Introduction: 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. Methods: 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. Results: 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. Conclusion: 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.

Age-related macular degeneration (AMD) is a substantial healthcare burden worldwide, affecting 8.7% of adults aged 45–85. Projections indicate that by 2040, 288 million people will have AMD globally [1]. Dry and neovascular (exudative or wet) AMD are the two main clinical presentations of this disease [2]. Neovascular AMD, characterized by macular neovascularization (MNV), accounts for about 90% of patients with severe vision impairment due to AMD [3]. Hence, there are significant efforts aimed at finding appropriate treatments for neovascular AMD.

Vascular endothelial growth factor (VEGF) is an angiogenic factor that plays a role in MNV [4]. Therefore, different therapeutic regimens of anti-VEGF injections have been proposed for treating neovascularization in AMD [5, 6]. The most common anti-VEGF agents used for controlling MNV in AMD patients include ranibizumab (Lucentis®), bevacizumab (Avastin®), aflibercept (Eylea®), brolucizumab (Beovue®), and conbercept (Lumitin) [7, 8]. Similar efficacy has been reported for these agents [7, 8].

However, the response to anti-VEGF treatment can vary among some patients and has been attributed to age, ethnicity, previous photodynamic therapy, baseline visual acuity, MNV lesion types, and genetic factors [9]. Among genetic factors, single nucleotide polymorphisms (SNPs) in the complement factor H (CFH) gene have been shown to affect AMD development and response to anti-VEGF agents. CFH Y402H polymorphism can lead to complement pathway overactivation, which results in the development of AMD [10]. Additionally, the role of SNP rs1061170 (Y402 H) in the CFH gene in determining the response of AMD to anti-VEGF agents has been investigated extensively [11‒13]. However, these studies report inconsistent results [11‒13].

A previous meta-analysis found that SNP rs1061170/Y402H of the CFH gene might influence response to treatment [14]. However, the results of this study were inconclusive due to the small sample size, especially for those of Asian ethnicities [14]. Furthermore, the effects of possible confounding factors, e.g., other gene polymorphisms, smoking, the stage of AMD, and definition of outcomes were not discussed in this study [14]. In this study, we systematically review and analyze the SNP rs1061170/Y402H in the CFH gene and its possible effects on the response to anti-VEGF therapy in a larger number of Asian patients with AMD.

Literature Search and Protocol

This study adhered to the recommendations provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [15]. The study protocol is registered in PROSPERO with the identifying number CRD42021253441.

A comprehensive computerized search was performed of the PubMed, Scopus, EMBASE, Cochrane Library, and Web of Science databases using the MeSH and non-MeSH terms, “AMD OR age-related macular degeneration OR macular degeneration OR maculopathy” AND “Bevacizumab OR Aflibercept OR Ranibizumab OR Anti-VEGF OR Anti-vascular endothelial growth factor” AND “complement factor H OR CFH” on December 8, 2021 (see online suppl. File 1 [online suppl. table S1] for more details; for all online suppl. material, see https://doi.org/10.1159/000539377). Google Scholar was also searched, and the first 100 citations sorted by relevance were checked manually for appropriate articles. No limitations were considered for our search. Reference lists of the included publications were also searched to retrieve more articles. Based on the PRISMA statement first, the titles and the abstracts of the search results were assessed and irrelevant studies were excluded. Next, full texts of the remaining studies were reviewed and a final list of studies was selected for inclusion in the meta-analysis.

Selection Criteria

Inclusion Criteria

Original articles including observational and interventional studies were included if they met the following criteria:

  • Patients had AMD

  • The patients only underwent anti-VEGF therapy for AMD

  • Number of responders and non-responders to anti-VEGF therapy (which was essential to calculate odds ratio [OR]) could be retrieved for 3 CFH Y402H genotypes

Exclusion Criteria

Case reports, review articles, duplicate publications, and conference abstracts were excluded. Other exclusion criteria were as follows:

  • Patients did not receive anti-VEGF therapy

  • Inadequate data to estimate OR in the article

Two authors (A.R. and S.A.M.) independently performed the literature search and screened the articles. Disagreements were discussed with another author (J.F.A.) and consensus was achieved. The search protocol and final list of studies were reviewed and consensus was achieved in case of disagreement.

