Association of HTRA1 rs11200638 with age-related macular degeneration (AMD) in Brazilian patients

Age-related macular degeneration is a multifactorial disease that can lead to vision impairment in older individuals. Although the etiology of age-related macular degeneration remains unknown, risk factors include age, ethnicity, smoking, hypertension, obesity, and genetic factors. Two main loci have been identified through genome-wide association studies, on chromosomes 1 and 10. Among the variants located at the 10q26 region, rs11200638, located at the HTRA1 gene promoter, has been associated with age-related macular degeneration in several populations and is considered the main polymorphism. We conducted a replication case–control study to analyze the frequency and participation of rs11200638 in the etiology of age-related macular degeneration in a sample of patients and controls from the State of São Paulo, Brazil, through polymerase chain reaction and enzymatic digestion. The frequency of the A allele was 57.60% in patients with age-related macular degeneration and 36.45% in controls (p value < 1e–07), representing a 2.369-fold higher risk factor for the disease. Both the AA and AG genotypes were observed more frequently in the age-related macular degeneration group compared to the control group (p = 1.21^e–07 and 0.0357, respectively). No statistically significant results were observed after stratification in dry versus wet types or advanced versus non-advanced forms. To our knowledge, this is the first time the association between rs11200638 and overall age-related macular degeneration has been reported in South America.     

Association between SERPING1 rs2511989 polymorphism and age-related macular degeneration: Meta-analysis

AIM: To investigate the association between SERPING1 rs2511989 (G>A) polymorphism and age-related macular degeneration (AMD). METHODS: A 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. RESULTS: Eight 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). CONCLUSION: This 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.     

Association of combined cigarette smoking and ARMS2/LOC387715 A69S polymorphisms with age-related macular degeneration: A meta-analysis

Purpose: The age-related maculopathy susceptibility2 (ARMS2)/LOC387715 A69S (rs10490924) polymorphism and cigarette smoking have been shown to have significant association with AMD. In this meta-analysis we used the results of available association studies of combined ARMS2/LOC387715 genotypes and cigarette smoking with AMD to estimate the possible synergistic or multiplicative effects.

Methods: Heterogeneity of studies was evaluated using the Cochran Q-test and the I-square index. To compensate for the heterogeneity of the variables in the study we used a random effects model. Meta-analysis was performed using STATA. To estimate the additive or supra-additive effects, we calculated relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), synergy index (S), and multiplicative index (V).

Results: We could include four studies with 1982 AMD patients and 1797 control subjects. Considering the GG-no smoking as a reference line the meta-analysis result of AMD odds ratios for stratified combined factors was 3.05 (95% CI 2.32–4.02) for nonGG-no smoking, 2.24 (95% CI 1.39–3.63) for GG-smoking and 4.59 (95% CI 3.51–6.01) for nonGG-smoking. The meta-analysis of synergy analysis revealed RERI = 2.01 (95% CI 1.01–3.25), AP = 0.40 (95% CI 0.22–0.54), S = 2.02 (95% CI 1.35–3.01), and V = 1.31 (95% CI 0.94–1.83).

Conclusion: This analysis revealed the synergistic effect of these two factors indicating that there is a common pathway of ARMS2/LOC387715 and smoking in AMD pathogenesis which may be the complement system pathway.     

A review and meta-analysis of the association between C-reactive protein and age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in people over 60 in western countries. Inflammatory markers have been implicated in the development and progression of AMD. C-reactive protein (CRP) is an inflammatory marker known to be associated with cardiovascular disease, and a link between AMD and CRP has been suggested. In this systematic review we summarize the currently available evidence from clinic-based and population-based studies investigating this association. A meta-analysis of evidence from eleven studies (41,690 study participants) shows that high serum levels (>3 mg/L) of CRP are associated with a two-fold likelihood of late onset AMD, compared to low levels (<1mg/L). Sub-group meta-analyses show a higher association in studies using ophthalmoscopic examination, compared to those using photographic grading (pooled odds ratio 3.83 vs 1.36), to determine AMD status, or in clinic-based samples compared to population-based studies.     

Association between complementary factor H Y402H polymorphisms and age-related macular degeneration in Chinese: Systematic review and meta-analysis

AIM

Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and complement factor H (CFH) polymorphism has been found to associate with the AMD. To investigate whether the Y402H variant in CFH is associated with AMD in Chinese populations, a systematic review and meta-analysis were performed to estimate the magnitude of the gene effect and the possible mode of action.

