C-Reactive Protein Levels and Complement Factor H Polymorphism Interaction in Age-related Macular Degeneration and Its Progression

doi:10.1016/j.ophtha.2010.02.003

Ophthalmology

Volume 117, Issue 10, October 2010, Pages 1982-1988

Presented at: Association for Research in Vision and Ophthalmology annual meeting, May 2009, Fort Lauderdale, Florida.

https://doi.org/10.1016/j.ophtha.2010.02.003 Get rights and content

Purpose

To determine the effect of elevated level of C-reactive protein (CRP) and its joint effect with the complement factor H (CFH) polymorphism on prevalent age-related macular degeneration (AMD) and its progression.

Design

Two-arm case-control study: (a) Study on prevalent AMD cases and population-based controls; (b) longitudinal study on AMD progression, comparing those in whom AMD progressed with those with no progression.

Participants

(a) A cross-sectional sample of 544 participants, of whom 312 had features of early or late AMD and 232 were controls; (b) a sample of 254 early AMD cases, followed for 7 years.

Methods

The study was conducted in Melbourne, Australia. Macular stereo photographs were graded for AMD according to the International Classification and Grading System. High-sensitivity CRP was measured in fresh serum, and genotyping was performed through the Australian Genome Research Facility. The association of CRP with outcomes was tested using multivariate logistic regression analysis adjusted for age, smoking, anti-inflammatory medications, and the CC genotype of the CFH gene. Risk factor interaction was explored using an additive model.

Main Outcome Measures

Prevalent early AMD, prevalent late AMD, progressed AMD, and measures of risk factor interaction.

Results

Elevated CRP levels were associated with late AMD: odds ratio (OR), 3.12; 95% confidence interval (CI), 1.38–7.07. An association of elevated CRP with AMD progression was weaker: OR, 1.90 (95% CI, 0.88–4.10). A combination of elevated CRP and the CC (Y402H) genotype resulted in a super-additivity of the risks, with odds ratios of 19.3 (95% CI, 2.8–134) for late AMD, and 6.8 (95% CI, 1.2–38.8) for AMD progression, with the attributable proportion of risk owing to CRP–CFH interaction calculated at 26% for prevalent late AMD and 22% for AMD progression.

Conclusions

Synergistic influence of CRP levels and the at risk genotype of the CFH gene resulted in a super-additive risk for prevalent late AMD and AMD progression. Testing for the combination of these 2 risk factors to predict a high risk of AMD and its progression would allow for targeted trials of new intervention strategies.

Financial Disclosure(s)

The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Section snippets

Study Design

The details of the methodology involved in the CHARM study and recruitment have been described previously.23, 26, 27 The study protocol was approved by the Royal Victorian Eye and Ear Hospital Human Research and Ethics Committee (project #99/372H). This study was conducted in accordance with the Declaration of Helsinki and written informed consent was obtained from all participants.

In brief, to assess progression of early AMD, participants were chosen from 2 previous studies conducted in

Prevalent Age-related Macular Degeneration and Elevated C-Reactive Protein Level

The complete data on macular grading, CRP levels, and covariates were collected from 557 participants. The levels of CRP ranged from <0.5 mg/L to 78 mg/L, with a median of 2.1 mg/L. Thirteen (2%) cases who had CRP levels ≥20 mg/L were excluded before analysis because the very high CRP level might be indicative of concomitant acute inflammation. There was no significant difference in AMD prevalence and baseline characteristics between these individuals and the rest of the sample. The age of the

Discussion

We report on an epidemiologic association of prevalent late AMD with elevated CRP levels and the CC risk genotype of the CFH gene. We also present evidence of a departure from additivity of the risks, supporting the hypothesis on risk factor interaction between CRP levels and the CFH alleles when considering both prevalent late AMD and AMD progression. We did not find any association between CRP levels and early AMD.

