Abstract
Background:
Neovascular age-related macular degeneration (nAMD) is one of the main causes of blindness in developed countries. Complement factor H (CFH) is one of the genes involved in the pathogenesis of nAMD. This study investigated the rs10737680 polymorphism in CFH and its conferred susceptibility to nAMD in Yogyakarta, Indonesia.
Methods:
This case-control hospital-based study recruited participants consisting of 96 patients with nAMD and 101 controls without nAMD from the Eye Polyclinic of Sardjito Hospital, YAP Eye Hospital, and Hardjolukito Hospital Yogyakarta. nAMD was diagnosed when fundus examination, fundus photographs, and optical coherence tomography revealed hard or soft drusen in the macular area measuring > 63 µm that appeared below the retinal pigment epithelium, with or without macular hypo- or hyperpigmentation, and was accompanied by choroidal neovascularization. Genomic DNA was extracted using a commercial DNA isolation kit. The restriction fragment length polymorphism technique was used to identify the rs10737680 polymorphism in CFH.
Results:
The mean (standard deviation [SD]) age of the nAMD group was not homogeneous with that of the control group (P < 0.05); 65.41 (9.74) years versus 68.24 (7.82) years. The number of patients with hypertension in the nAMD group was significantly higher than in the control group (P < 0.05). In the nAMD group, the genotype distribution indicated homozygous risk allele in 34.38%, heterozygous risk allele in 57.29%, and homozygous non-risk allele in 8.33%. In the control group, the genotype distribution indicated homozygous risk allele in 21.78%, heterozygous risk allele in 36.63%, and homozygous non-risk allele in 41.58%. Statistical analysis between the two study groups according to homozygous risk allele genotype (odds ratio [OR], 7.87; 95% confidence interval [CI], 2.88–22.79) and heterozygous genotype (OR, 7.80; 95% CI, 3.11–21.19) showed a significant difference (both P < 0.01).
Conclusions:
Homozygous risk allele was less frequent than heterogeneous risk allele in patients with nAMD; however, both increased the risk for nAMD. Although the homozygous or heterozygous risk-alleles were detected in most patients, yet other important genetic or environmental factors could be involved in the pathogenesis of nAMD. Overall, we found a significant association between rs10737680 polymorphism in CFH and the susceptibility to nAMD in Yogyakarta, Indonesia; however, future studies are needed to fully delineate the mechanism.
Key Words: rs10737680, gene polymorphisms, complement factor H, factor H, choroidal neovascularization, age-related macular degeneration, Yogyakarta, Indonesia
INTRODUCTION
Neovascular age-related macular degeneration (nAMD) is one of the main causes of blindness in developed countries. It is a chronic progressive disease that affects the macula and causes irreversible central vision loss if untreated. Vision loss can lead to limitations in various physical and social activities, affecting emotions and increasing the utilization of health resources and the burden of high social costs [1]. The number of nAMD cases is predicted to rise, reaching 288 million by the year 2040 [2]. The prevalence of nAMD in the Asian population aged 40 to 79 years was reported as 6.8% for early-stage nAMD and 0.56% for advanced nAMD [3].
nAMD is a complex disease, and the pathogenesis is not well understood [4]. Histopathological and biochemical evidence suggests that nAMD is associated with oxidative damage, lipofuscin accumulation, and chronic inflammation [5]. nAMD is multifactorial, associated with both genetic and environmental factors [6, 7].
Nucleotide sequencing technology (DNA sequencing) currently allows extensive DNA polymorphism screening to identify causative mutations in complex diseases such as nAMD. Genes associated with nAMD in various ethnic groups have been reported [8]. The locus of chromosome 1q31 is one of those most consistently associated with nAMD [9, 10]. Several large-scale genetic studies have also supported this association, and subsequent research identified complement factor H (CFH) as one of the genes involved in the pathogenesis of nAMD. This finding was supported by the identification of CFH as an inflammatory mediator and proteins associated with the complement pathway in drusen formation from the early stage of nAMD. These findings were interpreted as evidence that complement hyperactivation could affect the risk, treatment response, and progression of nAMD [11-15]. CFH polymorphism is generally known to be associated with nAMD. However, our previous study showed no association between the rs3753394 polymorphism in CFH and nAMD [16]. We are eager to find another variant of CFH that might be associated with the susceptibility to nAMD.