Data Extraction

Demographic data including first author’s name, year of publication, location of the study, study design, patient ethnicity, number of the patients and eyes, mean age, gender (male-to-female ratio), C allele frequency, proportion of smokers, proportion of patients with classic MNV, type of anti-VEGF drug, duration of follow-up, and definition of response to treatment were extracted from the articles. Due to the differences in the definition of response to treatment, we categorized the definitions into two main groups similar to the previous literature [16]: (1) improvement in visual acuity measured by letter or line gain (functional response), OR (2) decrease in lesion size or reduction in subretinal/intraretinal fluid measured by OCT (anatomical response). Meta-analysis was performed for six genetic models, adopted from previous studies: the allele contrast model (Y402H, T vs. C), the recessive model (Y402H, TC + TT vs. CC), the dominant model (Y402H, TT vs. CC + TC), the homozygote contrast (additive) model (Y402H, TT vs. CC), the heterozygote model (Y402H, TT vs. TC), and the co-dominant model (Y402H, TC vs. CC + TT) [14, 17]. The OR with the 95% confidence interval (CI) was used to measure treatment response in the six different genetic models. Therefore, the number of responders and non-responders in each genotype was also extracted from the studies. Additionally, data were retrieved from the studies on the effects of the combination of risk alleles of other genes with Y402H polymorphism. Two authors, A.R. and S.A.M., extracted data independently; disagreements were discussed with another author (J.F.A.); and consensus was achieved.

Risk of Bias Assessment

We used the Newcastle-Ottawa Scale (NOS) for assessing the risk of bias in the included studies [18]. NOS evaluates the quality of the studies in three categories: selection (4 points), comparability (2 points), and outcome (3 points). Details on the NOS scoring system is presented elsewhere [18]. Two authors, A.R. and S.A.M. performed the risk of bias assessment, and the results were checked by another author (J.F.A.).

Statistical Analysis

Statistical analyses were performed with STATA version 14.0 software (STATA Corporation, College Station, TX, USA). Dichotomous outcomes are presented as OR with 95% CI. p < 0.05 is considered statistically significant. The χ2 test was used to assess heterogeneity between studies. I2 is used to present heterogeneity as follows: I2 = 0 indicates no heterogeneity and heterogeneity was expressed as I2 > 0 with larger values indicating more heterogeneity. Heterogeneity between studies was considered significant if I2 exceeded 50%. We used a random-effects model to conduct the meta-analysis and subgroup analysis. Subgroup analysis was performed based on ethnicity, gender ratio, mean age, proportion of patients with classic MNV, proportion of smokers, duration of follow-up, type of anti-VEGF agent, and definition of outcome. Sensitivity analysis was performed to assess the effect of every single study on the overall results. Funnel plots and Eager’s tests were used to assess publication bias.

Search Results

A total of 1,092 articles were identified through computerized database searches and checking the reference lists of the articles. After removing duplicate publications, 767 articles entered the screening stage and 680 of these were excluded. Full texts of 87 articles were evaluated, and 25 papers were finally included in the meta-analysis [11, 12, 19‒41]. Figure 1 presents the details of the flow diagram of our study.

Fig. 1.

Flow diagram of the literature search and study selection.

Fig. 1.

Flow diagram of the literature search and study selection.

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Characteristics of the Articles Included in the Meta-Analyses

In total, 4,835 eyes of 4,681 patients were assessed in the 25 studies. The mean patient age was 75.45 years with a male-to-female ratio of 1.003. Of the 25 studies, 13 were retrospective, 11 were prospective, and 1 was cross-sectional. Most of the studies were performed on a Caucasian ethnicity, followed by six Asian studies, and two African studies. There were 15 studies that considered improvement of visual acuity (VA) for the definition of outcome (functional response), while 5 studies used an OCT outcome (anatomical response). Table 1 presents the patient demographics, study design, number of eyes, ethnicity, C allele frequency, mean age, male-to-female ratio, anti-VEGF agent, duration of follow-up, the definition of response to treatment, and the study quality.

Table 1.