Previous studies have reported an association between CRP levels and AMD, or

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Aspirin and omega-3 fatty acids (FAs) have potential disease-modifying roles in diabetic retinopathy (DR) and age-related macular degeneration (AMD), but randomized evidence of these effects is limited. We present the rationale and baseline characteristics of ASCEND-Eye, a sub-study of the double-blind, 2x2 factorial design, randomized placebo-controlled ASCEND (A Study of Cardiovascular Events iN Diabetes) trial of 100 mg aspirin daily and, separately, 1g omega-3 FAs daily for the primary prevention of serious cardiovascular events, in 15,480 British adults, aged 40 years or older with diabetes.
Eye events will be derived from three sources: 1) participant follow-up questionnaires from ASCEND, 2) electronic NHS Diabetic Eye Screening Programme (DESP) data and 3) responses to the National Eye Institute's Visual Function Questionnaire-25 (NEI-VFQ-25) sent to a subset of participants after the main trial ended. Analytic cohorts and outcomes relevant to these data sources are described. The primary outcome is referable diabetic eye disease, a secondary outcome is incident AMD events.
Participant-reported events were ascertained for the full cohort of randomized individuals who were followed up over 7.4 years in ASCEND (n = 15,480). Linked DESP data were available for 48% of those (n = 7360), and 57% completed the NEI-VFQ-25 (n = 8839). The baseline characteristics of these three cohorts are presented.
Establishing the risks and benefits of drugs commonly taken by people with diabetes, the elderly, or both, and finding new treatments for DR and AMD is important. ASCEND-Eye provides the opportunity to evaluate the effect of aspirin and, separately, omega-3 FAs for both conditions.
Eudract No. 2004-000991-15; Multicentre Research Ethics Committee Ref No. 03/8/087; ClinicalTrials.gov No. NCT00135226; ISRCTN No. ISRCTN60635500.
Revisiting the role of factor H in age-related macular degeneration: Insights from complement-mediated renal disease and rare genetic variants
2021, Survey of Ophthalmology
Ophthalmologists are long familiar with the eye showing signs of systemic disease, but the association between age-related macular degeneration and abnormal complement activation, common to several renal disorders, has only recently been elucidated. Although complement activation products were identified in drusen almost three decades ago, it was not until the early 21st century that a single-nucleotide polymorphism in the complement factor H gene was identified as a major heritable determinant of age-related macular degeneration, galvanizing global efforts to unravel the pathogenesis of this common disease. Advances in proteomic analyses and familial aggregation studies have revealed distinctive clinical phenotypes segregated by the functional effects of common and rare genetic variants on the mature protein and its splice variant, factor H–like protein 1. The predominance of loss-of-function, N-terminal mutations implicate age-related macular degeneration as a disease of general complement dysregulation, offering several therapeutic avenues for its modulation. Here, we explore the molecular impact of these mutations/polymorphisms on the ability of variant factor H/factor H–like protein 1 to localize to polyanions, pentraxins, proinflammatory triggers, and cell surfaces across ocular and renal tissues and exert its multimodal regulatory functions and their clinical implications. Finally, we critically evaluate key therapeutic and diagnostic efforts in this rapidly evolving field.
Baseline characteristics and age-related macular degeneration in participants of the “ASPirin in Reducing Events in the Elderly” (ASPREE)-AMD trial
2020, Contemporary Clinical Trials Communications
To describe the baseline participant characteristics in the ASPREE-AMD study, investigating the effect of aspirin on AMD incidence and progression.
Australian participants from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, randomized to 100 mg aspirin daily or placebo, had non-mydriatic, digital color fundus images graded according to the Beckman AMD classification. Associations with AMD were determined for baseline characteristics and genetic risk variants.
ASPREE-AMD sub-study enrolled 4993 participants with gradable macular images. Median age was 73.4 years (IQR, 71.5, 76.6), 52% were female, 10% had diabetes mellitus, 73% had hypertension, and 44% were former/current smokers. Early, intermediate and late AMD (detected in 20.6%, 16.1%, 1.1%, respectively), significantly associated with age, were also associated with increasing HDL levels: OR = 1.52 (95%CI, 1.26, 1.84), OR = 1.43 (1.17, 1.77) and OR = 1.96 (1.02, 3.76), respectively. Female sex was associated with early [OR = 1.37 (1.16, 1.62)], and intermediate [OR = 1.35 (1.12, 1.63)] AMD, as was previous regular use of aspirin, with OR = 1.46 (1.11, 1.92) and OR = 1.37 (1.01, 1.85), respectively. Current smoking had increased odds for late AMD, OR = 4.02 (1.42, 11.36). Genetic risk variant rs3750846 (ARMS2/HTRA1) was associated with each AMD stage (p < 0.001), risk variants rs570618 and rs10922109 (CFH) with intermediate and late AMD (p < 0.001), and rare variant rs147859257 (C3) with late AMD (p < 0.001). The randomized groups were well balanced for all analyzed AMD risk factors.
Observed associations are typical of AMD. The ASPREE-AMD clinical trial provides a unique opportunity to determine the risks and benefits of low-dose aspirin for AMD incidence and progression in elderly population.
Australian New Zealand Clinical Trial Registry: ACTRN 12613000755730.
Systemic levels of C-reactive protein in patients with age-related macular degeneration: A systematic review with meta-analyses