A Genome-Wide Association Study (GWAS) in 2010 found that the rs10737680 polymorphism in CFH was greatly associated with early-stage nAMD [17]. A study that considered the effects of two polymorphisms in CFH, Y402H and rs10737680, also found that rs10737680 tends to have a stronger influence than Y402H on the risk of nAMD and its progression [18]. The rs10737680 polymorphism in CFH was also proven associated with nAMD in studies in Asian countries near Indonesia, such as China [19, 20], Thailand [21], and Japan [22]. Data on the rs10737680 polymorphism in CFH is not yet available in Yogyakarta, Indonesia.
This study aimed to investigate the rs10737680 polymorphism in CFH in Yogyakarta, Indonesia, to provide basic data that could open insights into the pathogenesis of nAMD in this area. This can be useful for the development of suitable therapy for patients with nAMD in Yogyakarta, Indonesia.
METHODS
This case-control hospital-based study evaluated the rs10737680 CFH polymorphism using the DNA of participants aged > 55 years, with and without nAMD, at the Eye Polyclinic of Sardjito Hospital, YAP Eye Hospital, and Hardjolukito Hospital Yogyakarta. The data used were secondary research data collected by Supanji et al. from 2016 to 2020 [23]. This study followed the tenets of the Declaration of Helsinki (2008) and was approved by the Medical and Health Research Ethics Committee of the Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada (Approval No: KE/FK/0536/EC/22 May 2019 Amendment March 4, 2021). Written informed consent was obtained from all study participants.
Using a quantitative approach, this study assessed the effect of the rs10737680 polymorphism in CFH on susceptibility to nAMD. Participants in the nAMD group were aged > 55 years, diagnosed with nAMD, had no other retinal diseases, and had no current systemic illnesses such as diabetes mellitus, chronic kidney failure, and heart disease. nAMD diagnosis was determined by dilated fundus examination using an indirect ophthalmoscope (Keeler BIO, Keeler Ltd., Windsor, United Kingdom), fundus photography (Haag-Streit Fundus Module 300; Haag-Streit, Bern, Switzerland), and optical coherence tomography (Zeiss Stratus OCT; Carl Zeiss Ophthalmic Systems, Dublin, CA, USA) revealing hard or soft drusen in the macular area measuring > 63 µm, appearing below the retinal pigment epithelium, with or without macular hypopigmentation/hyperpigmentation, and accompanied by choroidal neovascularization. Diagnosis was confirmed by a vitreoretinal specialist. The inclusion criteria for the control group were age > 60 years, no diagnosis of nAMD, no other retinal diseases, and no current systemic illnesses such as diabetes mellitus, chronic kidney failure, and heart disease. The exclusion criterion for this study was unwillingness to participate.
Genotyping: The rs10737680 polymorphism in CFH was identified through the isolation of DNA from approximately 300 µL of whole blood collected from both patients and controls. Genomic DNA was extracted using a commercial DNA isolation kit (Cat. No.: GB100; Geneaid, Taiwan). The quality and quantity of isolated DNA were estimated using spectrophotometry and agarose gel electrophoresis. The genetic variants of rs10737680 (C/A) in the CFH intron were determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. A forward primer (5′-CCTTGTGTTGATTAAAGCCT-3′) and a reverse primer (5′-TTATAAGACTATCAGGTTCACATGC-3′) were used for PCR. The amplification conditions included one cycle of pre-denaturation for 10 min at 95 ºC followed by 35 cycles of denaturation at 95 ºC for 45 s, annealing at 55 ºC for 45 s, and extension at 72 ºC for 5 s. Last, one cycle of final extension was conducted at 72 ºC for 5 min before cooling and storage. The amplified PCR products were digested by the restriction enzyme DdeI overnight at 37 °C. Fragments derived from patients with CC were not digested by DdeI and showed only a 300-bp DNA band, those from patients with CA were partially digested to show three DNA bands (100, 200, and 300 bp), and those from patients with AA were completely digested to show two DNA bands (100 and 200 bp).