METHODS

A meta-analysis was performed using data available from ten case-control studies assessing association between the CFH Y402H polymorphism and AMD in Chinese populations involving 1538 AMD. Data extraction and study quality assessment were performed in duplicate. Summary odds ratios (ORs) and 95% confidence intervals (CIs) an allele contrast and genotype contrast were estimated using fixed- effects models. The Q-statistic test was used to assess heterogeneity, and Funnel plot was used to evaluate publication bias.

RESULTS

Seven of ten case-control studies were neovascular AMD, and few studies came from west and north of China. There was strong evidence for association between CFH and AMD in Chinese population, with those having risk allele C 2.35 times more likely to have AMD than subjects with T allele. Evidence of publication bias was not observed in our meta-analysis.

CONCLUTION

This meta-analysis summarizes the strong evidence for an association between CFH and AMD in Chinese and indicates each C allele increasing the odds of AMD by 2.33-fold.But more evidences about the relation between CFH polymorphism and different type of Chinese AMD from various district were needed.     

TLR3与年龄相关性黄斑变性疾病的相关性

年龄相关性黄斑变性(age-related macular degeneration, ARMD)是一种多发于50岁以上人群的慢性进展性疾病, 是发达国家老年人群的主要致盲性眼病,也是发展中国家老年人群不可逆视力损害的主要原因, ARMD包括地图状萎缩及脉络膜新生血管两类。由于其具体病因和发病机制尚不明确, 大多数学者认为这是一种多因素疾病。近年来Toll样受体3(Toll-like receptor 3,TLR3)与ARMD关系的研究成为热点,本文就近年来相关研究进展做一综述。     

Complement factor B polymorphism (rs641153) and susceptibility to age-related macular degeneration:evidence from published studies

AIM

To determine whether single nucleotide polymorphism (SNP) rs641153 is associated with the risk of age-related macular degeneration (AMD), we performed a systematic meta-analysis of 15 eligible studies. SNP in the complement factor B (CFB) gene is considered to have significant association with AMD susceptibility, but there is great discrepancy in these results.

METHODS

The eligible studies were identified by searching the databases of PubMed, EMBASE, and Web of Science. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association. All data were analyzed using Stata software.

RESULTS

The association between rs641153 and AMD risk was statistically significant under the homozygous model (AA vs GG:OR=0.26, 95%CI=0.15-0.45, P_h=0.973, I²=0.0%, fixed effects), dominant model (AA+GA vs GG:OR=0.49, 95%CI=0.40-0.59, P_h=0.004, I²=56.4%, random effects) and recessive model (AA vs GA+GG:OR=0.30, 95%CI=0.17-0.51, P_h=0.983, I²=0.0%, fixed effects). The same results were also observed in the stratified analyses by ethnicity, source of control and sample size.

CONCLUSION

Our meta-analysis suggests that rs641153 in the CFB gene may play a protective role in AMD susceptibility, the late AMD in particular, both in Caucasians and in Asians.     

Association between sunlight exposure and risk of age-related macular degeneration: a meta-analysis

Background

A substantial number of epidemiological studies have investigated the possible associations between sunlight exposure and Age-related Macular Degeneration (AMD), but the results from studies are inconsistent. The aim of this meta-analysis was to evaluate the association between sunlight exposure and the risk of AMD.

Methods

Relevant studies were searched using databases including PubMed, EMBASE, and Web of Science database. Two authors independently extracted data and assessed study quality. The random-effects model was used to calculate the pooled covariates-adjusted odds ratio (OR). Subgroup analyses based on study design, stage of AMD, method of exposure assessment, and study latitude were carried out. The heterogeneity across the studies was tested, as was publication bias.

Results

Fourteen eligible studies including 43,934 individuals based on the inclusion criteria were analyzed. The pooled OR for sunlight exposure and AMD was 1.10 (95% CI?=?0.98–1.23). In addition, similar insignificant results were observed in further subgroup analyses based on stage of AMD, method of exposure assessment, and study latitude. Sun-avoidance behavior did not decrease the risk of AMD (OR?=?1.12, 95% CI?=?0.76–1.67). Moderate heterogeneity was observed in most of analyses.

Conclusion

The results indicate that sunlight exposure may not be associated with increased risk of AMD based on current published data.