Characteristics of the studies included in the meta-analysis

First author, yearDesignEyesEthnicityFrq (C), %Mean ageM/F ratioTreatmentFollow-up, monthsDefinition of response to treatmentQuality of the study
Brantley [12] (2007) Retros 86 CA 55.2 79.8 0.56 Beva Improvement in VA High 
Cobos [37] (2018) Retros 403 CA 47.3 80.8 0.75 Rani After loading phase reduction of CFT High 
Dikmetas [24] (2013) Pros 193 CA 58.3 71 1.14 Rani 13.3 An increase in VA of ≥5 letters High 
Gourgouli [41] (2020) Pros 52 CA 55.7 76 0.58 Rani No change/improvement on the Snellen chart in VA and OCT improvement High 
Habibi [25] (2013) Retros 70 AF 41.4 73.3 2.28 Beva Within 2-line (stable) or 2-line gain (improvement) in VA High 
Habibi [34] (2016) Retros 90 AF 61.1 72.9 2.2 Beva 12 A reduction of less than 2 lines High 
Hagstrom [26] (2013) Pros 834 CA 55.8 78.5 0.64 Rani or Beva 12 >15-letter increase in VA from baseline High 
Hautamaki [27] (2013) Retros 96 CA 61.5 78 0.57 Beva 3.5 No cystic changes or neuroepithelial detachment after three injections High 
Kitchens [28] (2013) Retros 97 CA 50.5 80 0.49 Rani or Beva VA: gained of 3 lines at month 9/OCT: no sub- or intraretinal fluid at least 1 month after the third monthly injection High 
Kloeckener-Gruissem [19] (2011) Retros 243 CA 51 78.9 0.58 Rani 12 >75th percentile improvement in VA High 
Kubicka-Trzaska [35] (2016) Pros 106 CA 59.4 71.2 0.51 Rani or Beva CRT decrease >10% and BCVA improvement >1 line by Snellen scale High 
Lotery [29] (2013) Retros 254 CA 56.3 77.7 0.63 VEGF inhibitor 12 Changes in TRT ≥75th percentile at a 12-month follow-up High 
Matsumiya [30] (2014) Retros 120 AS 13.3 76.1 3.29 Rani Dry lesion in OCT at 3 months High 
McKibbin [20] (2012) Pros 104 CA 49.6 81.5 0.79 Rani >5 letter score gain in BCVA after 6 months High 
Menghini [21] (2012) Retros 127 CA 49.6 79.3 0.58 Rani 24 ≥5 letter increase in VA at a 12-month follow-up High 
Mohamad [38] (2018) Pros 134 AS 52.6 69.4 1.58 Rani ≥3 lines improvement in the Snellen chart or a decrease of >100 μm in CRT Mod 
Nischler [11] (2011) Pros 197 CA 48.2 76.9 0.51 Beva 11.3 ≥3 lines gain in distance VA High 
Orlin [22] (2012) Retros 143 CA 47.2 80.6 0.47 Rani or Beva 24 Improvement/no change in VA in at least one eye High 
Park [31] (2014) Pros 273 AS 10.2 69.5 1.29 Rani ≥8 letter gain at 5 months High 
Park [32] (2014) Pros 394 AS 9.7 69.4 1.25 Rani or Beva 24 ≥15-letter gain High 
Rodríguez [40] (2019) Cross-sectional 61 CA 29.7 76.6 0.85 Rani 12 0.1 LogMAR or more gain in VA Mod 
van Asten [33] (2014) Retros 391 CA 57.2  0.78 Rani Loss of <30% of letters from baseline High 
Yamashiro [23] (2012) Retros 74 AS 16.7 75 2.5 Rani 12 Resolved retinal exudation High 
Yan [39] (2018) Pros 184 AS 10 65.4 2.01 Con 12 >5 letter gain at 6.12 months High 
Yildiz [36] (2016) Pros 109 CA 31.7 70 1.37 Anti-VEGF Three lines of BCVA gain, decrease in subretinal/intraretinal fluid, lesion size, and retinal hemorrhage High 
First author, yearDesignEyesEthnicityFrq (C), %Mean ageM/F ratioTreatmentFollow-up, monthsDefinition of response to treatmentQuality of the study
Brantley [12] (2007) Retros 86 CA 55.2 79.8 0.56 Beva Improvement in VA High 
Cobos [37] (2018) Retros 403 CA 47.3 80.8 0.75 Rani After loading phase reduction of CFT High 
Dikmetas [24] (2013) Pros 193 CA 58.3 71 1.14 Rani 13.3 An increase in VA of ≥5 letters High 
Gourgouli [41] (2020) Pros 52 CA 55.7 76 0.58 Rani No change/improvement on the Snellen chart in VA and OCT improvement High 
Habibi [25] (2013) Retros 70 AF 41.4 73.3 2.28 Beva Within 2-line (stable) or 2-line gain (improvement) in VA High 
Habibi [34] (2016) Retros 90 AF 61.1 72.9 2.2 Beva 12 A reduction of less than 2 lines High 
Hagstrom [26] (2013) Pros 834 CA 55.8 78.5 0.64 Rani or Beva 12 >15-letter increase in VA from baseline High 
Hautamaki [27] (2013) Retros 96 CA 61.5 78 0.57 Beva 3.5 No cystic changes or neuroepithelial detachment after three injections High 
Kitchens [28] (2013) Retros 97 CA 50.5 80 0.49 Rani or Beva VA: gained of 3 lines at month 9/OCT: no sub- or intraretinal fluid at least 1 month after the third monthly injection High 
Kloeckener-Gruissem [19] (2011) Retros 243 CA 51 78.9 0.58 Rani 12 >75th percentile improvement in VA High 
Kubicka-Trzaska [35] (2016) Pros 106 CA 59.4 71.2 0.51 Rani or Beva CRT decrease >10% and BCVA improvement >1 line by Snellen scale High 
Lotery [29] (2013) Retros 254 CA 56.3 77.7 0.63 VEGF inhibitor 12 Changes in TRT ≥75th percentile at a 12-month follow-up High 
Matsumiya [30] (2014) Retros 120 AS 13.3 76.1 3.29 Rani Dry lesion in OCT at 3 months High 
McKibbin [20] (2012) Pros 104 CA 49.6 81.5 0.79 Rani >5 letter score gain in BCVA after 6 months High 
Menghini [21] (2012) Retros 127 CA 49.6 79.3 0.58 Rani 24 ≥5 letter increase in VA at a 12-month follow-up High 
Mohamad [38] (2018) Pros 134 AS 52.6 69.4 1.58 Rani ≥3 lines improvement in the Snellen chart or a decrease of >100 μm in CRT Mod 
Nischler [11] (2011) Pros 197 CA 48.2 76.9 0.51 Beva 11.3 ≥3 lines gain in distance VA High 
Orlin [22] (2012) Retros 143 CA 47.2 80.6 0.47 Rani or Beva 24 Improvement/no change in VA in at least one eye High 
Park [31] (2014) Pros 273 AS 10.2 69.5 1.29 Rani ≥8 letter gain at 5 months High 
Park [32] (2014) Pros 394 AS 9.7 69.4 1.25 Rani or Beva 24 ≥15-letter gain High 
Rodríguez [40] (2019) Cross-sectional 61 CA 29.7 76.6 0.85 Rani 12 0.1 LogMAR or more gain in VA Mod 
van Asten [33] (2014) Retros 391 CA 57.2  0.78 Rani Loss of <30% of letters from baseline High 
Yamashiro [23] (2012) Retros 74 AS 16.7 75 2.5 Rani 12 Resolved retinal exudation High 
Yan [39] (2018) Pros 184 AS 10 65.4 2.01 Con 12 >5 letter gain at 6.12 months High 
Yildiz [36] (2016) Pros 109 CA 31.7 70 1.37 Anti-VEGF Three lines of BCVA gain, decrease in subretinal/intraretinal fluid, lesion size, and retinal hemorrhage High 