Statistical analysis was conducted using the STATA statistical program (Version 15.1; StataCorp, College Station, TX, USA). Extracted data were tested for normality. A descriptive analysis assessed the characteristics of the research sample. These characteristic differences were analyzed by Chi-square tests for nominal and ordinal data. The t-test was used to analyze numerical data. The magnitude of the effect of the rs10737680 polymorphism on the susceptibility to nAMD was analyzed by calculating the odds ratio (OR). The risk factors were considered significant at a P-value < 0.05 with 95% confidence interval (CI). Multiple logistic regression analysis was used to determine the relationships between independent and dependent variables by controlling for confounding variables.
RESULTS
The participants of this study consisted of 96 patients with nAMD and 101 controls. The demographic characteristics of the research participants are shown in Table 1. The mean age of the nAMD group was not homogeneous with that of the control group (P < 0.05). The number of patients with hypertension in the nAMD group (53.13%) was significantly higher than in the control group (20.79%) (P < 0.05). However, sex distribution and smoking status were not significantly different between the two groups (both P > 0.05) (Table 1).
Table 1.
Demographic characteristics of study participants
| Variable | nAMD (n = 96) | Control (n = 101) | P -value |
|---|---|---|---|
| Age (y), Mean ± SD | 65.41 ± 9.74 | 68.24 ± 7.82 | 0.025 |
| Sex (Male / Female), n (%) | 41 (42.71) / 55 (57.29) | 45 (44.55) / 56 (55.45) | 0.790 |
| Blood Pressure, n (%) | < 0.01 | ||
| Hypertension | 51 (53.13) | 21 (20.79) | |
| Normotension | 45 (46.88) | 80 (79.21) | |
| Smoking status, n (%) | 0.95 | ||
| Yes | 27 (28.13) | 28 (27.72) | |
| No | 69 (71.88) | 73 (72.28) | |
Abbreviations: nAMD, neovascular age-related macular degeneration; n, number; %, percentage; y, years; SD, standard deviation. P-values < 0.05 are shown in bold.
The heterozygous and homozygous risk allele genotypes affected the susceptibility to nAMD (Table 2). The frequencies of both were significantly higher in the nAMD group than in the control group (both P < 0.01). The homozygous risk allele genotype significantly increased the risk of nAMD by a factor of 7.87 when compared to individuals without the polymorphism (95% CI, 2.88–22.79). The risk of developing nAMD increased significantly by a factor of 7.80 for individuals with the heterozygous rs10737680 genotype when compared to normal individuals (95% CI, 3.11–21.19).
Table 2.
Genotype analysis of CFH rs10737680 in study groups
| Genotype | nAMD (n = 96) | Control (n = 101) | P -value | OR (95% CI) |
|---|---|---|---|---|
| Homozygous risk allele, n (%) | 33 (34.38) | 22 (21.78) | < 0.01 | 7.87 (2.88–22.79) |
| Heterozygous risk allele, n (%) | 55 (57.29) | 37 (36.63) | < 0.01 | 7.80 (3.11–21.19) |
| Wild allele, n (%) | 8 (8.33) | 42 (41.58) | ref* |
Abbreviations: CFH, complement factor H gene; nAMD, neovascular age-related macular degeneration; n, number; %, percentage; OR, odds ratio; CI, confidence interval; ref*, *reference. P-values < 0.05 are shown in bold.
Hypertension significantly increased the susceptibility to nAMD (OR, 3.88; 95% CI, 1.99–7.58) (Table 3). Increasing blood pressure as little as 10 mmHg will increase the susceptibility to nAMD by a factor of 3.88. The OR for CFH rs10737680 was still high after multiple analyses of the significant bivariate variables, which are genotype and blood pressure. The OR of homozygous risk allele genotypes was 7.09 (95% CI, 2.70–18.61), and the OR of heterozygous risk allele was 7.07 (95% CI, 2.89–17.31). Both homozygous and heterozygous risk allele genotypes increase the risk of nAMD compared to those with wild alleles.
Table 3.