     

Complement factor B polymorphism (rs641153) and susceptibility to age-related macular degeneration:evidence from published studies

AIM:To determine whether single nucleotide polymorphism (SNP) rs641153 is associated with the risk of age-related macular degeneration (AMD), we performed a systematic meta-analysis of 15 eligible studies. SNP in the complement factor B (CFB) gene is considered to have significant association with AMD susceptibility, but there is great discrepancy in these results.METHODS: The eligible studies were identified by searching the databases of PubMed, EMBASE, and Web of Science. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association. All data were analyzed using Stata software.RESULTS:The association between rs641153 and AMD risk was statistically significant under the homozygous model (AA vs GG:OR=0.26, 95%CI=0.15-0.45, Ph=0.973, I²=0.0%, fixed effects), dominant model (AA+GA vs GG:OR=0.49, 95%CI=0.40-0.59, Ph=0.004, I²=56.4%, random effects) and recessive model (AA vs GA+GG:OR=0.30, 95%CI=0.17-0.51, Ph=0.983, I²=0.0%, fixed effects). The same results were also observed in the stratified analyses by ethnicity, source of control and sample size.CONCLUSION:Our meta-analysis suggests that rs641153 in the CFB gene may play a protective role in AMD susceptibility, the late AMD in particular, both in Caucasians and in Asians.     

Treatment of dry age-related macular degeneration: A review

Age-related macular degeneration is a global disease with a significant societal impact. The advent of anti-vascular endothelial growth factor therapy (anti-VEGF) has revolutionised the treatment of neovascular age-related macular degeneration (nAMD). Dry age-related macular degeneration (dAMD) is being investigated for possible therapeutic options. The therapeutic categories undergoing clinical trials include complement pathway inhibitors, visual cycle modulators, reduction of toxic byproducts, antioxidative therapy, neuroprotective agents, laser therapy, surgical options, gene therapy, stem cell therapy, and miscellaneous treatments. Two intravitreal anti-complement factors (pegcetacoplan and avacincaptad pegol) have recently shown phase 3 clinical trial evidence of a reduction in the growth of geographic atrophy. In this review, we provide an update on treatment options currently undergoing clinical research trials for the management of dAMD and preventing the progression of Geographic Atrophy (GA).     

Meta-analysis of the association of the HTRA1 polymorphisms with the risk of age-related macular degeneration

HTRA1 was considered as one of important age-related macular degeneration (AMD) candidate genes. However, due to population heterogeneity and bias from case-control study, the association between HTRA1 and AMD needs further confirmation across different studies in different population. In this study, a meta-analysis was performed in 14 case-control studies which were published before August 31, 2008. Effect of HTRA1 polymorphism with AMD was synthetically evaluated. The pooled odds ratio (OR) for heterozygous genotype GA versus wild homozygous genotype GG is 2.13 (95% CI: 1.90, 2.39), the OR of homozygous genotype AA versus GG is 6.92 (95% CI: 5.74, 8.34) and the OR of allele A carrier (GA + AA) versus GG is 3.02 (95% CI: 2.57, 3.53). Sub-analysis indicated that the risk of HTRA1 rs11200638 on wet AMD was stronger than dry AMD, and it seems that HTRA1 rs11200638 could increase the risk of AMD in all races. This study strengthens the hypothesis of association between rs11200638 in the promoter of HTRA1 polymorphism and AMD. The variant of HTRA1/625G → A could be a potentially promising genetic biomarker of AMD.     

Association of the DNA repair SMUG1 rs3087404 polymorphism and its interaction with high sensitivity C-reactive protein for age-related macular degeneration in Iranian patients

Background: Age-related macular degeneration (AMD) is a complex disease and recently the role of DNA repairing genes in its susceptibility has been studied. It has been hypothesized that polymorphism in DNA repair system genes reduce the capacity to repair DNA damages which may lead to a greater susceptibility to AMD. C-reactive protein (CRP) production is shown to enhance inflammatory processes by increasing oxidative stress and inducing DNA damage. We planned to evaluate the possible association of SMUG1 variants and their possible interaction with high sensitivity CRP levels in AMD.

Materials and methods: We included 500 case-control samples consisting of 279 advanced type AMD patients and 221 genetically unrelated healthy controls enrolled for evaluation. Extracted-DNA samples were amplified to obtain fragments including the polymorphic region SMUG1 rs3087404. We calculated relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S) to clarify possible interaction of different genotypes and CRP levels for AMD.

Results: The distribution of the genotypes were not significantly different in the AMD patients compared to that of controls (p = 0.849). The allele frequency for SMUG1 was not different between study groups. No difference of SMUG1 polymorphism between case and control groups was evident in higher CRP levels (CRP>3mg/dl) compared with lower CRP levels. SMUG1/CRP synergy indices calculated as RERI = ?0.12 and AP = ?0.18 while S was not calculable.