AF, African; AS, Asian; BCVA, best corrected visual acuity; Beva, bevacizumab; CA, Caucasian; CFT, central foveal thickness; CMT, central macular thickness; Con, conbercept; CRT, central retinal thickness; Frq (C), frequency of C allele; LogMAR, logarithm of the minimum angle of resolution; M/F ratio, male-to-female ratio; Mod, moderate; OCT, optical coherence tomography; Prosp, prospective; Rani, ranibizumab; Retros, retrospective; TFT, total foveal thickness; VA, visual acuity.

Meta-Analysis

For the overall population, statistically significant better responses to anti-VEGF therapy were reported for T over C (OR = 1.25, 95% CI = 1.04–1.50, p = 0.017), TT over CC (OR = 1.60, 95% CI = 1.06–2.4, p = 0.024), and TT + TC over CC (OR = 1.68, 95% CI = 1.23–2.28, p = 0.001) genotypes (functional and anatomical response are pooled together). In the other three genetic models (TT vs. TC, TT vs. TC + CC, and TC vs. TT + CC), no significant differences were observed between genotypes (p > 0.05, all comparisons). While not statistically significant, TC had a relatively better response to treatment compared to TT + CC (OR = 1.22, 95% CI = 0.98–1.52, p = 0.075).

Subgroup Analysis of the Effect of Y402H Polymorphism on the Response to Anti-VEGF Treatment in AMD Based on Patient Ethnicity, Age, and Gender

Among Caucasian patients, a significant difference in treatment response was observed in T versus C (OR = 1.32, 95% CI = 1.05–1.67, p = 0.019), TT versus CC (OR = 1.82, 95% CI = 1.12–2.95, p = 0.015), TC versus TT + CC (OR = 1.34, 95% CI = 1.04–1.73, p = 0.024), and TT + TC versus CC (OR = 1.80, 95% CI = 1.25–2.58, p = 0.002). Among Asian patients, no significant differences in treatment response were observed in all six genetic models (p > 0.05, all comparisons). However, the study indicated a pattern where individuals with TT and CC genotypes showed more favorable treatment responses in comparison to those with the TC genotype (TT versus TC [OR = 1.31, 95% CI = 0.93–1.82], p = 0.115) (TC versus TT + CC [OR = 0.77, 95% CI = 0.55–1.07], p = 0.124). Among African patients, only TC had a statistically significantly better response than TT + CC (OR = 2.55, 95% CI = 1.06–6.14, p = 0.036) and there was no statistical difference between the other genetic models. TT and CC had a similar response to treatment (OR = 0.83, 95% CI = 0.26–2.62, p = 0.765), while TC was superior to TT; however, the difference was not statistically significant (OR = 0.33, 95% CI = 0.07–1.47, p = 0.154) (shown in Fig. 2).

Fig. 2.

Y402H polymorphism effect on response to anti-VEGF treatment in age-related macular degeneration (AMD) and subgroup analyses based on ethnicity. a TT versus TC. b TT versus CC. c T versus C. d TT + TC versus CC. e TC versus TT + CC. f TT versus TC + CC.

Fig. 2.

Y402H polymorphism effect on response to anti-VEGF treatment in age-related macular degeneration (AMD) and subgroup analyses based on ethnicity. a TT versus TC. b TT versus CC. c T versus C. d TT + TC versus CC. e TC versus TT + CC. f TT versus TC + CC.