Analysis of CFH rs107373680 and blood pressure
| Variable | P -value | OR (95% CI) |
|---|---|---|
| Blood Pressure | ||
| Hypertension | < 0.01 | 3.88 (1.99–7.58) |
| Normotension | ref* | - |
| rs 10737680 | ||
| Homozygous risk allele | < 0.01 | 7.09 (2.70–18.61) |
| Heterozygous risk allele | < 0.01 | 7.07 (2.89–17.31) |
| Wild allele | ref* | - |
Abbreviations: CFH, complement factor H gene; OR, odds ratio; CI, confidence interval; ref*, *reference. P-values < 0.05 are shown in bold.
DISCUSSION
We found that individuals with the CFH rs10737680 polymorphism had increased risk of nAMD compared to individuals without this risk allele. Because both groups were comparable in terms of sex and smoking status, we could infer that neither of these had an effect on susceptibility to nAMD. Zhuang et al. also found that the rs10737680 polymorphism risk allele significantly affected the incidence of nAMD in China (P = 0.001), with an OR of 1.739 (95% CI, 1.237–2.445) [19].
Homozygous and heterozygous genotypes of the rs10737680 polymorphism significantly affected the susceptibility to nAMD in our study, with ORs of 7.87 and 7.80, respectively, which are higher than those reported in China [19, 20]. Tian et al. showed an association between the homozygous rs10737680 polymorphism genotype and the incidence of nAMD, with an OR of 2.01 (P < 0.001) [20]. Zhuang et al. found ORs of 1.506 (95% CI, 0.711–3.191) for the homozygous genotype and 3.186 (95% CI, 1.444–7.029) for the heterozygous genotype [19].
Several studies support the hypothesis that polymorphisms in CFH can cause nAMD [11-15]. CFH is located on chromosome 1q31, a region known to be involved in nAMD [24]. CFH is a protein that helps to regulate the body’s immune response through the complement system, which works by destroying foreign invaders such as bacteria and viruses, triggering an inflammatory response, and removing debris from cells and tissues [25-27]. CFH protects host cells from damage due to rapid and progressive complement activation. Errors in CFH coding due to mutations or polymorphisms cause dysfunction of CFH as a regulator of the complement system, rendering alternative pathways overactive, and this is thought to be a key component in the pathogenesis of nAMD [28]. In particular, the investigators propose that complement cascade dysfunction could lead to inflammatory changes in the retina, leading to an nAMD phenotype. This theory is reinforced by the detection of complement factors in drusen, high activation of alternative complement factors in individuals with nAMD, and specific complement factor gene (SNPs) variants that increase the prevalence of nAMD. The activation products C3a, C5a, and C5b-9 are also increased systemically in patients with nAMD. These complement components accumulate over time, and the normal process of recognizing healthy cells becomes less effective [10, 29]. The molecular role of the CFH rs10737680 polymorphism and nAMD pathogenesis is not specifically known; however, many studies have concluded that this gene variant independently increases the risk of nAMD [19- 21]. We found that presence of the rs10737680 polymorphism significantly increased the risk of nAMD compared to absence of the risk allele.
The potential involvement of hypertension in the susceptibility to nAMD has also been stated in several studies [30-32]; however, it is not always identified as a risk factor for nAMD [31]. A large meta-analysis of data from prospective, cross-sectional, or case-control studies with a total of 94,058 patients indicated that although the ORs between studies are inconsistent, the combination of case-control studies showed that the relationship between hypertension and nAMD was statistically significant (OR, 1.48; 95% CI, 1.22–1.78) [31]. Hypertension is associated with decreased choroidal blood flow, disrupting vascular homeostasis; however, this is not a major contributor to nAMD pathogenesis [33-35]. In our study, the frequencies of hypertension were significantly different between the nAMD and control groups; therefore, hypertension affected the susceptibility to nAMD. Multiple logistic regression analysis showed that individuals with homozygous and heterozygous risk allele genotypes had an increased risk of developing nAMD if they were also hypertensive.