2020, Mechanisms of Ageing and Development
Citation Excerpt :
Ghorbanihaghjo et al. (2010) found that serum CRP was higher in patients with AMD. Robman et al. (2010) found elevated levels of serum CRP in patients with late AMD, but not early AMD, in the Cardiovascular Health and Age Related Maculopathy study. Seddon et al. (2010) found that elevated serum CRP was associated with late AMD, and that the risk of an elevated CRP was significantly higher among those with single nucleotide polymorphism in the CFH gene (Y402 H).
Ageing of the retina is associated with the gradual accumulation of basal deposits and the formation of drusen. However, in some individuals this process is exacerbated and causes development of age-related macular degeneration. Late features of age-related macular degeneration include geographic atrophy of the neuroretina or choroidal neovascularization. Such changes lead to blurred vision, metamorphopsia, and scotoma, and is the leading cause of vision loss in developed countries. Chronic low-grade inflammation has been investigated because of its relationship to ageing and its role in the gap between chronological and biological ageing. Here, we systematically reviewed studies investigating systemic C-reactive protein in patients with age-related macular degeneration. We identified 53 studies with 60,598 participants (10,392 patients and 38,901 controls). Our meta-analyses revealed that early age-related macular degeneration was not associated to systemic C-reactive protein (Cohen’s d = 0.03 [−0.04 to 0.10]; OR = 1.06 [0.93–1.20]; P = 0.39) whereas late age-related macular degeneration (Cohen’s d = 0.38 [0.24 to 0.51]; OR = 1.99 [1.55–2.52]; P < 0.0001), and neovascular age-related macular degeneration (Cohen’s d = 0.40 [0.24 to 0.56]; OR = 2.07 [1.55–2.76]; P < 0.0001) was associated with a small-to-moderate increase in systemic C-reactive protein. Our review provides an overview of this extensively studied field, provide summary estimates that provide insight into when and to what extent systemic C-reactive protein is associated with age-related macular degeneration, and help in distinguishing the potentially reversible disease processes from that of irreversible retinal ageing.
Dual roles of different redox forms of complement factor H in protecting against age related macular degeneration
2018, Free Radical Biology and Medicine
Complement Factor H (CFH) is an important inhibitor of the alternate complement pathway in Bruch's membrane (BM), located between the choriocapillaris and the retinal pigment epithelium. Furthermore dysfunction of its activity as occurs with certain polymorphisms is associated with an increased risk of age related macular degeneration (AMD).
The retina is a site of high generation of reactive oxygen species (ROS) and dysfunction of redox homeostasis in this milieu also contributes to AMD pathogenesis. In this study we wanted to explore if CFH exists in distinct redox forms and whether these species have unique protective biological functions. CFH can be reduced by the naturally occurring thioredoxin − 1 in CFH domains 1–4, 17–20. We found a duality of function between the oxidised and reduced forms of CFH. The oxidised form was more efficient in binding to C3b and lipid peroxidation by-products that are known to accumulate in the retinae and activate the alternate complement pathway.
Oxidised CFH enhances Factor I mediated cleavage of C3 and C3b whereas the reduced form loses this activity. In the setting of oxidative stress (hydrogen peroxide)-mediated death of human retinal pigment epithelial cells as can occur in AMD, the free thiol form of CFH offers a protective function compared to the oxidised form. We found for the first time using a novel ELISA system we have developed for free thiol CFH, that both redox forms of CFH are found in the human plasma. Furthermore there is a distinct ratio of these redox forms in plasma depending if an individual has early or late AMD, with individuals with early AMD having higher levels of the free thiol form compared to late AMD.
Age-related macular degeneration in a randomized controlled trial of low-dose aspirin: Rationale and study design of the ASPREE-AMD study
2017, Contemporary Clinical Trials Communications
Although aspirin therapy is used widely in older adults for prevention of cardiovascular disease, its impact on the incidence, progression and severity of age-related macular degeneration (AMD) is uncertain. The effect of low-dose aspirin on the course of AMD will be evaluated in this clinical trial.
A sub-study of the ‘ASPirin in Reducing Events in the Elderly’ (ASPREE) trial, ASPREE-AMD is a 5-year follow-up double-blind, placebo-controlled, randomized trial of the effect of 100 mg daily aspirin on the course of AMD in 5000 subjects aged 70 years or older, with normal cognitive function and without cardiovascular disease at baseline. Non-mydriatic fundus photography will be performed at baseline, 3-year and 5-year follow-up to determine AMD status.
The incidence and progression of AMD. Exploratory analyses will determine whether aspirin affects the risk of retinal hemorrhage in late AMD, and whether other factors, such as genotype, systemic disease, inflammatory biomarkers, influence the effect of aspirin on AMD.
The study findings will be of significant clinical and public interest due to a potential to identify a possible low cost therapy for preventing AMD worldwide and to determine risk/benefit balance of the aspirin usage by the AMD-affected elderly. The ASPREE-AMD study provides a unique opportunity to determine the effect of aspirin on AMD incidence and progression, by adding retinal imaging to an ongoing, large-scale primary prevention randomized clinical trial.