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Subgroup analysis based on mean patient age indicated no significant differences between studies with a mean age of less than 75 and more than 75 years. There was no significant difference between studies with a male-to-female ratio <1 and male-to-female ratio >1 (shown in online suppl. Fig. S1, S2). Subgroup analysis of the effect of Y402H polymorphism on response to anti-VEGF treatment in AMD based on the type of MNV and proportion of smokers.

Studies that enrolled varying proportions of classic MNV and smokers in their study samples reported no difference in the response to anti-VEGF therapy between groups (shown in online suppl. Fig. S3, S4). Additionally, in Habibi et al.’s [25] study, the non-uniform distribution of classic MNV (5.4% of TT, 54.1% of TC, and 40.5% of CC had classic MNV) and different proportions of smokers with TT, TC, and CC genotypes [25] (11.5% of TT, 51.9% of TC, and 36.5% of CC were smokers) did not yield to a significant difference in OR of this study with a pooled OR.

Subgroup Analysis of the Effect of Y402H Polymorphism on Response to Anti-VEGF Treatment in AMD Based on the Type of Anti-VEGF Agent, Duration of Follow-Up, and Definition of Outcome

Subgroup analysis that compared the effectiveness of various anti-VEGF agents indicated similar results for bevacizumab and ranibizumab. However, conbercept (Lumitin, Chengdu Kanghong Biotech Corporation Ltd., Chengdu, Sichuan, China) demonstrated greater efficacy in individuals with homozygous genotypes (TT and CC) compared to those with TC genotypes (TC versus TT + CC [OR = 0.46, 95% CI = 0.21–0.97, p = 0.046] for conbercept [OR = 1.28, 95% CI = 0.92–1.77, p = 0.139] for ranibizumab) (shown in Fig. 3).

Fig. 3.

Y402H polymorphism effect on response to anti-VEGF treatment in age-related macular degeneration (AMD) and subgroup analyses based on type of anti-VEGF agent. a TT versus TC. b TT versus CC. c T versus C. d TT + TC versus CC. e TC versus TT + CC. f TT versus TC + CC.

Fig. 3.

Y402H polymorphism effect on response to anti-VEGF treatment in age-related macular degeneration (AMD) and subgroup analyses based on type of anti-VEGF agent. a TT versus TC. b TT versus CC. c T versus C. d TT + TC versus CC. e TC versus TT + CC. f TT versus TC + CC.

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In the analysis, a trend was observed where studies with a follow-up duration longer than 12 months exhibited higher odds ratios (ORs) compared to studies with less than 6 months of follow-up, prominently for two genetic models (TT versus TC [OR = 1.57, 95% CI = 0.64–3.85, p = 0.329] for longer than 12 months [OR = 0.75, 95% CI = 0.56–1.01, p = 0.055] for shorter than 6 months) (TT versus TC + CC [OR = 2.00, 95% CI = 0.77–5.20, p = 0.155] for longer than 12 months [OR = 0.83, 95% CI = 0.62–1.11, p = 0.211] for shorter than 6 months). However, none of the differences were statistically significant (shown in online suppl. Fig. S5).

By modifying the response definition, we identified distinct trends among genotypes in response to anti-VEGF therapy. Specifically, a trend indicated that TT and TC genotypes, along with the T allele, were associated with a more favorable response when considering functional outcomes (outcomes defined by visual acuity changes). Conversely, the CC genotype and the C allele demonstrated a more favorable response when evaluating anatomical outcomes (outcomes defined by optical coherence tomography changes) (T versus C [OR = 1.45, 95% CI = 1.14–1.83, p = 0.002] for VA outcomes [OR = 0.82, 95% CI = 0.67–1.02, p = 0.064] for OCT outcomes) (TT versus CC [OR = 1.95, 95% CI = 1.16–3.28, p = 0.012] for VA outcomes [OR = 0.62, 95% CI = 0.39–0.98, p = 0.042] for OCT outcomes) (TT + TC versus CC [OR = 2.00, 95% CI = 1.35–2.94, p = 0.001] for VA outcomes [OR = 0.81, 95% CI = 0.55–1.18, p = 0.283] for OCT outcomes) (shown in Fig. 4).

Fig. 4.

Y402H polymorphism effect on anatomical (OCT changes) versus functional (VA improvement) response to treatment with anti-VEGF treatment in age-related macular degeneration (AMD). a TT versus TC. b TT versus CC. c T versus C. d TT + TC versus CC. e TC versus TT + CC. f TT versus TC + CC.

Fig. 4.

Y402H polymorphism effect on anatomical (OCT changes) versus functional (VA improvement) response to treatment with anti-VEGF treatment in age-related macular degeneration (AMD). a TT versus TC. b TT versus CC. c T versus C. d TT + TC versus CC. e TC versus TT + CC. f TT versus TC + CC.