This study is limited by the lack of subgroup analysis based on severity of nAMD, which could elucidate the differences in the rs10737680 polymorphism over a broad clinical spectrum of nAMD. Additionally, the included participants in this case-control study were from Yogyakarta, Indonesia; thus, we should be cautious in generalizing our results to different worldwide populations with various racial backgrounds. However, with the proven relationship between the rs10737680 polymorphism in CFH and the susceptibility to nAMD in Yogyakarta, Indonesia, as in similar previous investigations of ARMS2, CFH Y402H [22], and HTRA1 [36], further biomolecular research could determine the mechanism by which the rs10737680 polymorphism affects the function of CFH in the inflammatory process and increases susceptibility to nAMD. This may serve as a basis for future pharmacogenetic research.
CONCLUSIONS
This study showed that the rs10737680 polymorphism in CFH significantly increased the susceptibility to nAMD. Patients with the homozygous or heterozygous risk allele genotypes had significant susceptibility to nAMD compared with controls. The frequency of homozygous risk allele was low in patients with nAMD, yet it increased the risk for nAMD with an OR of 7.87. Likewise, the heterozygous risk allele increased the risk for nAMD with an OR of 7.80 and was more frequent in patients with nAMD. While the homozygous or heterozygous risk-allele genotypes were detected in most patients with nAMD, however other important genetic or environmental factors could also be associated with the pathogenesis of nAMD. Although the genetic influence of the CFH rs10737680 polymorphism was significant in patients with nAMD in Yogyakarta, Indonesia, future studies are needed to fully elucidate the mechanism.
ETHICAL DECLARATION
Ethical approval:
This study followed the tenets of the Declaration of Helsinki (2008) and was approved by the Medical and Health Research Ethics Committee of the Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada (Approval No: KE/FK/0536/EC/22 May 2019 Amendment March 4, 2021). Written informed consent was obtained from all study participants.
Conflict of interests:
None
FUNDING
This research was supported by a University Research Excellence Grant, Ministry of Higher Education and Technology, Government of Indonesia. This research was also supported by DAMAS PPDS research fund (No.: 1513/UN1/FK-KMK/PP/PT/2019).
ACKNOWLEDGMENTS
The authors acknowledge the Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada for providing the DAMAS research grant (No.: 1513/UN1/FK-KMK/PP/PT/2019).
References
- 1.Biarnés M, Vassilev V, Nogoceke E, Emri E, Rodríguez-Bocanegra E, Ferraro L, et al. Precision medicine for age-related macular degeneration: Current developments and prospects. Expert Review of Precision Medicine and Drug Development. 2018;3(4):249–63. [Google Scholar]
- 2.Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106–16. doi: 10.1016/S2214-109X(13)70145-1. [DOI] [PubMed] [Google Scholar]
- 3.Cheung CM, Tai ES, Kawasaki R, Tay WT, Lee JL, Hamzah H, et al. Prevalence of and risk factors for age-related macular degeneration in a multiethnic Asian cohort. Arch Ophthalmol. 2012;130(4):480–6. doi: 10.1001/archophthalmol.2011.376. [DOI] [PubMed] [Google Scholar]
- 4.Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration. Cochrane Database Syst Rev. 2017;7(7):CD000253. doi: 10.1002/14651858.CD000253.pub4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Zarbin MA. Pathogenesis of age-related macular degeneration. Medical Retina. 2012;1:125–133. [Google Scholar]
- 6.Emptage NP, Mizuiri D, Kealey S, Lum FC, Garratt S. American Academy of Ophthalmology Retina/Vitreus Panel Preferred Practice Pattern guidelines, Age-Related Macular Degeneration San Francisco, CA: American Academy of Ophthalmology. 2015. [Accessed: August 06, 2022]. ‘Age-Related Macular Degeneration’. Available at: www.aao.org/ppp. [Google Scholar]
