 2017, 53: 144-147).

CFH Y402H polymorphism and the complement activation product C5a: effects on NF-κB activation and inflammasome gene regulation

Background/aimsThe Y402H polymorphism in the complement factor H (CFH) gene is an important risk factor for age-related macular degeneration (AMD). Complement activation products and proinflammatory cytokines are associated with this...

Novel Mechanistic Interplay between Products of Oxidative Stress and Components of the Complement System in AMD Pathogenesis.

Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD includes soft drusen and pigmentary changes in the retinal pigment epithelium (RPE). As people age, such soft confluent drusen can progress into two forms of advanced AMD, geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD) and result in the loss of central vision. The exact mechanism for developing early AMD and progressing to advanced stage of disease is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as the cause of AMD progression. Together, complement factor H (CFH) and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress from activities such as smoking has also demonstrated a powerful contribution to AMD progression. To extend our previous finding that genetic polymorphisms in CFH results in OxPLs and the risk-form of CFH (CFH Y402H) has reduced affinity for oxidized phospholipids, and subsequent diminished capacity which subsequently diminishes the capability to attenuate the inflammatory effects of these molecules, we compared the binding properties of CFH and CFH related protein 1 (CFHR1), which is also associated with disease risk, to OxPLs and their effects on modulating inflammation and lipids uptake. As both CFH-402H and CFHR1 are associated with increased risk to AMD, we hypothesized that like CFH-402H, CFHR1 contribution to AMD risk may also be due to its diminished affinity for OxPLs. Interestingly, we found that association of CFHR1 with OxPLs was not statistically different than CFH. However, binding of CFHR1 did not elicit the same protective benefits as CFH in that both inflammation and lipid uptake are unaffected by CFHR1 association with OxPLs. These findings demonstrate a novel and interesting complexity to the potential interplay between the complement system and oxidative stress byproducts, such as OxPLs, in the mechanistic contribution to AMD. Future work will aim to identify the molecular distinctions between CFH and CFHR1 which confer protection by the former, but not latter molecules. Understanding the molecular domains necessary for protection could provide interventional insights in the generation of novel therapeutics for AMD and other diseases associated with oxidative stress.

CFH Y402H and VEGF Polymorphisms and Anti-VEGF Treatment Response in Exudative Age-Related Macular Degeneration

Purpose: The aim of this study was to evaluate the prevalence of single nucleotide polymorphisms (SNPs) in complement factor H (CFH) Y402H and VEGF rs2146323 and rs699947 in exudative age-related macular degeneration (AMD) and their relationship with intravitreal anti-VEGF treatment response. Methods: A total of 109 exudative AMD patients and 70 controls were included. Patients were classified as ‘good responders' and ‘nonresponders' based on the changes in best corrected visual acuity, central foveal thickness, lesion size, and the persistence of retinal hemorrhage after three dosages of anti-VEGF. We examined CFH, VEGF rs2146323 and rs699947 SNPs, and plasma interleukin-6 (IL-6) levels in both groups. Results: In total, 42 patients (38.5%) and 11 controls (15.7%) had homozygote wild genotype TT (p = 0.002). The variant C allele frequency was 45% in controls and 31.7% in patients (p = 0.011). A and C allele frequencies for VEGF rs699947 and rs2416323 were similar between the control and patient groups (p = 0.947, p = 0.378). Both SNPs were similar in responders and nonresponders. No significant difference was detected between plasma IL-6 levels of the control and AMD groups (p = 0.594), but the levels were higher in good responders than nonresponders (p < 0.001). Conclusion: CFH Y402H SNP might be protective for AMD in the Turkish population. VEGF rs2146323 and rs699947 SNPs have no relationship to exudative AMD formation, and none of these seem to have any effect on anti-VEGF response.

Clinical study of the correlation between complement factor H polymorphism and age-related macular degeneration.