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Table 2 presents the cumulative effects of the combination of polymorphisms of other genes (including ARMS2, HTRA1, C3, LOC387715, FZD4, VEGF, and CFH I62V) with CFH Y402H. Combination of ARMS2 A69S (rs10490924), HTRA1 (rs11200638), C3 R80G (rs2230199), VEGF (rs2010963), VEGF (rs3025039), VEGF (rs699947), VEGF (rs2146323) SNPs with CFH Y402H (rs1061170) did not affect the response to treatment [12, 26, 34, 36]. However, the combination of risk alleles of ARMS2 A69S (rs10490924), VEGF-A (rs699947), and VEGF-A (rs833069) with Y420H is a predictor of non-respondents to anti-VEGF therapy [33]. Additionally, the combination of GG at I62V and TT at Y402H was associated with a lower rate of dry lesions observed with OCT [30]. In contrast, heterozygous patients at both Y402H and FZD4 SNPs simultaneously were more likely to experience improved VA [19].

Table 2.

Effects of combination of genetic polymorphisms of Y402H with other genes on response to treatment with anti-VEGF agents in AMD patients

First authorGeneFinding
Brantley [12] (2007) ARMS2 A69S (rs10490924) or LOC387715 No relationship was observed between the number of risk alleles of CFH and LOC387715 genotypes and post-treatment VA 
Kloeckener-Gruissem [19] (2011) FZD4 (rs10898563) More possibility of VA improvement for patients who were heterozygous at both Y402H and FZD4 SNPs simultaneously 
Hagstrom [26] (2013) ARMS2 A69S (rs10490924), HTRA1 (rs11200638), C3 R80G (rs2230199) No relationship was observed between number of risk alleles of C3, ARMS2,HTRA1, CFH, and response to treatment 
van Asten [33] (2014) ARMS2 A69S (rs10490924), VEGF-A (rs699947), VEGF-A (rs833069) Risk allele accumulation of ARMS2, VEGF-A, and CFH is a predictor of non-respondents to anti-VEGF therapy 
Matsumiya [30] (2014) CFH I62V (rs800292) Combination of GG at I62V and TT at Y402H was associated with lower rate of dry OCT 
Habibi [34] (2016) VEGF (rs2010963), VEGF (rs3025039), VEGF (rs699947), C3 (rs2230199) Response to treatment is not affected by the number of high-risk alleles of combination of C3, VEGF, and CFH Y402H 
Yildiz [36] (2016) VEGF (rs699947), VEGF (rs2146323) Dual or triple combinations of genotypes of VEGF rs699947, VEGF rs2146323, and CFH Y420H showed similar distribution between respondents and non-respondents 
First authorGeneFinding
Brantley [12] (2007) ARMS2 A69S (rs10490924) or LOC387715 No relationship was observed between the number of risk alleles of CFH and LOC387715 genotypes and post-treatment VA 
Kloeckener-Gruissem [19] (2011) FZD4 (rs10898563) More possibility of VA improvement for patients who were heterozygous at both Y402H and FZD4 SNPs simultaneously 
Hagstrom [26] (2013) ARMS2 A69S (rs10490924), HTRA1 (rs11200638), C3 R80G (rs2230199) No relationship was observed between number of risk alleles of C3, ARMS2,HTRA1, CFH, and response to treatment 
van Asten [33] (2014) ARMS2 A69S (rs10490924), VEGF-A (rs699947), VEGF-A (rs833069) Risk allele accumulation of ARMS2, VEGF-A, and CFH is a predictor of non-respondents to anti-VEGF therapy 
Matsumiya [30] (2014) CFH I62V (rs800292) Combination of GG at I62V and TT at Y402H was associated with lower rate of dry OCT 
Habibi [34] (2016) VEGF (rs2010963), VEGF (rs3025039), VEGF (rs699947), C3 (rs2230199) Response to treatment is not affected by the number of high-risk alleles of combination of C3, VEGF, and CFH Y402H 
Yildiz [36] (2016) VEGF (rs699947), VEGF (rs2146323) Dual or triple combinations of genotypes of VEGF rs699947, VEGF rs2146323, and CFH Y420H showed similar distribution between respondents and non-respondents 

Sensitivity Analysis

Sensitivity analysis revealed that lower and upper CI of all studies did not exceed 1. Hence, it can be concluded that any single study did not affect the pooled OR in our meta-analysis (shown in online suppl. Fig. S6).

Publication Bias

Funnel plot symmetry was assessed for evaluation of publication bias and Eager’s tests were used to ascertain the findings for each genetic model. In spite of the asymmetry of funnel plots, all Eager’s tests were >0.05 and did not indicate publication bias (shown in online suppl. Fig. S7).