- 7.Supanji S, Perdamaian AB, Aulia R, Adelia RK, Prayogo ME, Widayanti TW, Wardhana FS, et al. Smoking as a Risk Factor for rs10490924 Variant Age-related Macular Degeneration in Yogyakarta, Indonesia. Malaysian Journal of Medicine and Health Sciences. 2020:16. [Google Scholar]
- 8.Ross RJ, Verma V, Rosenberg KI, Chan CC, Tuo J. Genetic markers and biomarkers for age-related macular degeneration. Expert Rev Ophthalmol. 2007;2(3):443–457. doi: 10.1586/17469899.2.3.443. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Fisher SA, Abecasis GR, Yashar BM, Zareparsi S, Swaroop A, Iyengar SK, et al. Meta-analysis of genome scans of age-related macular degeneration. Hum Mol Genet. 2005;14(15):2257–64. doi: 10.1093/hmg/ddi230. [DOI] [PubMed] [Google Scholar]
- 10.Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308(5720):385–9. doi: 10.1126/science.1109557. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Dikmetas O, Kadayıfcılar S, Eldem B. The effect of CFH polymorphisms on the response to the treatment of age-related macular degeneration (AMD) with intravitreal ranibizumab. Mol Vis. 2013;19:2571–8 . [PMC free article] [PubMed] [Google Scholar]
- 12.Brantley MA Jr, Fang AM, King JM, Tewari A, Kymes SM, Shiels A. Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab. Ophthalmology. 2007;114(12):2168–73. doi: 10.1016/j.ophtha.2007.09.008. [DOI] [PubMed] [Google Scholar]
- 13.Kloeckener-Gruissem B, Barthelmes D, Labs S, Schindler C, Kurz-Levin M, Michels S, et al. Genetic association with response to intravitreal ranibizumab in patients with neovascular AMD. Invest Ophthalmol Vis Sci. 2011;52(7):4694–702. doi: 10.1167/iovs.10-6080. [DOI] [PubMed] [Google Scholar]
- 14.Nischler C, Oberkofler H, Ortner C, Paikl D, Riha W, Lang N, et al. Complement factor H Y402H gene polymorphism and response to intravitreal bevacizumab in exudative age-related macular degeneration. Acta Ophthalmol. 2011;89(4):e344–9. doi: 10.1111/j.1755-3768.2010.02080.x. [DOI] [PubMed] [Google Scholar]
- 15.Veloso CE, Almeida LN, Nehemy MB. CFH Y402H polymorphism and response to intravitreal ranibizumab in Brazilian patients with neovascular age-related macular degeneration. Rev Col Bras Cir. 2014;41(6):386–92. doi: 10.1590/0100-69912014006002. [DOI] [PubMed] [Google Scholar]
- 16.Supanji S, Perdamaian AB, Anindita DA, Widayanti TW, Wardhana FS, Sasongko MB, et al. rs3753394 Complement Factor H (CFH) Gene Polymorphism in Patients with Age-Related Macular Degeneration (AMD) in Indonesian Population. BIO Web of Conferences. 2021;41:06001. [Google Scholar]
- 17.Fritsche LG, Igl W, Bailey JN, Grassmann F, Sengupta S, Bragg-Gresham JL, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016;48(2):134–43. doi: 10.1038/ng.3448. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Sardell RJ, Persad PJ, Pan SS, Whitehead P, Adams LD, Laux RA, et al. Progression Rate From Intermediate to Advanced Age-Related Macular Degeneration Is Correlated With the Number of Risk Alleles at the CFH Locus. Invest Ophthalmol Vis Sci. 2016;57(14):6107–6115. doi: 10.1167/iovs.16-19519. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Zhuang W, Li H, Liu Y, Zhao J, Ha S, Xiang W, et al. Association of specific genetic polymorphisms with age-related macular degeneration in a northern Chinese population. Ophthalmic Genet. 2014;35(3):156–61. doi: 10.3109/13816810.2014.921314. [DOI] [PubMed] [Google Scholar]
- 20.Tian J, Yu W, Qin X, Fang K, Chen Q, Hou J, et al. Association of genetic polymorphisms and age-related macular degeneration in Chinese population. Invest Ophthalmol Vis Sci. 2012;53(7):4262–9. doi: 10.1167/iovs.11-8542. [DOI] [PubMed] [Google Scholar]
- 21.Ruamviboonsuk P, Tadarati M, Singhanetr P, Wattanapokayakit S, Kunhapan P, Wanitchanon T, et al. Genome-wide association study of neovascular age-related macular degeneration in the Thai population. J Hum Genet. 2017;62(11):957–962. doi: 10.1038/jhg.2017.72. [DOI] [PubMed] [Google Scholar]