This study aimed to investigate the correlation between age-related macular degeneration (AMD) of the liver-kidney yin-deficiency type and complement factor H (CFH) polymorphism, and to determine whether the C allele of the T1277C (Y402H) variant is a risk factor for this condition. We performed a case-control investigation of 60 patients with liver-kidney yin-deficiency AMD and 60 normal control subjects. Peripheral blood was collected from each participant for DNA extraction. Following amplification by polymerase chain reaction, the DNA samples were sequenced, and polymorphism of the CFH gene was examined. Data were analyzed with the chi-square test, with P < 0.05 signifying statistical significance. The frequency of the C allele was significantly higher in the wet than in the dry AMD group (P = 0.044). In addition, the TC and CC genotypes were markedly more common in the former than in the control group (P = 0.013), and there was a significant difference in the distribution of the T and C alleles between wet AMD patients and control subjects (P < 0.05). Based on this, we conclude that liver-kidney yin-deficiency AMD is associated with the C allele and TC and CC genotypes of the CFH Y402H polymorphism. Among patients with this condition, CFH genotypes were normally distributed. The principal CFH genotypes that induce liver-kidney yin-deficiency AMD are the mutant homozygote CC and heterozygote TC forms. Moreover, C allele carriers are at higher risk of developing this disease.

Predictors of Response to Intravitreal Anti–Vascular Endothelial Growth Factor Treatment of Age-Related Macular Degeneration

To identify factors that influence visual and anatomic response to treatment with intravitreal anti-vascular endothelial growth factor (VEGF) for neovascular age-related macular degeneration (AMD). Observational cohort study. Seventy-two patients were included in this study. Best-corrected Snellen visual acuity (VA) and central foveal thickness measured on optical coherence tomography (OCT) at time of treatment and post-treatment follow-up visits were recorded. Associations between demographic, behavioral, and genetic risk factors and the 2 outcomes were analyzed using mixed-effects linear regression models. Two loci in complement factor H (CFH) were included in a risk score to determine the association between CFH risk and improvement in VA and central foveal thickness. There was a small improvement in VA following anti-VEGF treatment (mean: 3.7 ± 3.0 letters), which was not statistically significant. Significant improvement in VA was observed for the nonrisk CFH Y402H genotype (P < .001) and for a low CFH risk score (P = .019). Regarding the outcome of change in central foveal thickness, improvement was noted in all genotype groups, but reduction after treatment was significantly higher in the low CFH risk score group (P = .033). A significant improvement in mean VA was seen among smokers (P < .001), but this relationship was not observed for central foveal thickness. After anti-VEGF therapy, significant improvement in VA was observed for low-risk CFH genotypes and subjects with a low risk score. There was a statistically significant reduction in central foveal thickness overall, and subjects with a low CFH risk score improved more than the high-risk group.

Adherence to a Mediterranean diet, genetic susceptibility, and progression to advanced macular degeneration: a prospective cohort study

Adherence to a Mediterranean-type diet is linked to a lower risk of mortality and chronic disease, but the association with the progression of age-related macular degeneration (AMD) and genetic susceptibility is unknown. We examined the association of adherence to the Mediterranean diet and genetic susceptibility with progression to advanced AMD. Among 2525 subjects in the AREDS (Age-Related Eye Disease Study), 1028 eyes progressed to advanced AMD over 13 y. Baseline data for demographic and behavioral covariates were collected by using questionnaires. Dietary data were collected from food-frequency questionnaires. The alternate Mediterranean diet (aMeDi) score (range: 0-9) was constructed from individual intakes of vegetables, fruit, legumes, whole grains, nuts, fish, red and processed meats, alcohol, and the ratio of monounsaturated to saturated fats. Ten genetic loci in 7 genes [complement factor H (CFH), age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase 1 (ARMS2/HTRA1), complement component 2 (C2), complement factor B (CFB), complement component 3 (C3), collagen type VIII α 1 (COL8A1), and RAD51 paralog B (RAD51B)] were examined. Survival analysis was used to assess individual eyes for associations between incident AMD and aMeDi score, as well as interaction effects between aMeDi score and genetic variation on risk of AMD. A high aMeDi score (score of 6-9) was significantly associated with a reduced risk of progression to advanced AMD after adjustment for demographic, behavioral, ocular, and genetic covariates (HR: 0.74; 95% CI: 0.61, 0.91; P-trend = 0.007). The aMeDi score was significantly associated with a lower risk of incident advanced AMD among subjects carrying the CFH Y402H nonrisk (T) allele (P-trend = 0.0004, P-interaction = 0.04). The aMeDi score was not associated with AMD among subjects who were homozygous for the risk (C) allele. Higher adherence to a Mediterranean diet was associated with reduced risk of progression to advanced AMD, which may be modified by genetic susceptibility. This trial was registered at clinicaltrials.gov as NCT00594672.