AMD is one of the main causes of irreversible blindness in older adults. Exudative AMD comprises the major cause of blindness attributed to AMD. Anti-VEGF treatment is currently the routine treatment for AMD. Current results from multiple studies recommend that SNP rs1061170 in CFH might have an effect on treatment response [42]. This finding could be explained by the impact of this SNP on more accelerated disease progression [43]. In this meta-analysis, we included a total of 25 studies, comprising 13 retrospective studies, 11 prospective, and 1 cross-sectional study. Most of the studies enrolled patients of Caucasian ethnicity, followed by 6 studies that enrolled patients of Asian ethnicity and 2 studies that enrolled patients of African ethnicity. Overall, 4,835 eyes of 4,681 patients were investigated for the influence of SNP rs1061170/Y402H of the CFH gene on the response to treatment for exudative AMD.

The overall results of this study indicate the T allele’s superiority over the C allele and TT and TC genotypes over the CC genotype for the treatment response to anti-VEGF therapy. These outcomes concur with previous meta-analyses by Hong et al. and Chen et al. [14, 44]. The association between AMD and CFH Y402H (rs1061170) gene has been established and appears to become weaker in studies that enroll patients of Asian ethnicities compared to Causcasian ethnicities [45]. Yang et al. [46] showed that the minor allele of rs1061170 frequency is about 6.7% in the Han populations compared to 28.2% in those of European descent. However, the variation in response to treatment in different ethnicities has not been thoroughly investigated. In this meta-analysis, significant differences in treatment response were observed in Caucasian patients with T versus C, TT versus CC, TC versus TT + CC, and TT + TC versus CC genotypes. However, in African patients, only TC was superior to TT + CC, and other genetic models did not show a significant difference. There was no significant difference in treatment response in all six genetic models among Asian patients.

In this meta-analysis, we defined the response to medications into two subgroups of functional and anatomical response as studies vary in this regard. Our study indicated that there were significant differences in functional response based on VA changes and anatomical response based on OCT changes. The TT and TC genotypes and T allele were associated with a better functional response, while a better anatomical response was associated with the CC genotype and C allele. These results are consistent with Cobos et al.’s study [37]. The study revealed a significant association between the CC genotype of rs1061170 in the CFH gene and a more favorable anatomical response during the initial phase of ranibizumab treatment. These findings suggest that individuals with the risk allele for AMD tend to show better anatomical outcomes with ranibizumab initially compared to those without the allele. However, studies suggest that the overall outcomes are poorer in patients with the CFH rs1061170 risk genotype [12, 13, 47, 48]. The poorer outcomes may be because the central macular thickness and VA could be affected by the morphology, size, and level of macular edema, as well as photoreceptor disruption [49]. Additionally, differences between genotypes in response to treatment might be due to alterations their cell renewal ability, reconstruction of the retinal tissue, and the overall anatomical outcomes. However, it should also be noted that the variations in the definition of improvement of VA and OCT outcomes among studies might have contributed to these results. Table 2 summarizes the definition of response to treatment in each study. A standardized definition of response to treatment should be applied in future studies. In addition, the differences in anatomical and functional response might be due to the variation in ethnicities, as mentioned earlier.

In the present study, a comparison of the efficacy of different anti-VEGF agents with subgroup analysis revealed that bevacizumab and ranibizumab had very similar outcomes. However, conbercept was more effective in homozygous genotypes (TT and CC) compared to TC (TC versus TT + CC [OR = 0.46, p = 0.046] for conbercept [OR = 1.28, p = 0.139] for ranibizumab). These results are consistent with Wang et al.’s [49] meta-analysis that reported both conbercept and ranibizumab are effective choices for the treatment of AMD. However, conbercept showed better results with respect to visual gain in their setting. Our observation is also consistent with a study by Martin et al. [50] that reported similar effects on VA for both ranibizumab and bevacizumab over 2 years. Additionally, two studies from Asia concluded that conbercept is a cost-effective alternative for the treatment of neovascular AMD in their population [51, 52]. These results indicate that new therapeutic methods do not act in the same way for all AMD patients. Prior to reaching any conclusions, it is crucial to consider variations in populations and treatment settings when comparing the outcomes of conbercept to other Anti-VEGF options as it is mainly investigated in an Asian population. Furthermore, given the borderline p value, further investigation and analysis may be warranted to validate the significance of the observed trend. Therefore, it is crucial to perform a thorough molecular analysis of individuals with AMD. This detailed examination is necessary to identify the specific molecular factors influencing each patient, enabling the development of pharmacometrics tailored for the precise application of AMD in precision medicine. It is important to note that the impact of a particular genetic variant may not have direct clinical relevance and may require associations with other genetic variations or clinical indicators. Moreover, certain variants with potentially significant effects, and consequently clinical importance, remain unexplored at this time [53].