- 22.Goto A, Akahori M, Okamoto H, Minami M, Terauchi N, Haruhata Y, et al. Genetic analysis of typical wet-type age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese population. J Ocul Biol Dis Infor. 2009;2(4):164–175. doi: 10.1007/s12177-009-9047-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Supanji S, Romdhoniyyah DF, Sasongko MB, Agni AN, Wardhana FS, Widayanti TW, et al. Associations of ARMS2 and CFH Gene Polymorphisms with Neovascular Age-Related Macular Degeneration. Clin Ophthalmol. 2021;15:1101–1108. doi: 10.2147/OPTH.S298310. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Armento A, Ueffing M, Clark SJ. The complement system in age-related macular degeneration. Cell Mol Life Sci. 2021;78(10):4487–4505. doi: 10.1007/s00018-021-03796-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Brooks LD. SNPs: why do we care? Methods Mol Biol. 2003;212:1–14. doi: 10.1385/1-59259-327-5:001. [DOI] [PubMed] [Google Scholar]
- 26.Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11(9):785–97. doi: 10.1038/ni.1923. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Markiewski MM, Lambris JD. The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am J Pathol. 2007;171(3):715–27. doi: 10.2353/ajpath.2007.070166. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Donoso LA, Vrabec T, Kuivaniemi H. The role of complement Factor H in age-related macular degeneration: a review. Surv Ophthalmol. 2010;55(3):227–46. doi: 10.1016/j.survophthal.2009.11.001. [DOI] [PubMed] [Google Scholar]
- 29.Boyer DS, Schmidt-Erfurth U, van Lookeren Campagne M, Henry EC, Brittain C. THE PATHOPHYSIOLOGY OF GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION AND THE COMPLEMENT PATHWAY AS A THERAPEUTIC TARGET. Retina. 2017;37(5):819–835. doi: 10.1097/IAE.0000000000001392. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Hogg RE, Woodside JV, Gilchrist SE, Graydon R, Fletcher AE, Chan W, et al. Cardiovascular disease and hypertension are strong risk factors for choroidal neovascularization. Ophthalmology. 2008;115(6):1046–1052. doi: 10.1016/j.ophtha.2007.07.031. [DOI] [PubMed] [Google Scholar]
- 31.Chakravarthy U, Wong TY, Fletcher A, Piault E, Evans C, Zlateva G, et al. Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. BMC Ophthalmol. 2010;10:31. doi: 10.1186/1471-2415-10-31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Fraser-Bell S, Wu J, Klein R, Azen SP, Hooper C, Foong AW, et al. Cardiovascular risk factors and age-related macular degeneration: the Los Angeles Latino Eye Study. Am J Ophthalmol. 2008;145(2):308–16. doi: 10.1016/j.ajo.2007.10.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Katsi VK, Marketou ME, Vrachatis DA, Manolis AJ, Nihoyannopoulos P, Tousoulis D, et al. Essential hypertension in the pathogenesis of age-related macular degeneration: a review of the current evidence. J Hypertens. 2015;33(12):2382–8. doi: 10.1097/HJH.0000000000000766. [DOI] [PubMed] [Google Scholar]
- 34.Yang K, Wang FH, Liang YB, Wong TY, Wang JJ, Zhan SY, et al. Associations between cardiovascular risk factors and early age-related macular degeneration in a rural Chinese adult population. Retina. 2014;34(8):1539–53. doi: 10.1097/IAE.0000000000000118. [DOI] [PubMed] [Google Scholar]
- 35.Lutty GA, McLeod DS, Bhutto IA, Edwards MM, Seddon JM. Choriocapillaris dropout in early age-related macular degeneration. Exp Eye Res. 2020;192:107939. doi: 10.1016/j.exer.2020.107939. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Supanji S, Perdamaian ABI, Romdhoniyyah DF, Sasongko MB, Agni AN, Wardhana FS, et al. Association of the HtrA1 rs11200638 Polymorphism with Neovascular Age-Related Macular Degeneration in Indonesia. Ophthalmol Ther. 2022;11(1):125–133. doi: 10.1007/s40123-021-00402-w. [DOI] [PMC free article] [PubMed] [Google Scholar]