Pharmacogenetics of Complement Factor H Y402H Polymorphism and Treatment of Neovascular AMD with Anti-VEGF Agents: A Meta-Analysis

The purpose of this study is to investigate whether the Y402H polymorphism (rs1061170, a T-to-C transition at amino acid position 402) in the complement factor H (CFH) gene have a pharmacogenetics effect on the anti-vascular endothelial growth factor (VEGF) treatment for neovascular age-related macular degeneration (AMD). We performed a meta-analysis using databases including PubMed and EMBASE to find relevant studies. 13 published association studies were selected for this meta-analysis, including 2704 patients. For the CFH Y402H polymorphism, anti-VEGF treatment was much less effective in AMD patients with the CFH CC genotype (CC versus TT: odds ratio (OR) = 55, 95% confidence interval (CI), 0.31 to 0.95, P = 0.03; CC versus CT: OR = 0.60, 95% CI, 0.40 to 0.91, P = 0.02; and CC versus CT + TT: OR = 0.59, 95% CI, 0.38 to 0.90, P = 0.02, respectively). In subgroup analysis, CFH Y402H polymorphism was more likely to be a predictor of response for Caucasians (CC versus CT+TT: OR = 0.63, 95% CI, 0.42 to 0.95, P = 0.03). In conclusion, pharmacogenetics of CFH Y402H polymorphism may play a role in response to anti-VEGF treatment for neovascular AMD, especially for Caucasians.

Early and exudative age-related macular degeneration is associated with increased plasma levels of soluble TNF receptor II.

We have recently identified homeostatic alterations in the circulating T cells of patients with age-related macular degeneration (AMD). In cultures of retinal pigment epithelial cells, we have demonstrated that T-cell-derived cytokines induced the upregulation of complement, chemokines and other proteins implicated in AMD pathogenesis. The purpose of this study was to test whether increased plasma levels of cytokines were present in patients with AMD. We conducted a case-control study. Age-related macular degeneration status was assessed using standardized multimodal imaging techniques. Plasma was isolated from freshly drawn peripheral venous blood samples and analysed for interleukin (IL)15, IL18, interferon (IFN)γ, soluble tumour necrosis factor (TNF) receptor II (sTNFRII) and complement factor H (CFH) Y402H genotype. We included 136 individuals with early or late forms of AMD and 74 controls. Significantly increased levels of sTNFRII were observed in patients with early or exudative AMD (p < 0.01). After adjusting for CFH Y402H genotype, age, sex and smoking history, the level of sTNFRII remained a significant predictor for prevalence of AMD with odds ratios at 3.0 in the middle and 3.6 in the highest tertiles. Levels of IL15, IL18 and IFNγ were low and not associated with AMD. Increased plasma level of sTNFRII is found to be associated with AMD. The data supports the observations of low-grade, systemic inflammatory alterations in patients with AMD. However, it remains to be determined whether increased levels of TNFα can be found, which directly reflects an increased activity of macrophages and T cells.