Some studies have suggested that the responses to anti-VEGF therapy may be altered by the effects of multiple genes. Gene-to-gene interactions can mask exact genotype and phenotype effects. Therefore, combining a series of genetic factors and other biomarkers must be discussed to address this issue [54]. Our review showed that combination of ARMS2 A69S (rs10490924), HTRA1 (rs11200638), C3 R80G (rs2230199), VEGF (rs2010963), VEGF (rs3025039), VEGF (rs699947), VEGF (rs2146323) SNPs with CFH Y402H (rs1061170) did not affect the response to treatment [12, 26, 34, 36]. However, the combination of risk alleles of ARMS2 A69S (rs10490924), VEGF-A (rs699947), and VEGF-A (rs833069) with Y420H is a predictor of non-responders to anti-VEGF therapy [33]. Furthermore, the combination of GG at I62V and TT at Y402H was associated with a lower rate of dry lesions observed with OCT [30]. In contrast, i Kloeckener-Gruissem et al. [19] found that heterozygous patients at both Y402H and FZD4 SNPs simultaneously were more likely to experience improved VA. Smailhodzic et al. [54] proposed that an additive effect of CFH, ARMS2, and VEGF-A genotypes might be responsible for a lower response rate to ranibizumab treatment. However, the mechanism by which these genotypes interact with anti-VEGF therapy remains unknown. As the anti-VEGF drugs are injected locally, it seems unlikely that the pharmacokinetic effects of the drugs are responsible for these variations.

The duration of follow-up and its effects on response to medications might be a source of variation among studies. Our results showed that in genetic models of TT versus TC, studies with follow-up longer than 12 months were associated with higher OR compared to studies with follow-up less than 6 months ([OR = 1.57, p = 0.329] for longer than 12 months and [OR = 0.75, p = 0.055] for shorter than 6 months). The same outcomes was observed for genetic models of TT versus TC + CC ([OR = 2.00, p = 0.155] for longer than 12 months [OR = 0.83, p = 0.211] for shorter than 6 months). There is an observable trend suggesting that, with longer follow-up durations, there is an increasing likelihood of a positive response to anti-VEGF treatment in patients with the TT genotype compared to other genotypes.

Our meta-analysis has several strengths. We reviewed and analyzed the effects of SNP rs1061170/Y402H of the CFH gene and its possible confounders on AMD response to anti-VEGF therapy with a larger number of Asian participants compared to previous meta-analyses. The relatively small sample sizes of previous studies might have limited the reliable evaluation of the association between the CFH polymorphism rs1061170/Y402H and treatment response to anti-VEGF agents in AMD, especially among patients of Asian ethnicity. Hence, we included another 11 studies in our meta-analysis, most of which were high quality based on the Newcastle-Ottawa Scale (NOS). We also included more studies and patients in this meta-analysis and added more patients of Asian ethnicities. Additionally, we also studied the effects of possible confounding factors, e.g., other gene polymorphisms, smoking, and the pathological stage of AMD. Despite our rigorous methodology, limitations should be considered before drawing any conclusions. First, the heterogeneity in the results may be due to the differences in characteristics of the study designs, including follow-up time and the definition of response to treatment in OCT images and visual acuity. Second, among all included studies, only 2 studies enrolled patients of African ethnicity. Therefore, more studies of African patients are warranted in future meta-analyses. Third, studies on the effects of conbercept on different gene polymorphisms are limited. In this meta-analysis, we have only included one study of conbercept and, consequently, future studies should include more studies with conbercept as an anti-VEGEF medication. Prospective studies would allow more conclusive evidence. Hence we suggest other investigators perform prospective investigations aiming to assess and verify our new findings.

In summary, our findings suggest the T allele’s superiority over the C allele and TT and TC genotypes over the CC genotype for the treatment response to anti-VEGF therapy. We also found that ethnicity can impact the association of CFH Y402H polymorphisms and response to anti-VEGF treatments for AMD. We also observed that different anti-VEGF agents have different efficacy among patients harboring various CFH Y402H polymorphisms. Future studies, including those enrolling a larger number of African patients, or conbercept as the anti-VEGF medication, are needed to validate these findings.

This is a meta-analysis of previously published articles and does not contain any new studies with human participants or animals. Therefore, ethical approval, consent to participate, and consent for publication are not required. The current study adhered to the Declaration of Helsinki.

Amirhossein Roshanshad and Seyed Ali Moosavi: No conflicts of interest to declare. J. Fernando Arevalo: consultant/advisor at AbbVie, GENENTECH, THEA Laboratories, DORC, EyePoint Pharmaceuticals, and Alimera Sciences, Inc.; patents/royalty from Springer SBM LLC and ELSEVIER; and grant support from Topcon Medical Systems Inc.

The authors declare that there was no funding source to conduct this study.

A.R. designed the study; screened the titles and abstracts; assessed the risk of bias; gathered, analyzed, and interpreted the data; and wrote the draft. S.A.M. screened the titles and abstracts, assessed the risk of bias, gathered the data, and helped in writing the draft. J.F.A. contributed to study design, conceptualization, writing the draft, and revision. All authors read and approved the final manuscript.

All data generated or analyzed during this study are included in this article and its supplementary material files. Further inquiries can be directed to the corresponding author.

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