Conclusions: Our study showed that c.-31A/G-SMUG1 genotypes/alleles do not have any association with the occurrence or severity of advanced type AMD. There was no interaction of CRP levels and SMUG1 genotypes in AMD susceptibility.     

维生素D缺乏与年龄相关性黄斑变性发生的相关性研究

目的：探讨维生素D(Vit-D)缺乏与年龄相关性黄斑变性(ARMD)发生的相关性。

方法：选取2018-02/2019-02至运城市第一医院眼科门诊就诊及健康体检的423例45岁以上中老年人为研究对象,采用横断面调查研究方法,收集研究对象年龄、性别、ARMD家族史等一般临床资料,同时测定包括25-羟基维生素D\〖25(OH)D\〗等在内的生化指标,考察血清25(OH)D水平与各临床资料与生化指标的相关性。根据ARMD患病情况,分为ARMD组(231例)和非ARMD组(192例),考察Vit-D缺乏和ARMD发生的相关性。

结果：血清25(OH)D水平与男性、户外光暴露时长呈显著正相关(r=0.439、0.664,均P<0.01),与年龄、吸烟和饮酒则呈显著负相关(P<0.05)。二分类Logistic回归分析表明,Vit-D缺乏是ARMD发生的危险因素(OR=1.980,95%CI：1.829～2.201,P<0.01),其他与ARMD发生有关的因素包括：年龄、性别、ARMD家族史、高血压、糖尿病、低密度脂蛋白胆固醇、户外光暴露时长>5h/d,且均为ARMD发生的危险因素(P<0.05)。

结论：营养失衡方面的Vit-D缺乏可能与ARMD发生相关,适当太阳光照射或膳食补充Vit-D可能有助于预防或改善ARMD的发生发展。     

Association between systemic arterial stiffness and age-related macular degeneration

Background A number of epidemiological studies suggest that age-related macular degeneration (AMD) and cardiovascular disease share the same risk factors. Systemic arterial stiffness is a clear indicator of cardiovascular disease. We investigated whether there is an association between directly measured systemic arterial stiffness and the presence of AMD.Methods We used a SphygmoCor 2000 system to noninvasively measure two indicators of the systemic arterial stiffness, the arterial pulse wave velocity (PWV) and the central aortic blood pressure waveform, from which the augmentation pressure is determined. We studied 50 patients with AMD (12 men, 38 women, aged 60 to 91 years, mean 77 years) and 11 age-matched control subjects (3 men, 8 women, aged 66 to 92 years, mean 75 years). All study subjects received a complete ophthalmic examination including digital fundus photography. All of the patients with AMD were classified as stage 3 or worse in at least one eye according to the AREDS system.Results Pulse wave velocity was significantly higher in the patients with AMD (8.2±1.1 m/s, mean ± SD) compared with controls (7.1±0.8 m/s, p=0.0025), indicating increased arterial stiffness. There was no significant difference in PWV in AMD patients with and without choroidal neovascularization. There was no association between PWV and the presence of hypertension in either the patients or the controls. The central aortic augmentation pressure was significantly higher in the AMD patients than in the controls (p=0.040), also indicating increased arterial stiffness.Conclusions Patients with AMD have increased systemic arterial stiffness compared with age-matched controls. Treatments aimed at preventing or reversing systemic arterial stiffness may also be effective in preventing the onset or slowing the progression of AMD.     

Cognitive function,drusen, and age-related macular degeneration: a cross-sectional study

Purpose

To examine the cross-sectional relationship between drusen, late age-related macular degeneration (AMD), and cognitive function.

Methods

We included 2149 stroke-free participants from the population-based Tromsø Study in Norway. Retinal photographs were graded for presence of drusen and AMD. Cognitive function was assessed using the verbal memory test (short verbal memory), digit-symbol coding test (processing speed), and the tapping test (psychomotor tempo). We assessed the relationship between drusen, late AMD, and cognitive test scores, adjusted for potential confounders.

Results

Late AMD was associated with decreased performance in the verbal memory test (standardized β=−0.23, 95% confidence interval (CI): −0.51 to −0.01). Intermediate and large drusen were associated with decreased performance in the digit-symbol coding test (standardized β=−0.14 and –0.19, 95% CIs: −0.23 to −0.05 and −0.29 to −0.09, respectively). Participants with large drusen were more likely to have test scores in the lowest quartile of the digit-symbol coding test (odds ratio (OR)=1.9, 95% CI: 1.1–3.5) and the tapping test (OR=1.6, 95% CI: 1.0–2.6), but not in the verbal memory test (OR=1.0, 95% CI: 0.6–1.6).

Conclusions

The findings suggest a relationship between drusen deposition and reduced cognitive function. Although the relationships between drusen, late AMD, and the cognitive test results varied in strength and significance across the types of cognitive test, and may partly have been caused by residual confounding, it is not unlikely that a genuine but weaker relationship exists between drusen deposition and cognitive decline.     

Association of IGF1 polymorphism rs6214 with high myopia: A systematic review and meta-analysis

Purpose: To conduct a comprehensive evaluation of the association of Insulin-like growth factor 1 (IGF1) polymorphism rs6214 with high myopia through a systematic review and meta-analysis of candidate genetic association study.

Methods: All case-control association studies on IGF1 and high myopia reported up to 15 June 2016 in PubMed, Embase, Web of Science, and the Chinese Biomedical Database were retrieved. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for single-nucleotide polymorphism (SNP) using fixed and random effects models according to between study heterogeneity. Publication bias analyses were conducted using Begg’s test.

Results: A total of eight studies from published articles were included in our analysis. The meta-analyses for IGF1 rs6214, composed of 4242 high myopia patients and 4430 controls, showed low heterogeneity for the included populations in all the genetic models, except that of the allelic genetic model in the pooled populations. The analyses of all the genetic models in Chinese, Japanese, and overall pooled populations did not identify any significant association between high myopia and IGF1 rs6214.

Conclusions: This meta-analysis showed there was no association detected between IGF1 rs6214 and high myopia. Given the limited sample size, further investigations including more ethnic groups are required to validate the association.     

Matrix metalloproteinase-1 rs1799750 polymorphism and glaucoma: A meta-analysis

Purpose: Several studies indicated that -1607 1G/2G (rs1799750) polymorphism in matrix metalloproteinase-1 (MMP-1) promoter was correlated with glaucoma susceptibility, but the results remain controversial. We performed a meta-analysis to assess whether rs1799750 confers glaucoma risk.

Methods: Eligible studies were retrieved by systematically searching Pubmed, Embase, Web of Science, and Chinese Biomedical database. The degree of correlation was expressed as odds ratios (ORs) and 95% confidence interval (CI). The measurements were pooled by fixed effect model or random effect model.

Results: This meta-analysis included five case-control studies involving 1261 patients with glaucoma and 1089 controls. The pooled results showed a significant association between rs1799750 and glaucoma under the homozygote (OR = 1.71, 95% CI 1.12–2.62, p = 0.014), recessive (OR = 1.64, 95% CI 1.20–2.25, p = 0.002), and allelic (OR = 1.35, 95% CI 1.05–1.72, p = 0.017) models. Subgroup analyses showed that the rs1799750 was significantly associated with primary angle closure glaucoma under homozygote (OR = 2.23, 95% CI 1.03–4.83, p = 0.043) and allelic (OR = 1.61, 95% CI 1.07–2.42, P = 0.021) models, while it was significantly associated with primary open angle glaucoma (OR = 1.64, 95% CI 1.05–2.56, p = 0.030) and exfoliation glaucoma (OR = 1.42, 95% CI 1.02–1.97, p = 0.036) under recessive models. No evidence of publication bias was detected.

Conclusions: Meta-analysis of existing data showed that rs1799750 may affect individual susceptibility to glaucoma. Nevertheless, more studies with large sample size and various ethnicities are warranted in light of the limited studies.     

Association of HTRA1 polymorphism and bilaterality in advanced age-related macular degeneration

Single nucleotide polymorphism (SNP), rs11200638, in the promoter of HTRA1 has recently been shown to increase the risk for AMD. In order to investigate the association of this HTRA1 polymorphism and the bilaterality of AMD, we genotyped rs11200638 in control, unilateral, and bilateral advanced AMD patients. The A allele for SNP rs11200638 in HTRA1, was significantly more prevalent in bilateral wet AMD and GA patients than in unilateral groups (p=.02 and p=.03, respectively). The homozygote odds ratios of bilateral wet AMD and GA are significantly greater than those seen in unilateral groups (twofold and threefold increase, respectively). This finding is consistent with the role of HTRA1 in AMD pathogenesis and will help aid in the clinical management and prognosis of AMD patients.