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: Manuscript no. 2009-1521.

: Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

: Supported by the National Health & Medicine Research Council of Australia (Grant # 128201), Practitioner Fellowship (529905 RG), Royal Victorian Eye & Ear Hospital, Wagstaff Fellowship (LR), Perpetual Trustees Australia, ANZ Trustees, The Ophthalmic Research Institute of Australia, and the Lions Club of Victoria. The funding organizations had no role in the design or conduct of this research.

^⁎: A/Prof. Baird and Prof. Guymer contributed equally as the senior authors of this paper.

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Original articleC-Reactive Protein Levels and Complement Factor H Polymorphism Interaction in Age-related Macular Degeneration and Its Progression

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Financial Disclosure(s)

Section snippets

Study Design

Prevalent Age-related Macular Degeneration and Elevated C-Reactive Protein Level

Discussion

Prog Retin Eye Res

Am J Ophthalmol

Ophthalmology

Ophthalmology

Surv Ophthalmol

A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration

Proc Natl Acad Sci U S A

Complement factor H polymorphism and age-related macular degeneration

Science

Complement factor H variant increases the risk of age-related macular degeneration

Science

Complement factor H polymorphism in age-related macular degeneration

Science

Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration

JAMA

Gene-environment interaction in progression of AMD: the CFH gene, smoking and exposure to chronic infection

Hum Mol Genet

Association between C-reactive protein and age-related macular degeneration

JAMA

Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration

JAMA

Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid

Proc Natl Acad Sci U S A

C-reactive protein level and risk of aging macula disorder: the Rotterdam Study

Arch Ophthalmol

High-sensitivity C-reactive protein, other markers of inflammation, and the incidence of macular degeneration in women

Arch Ophthalmol

Comprehensive analysis of CRP, CFH Y402H and environmental risk factors on risk of neovascular age-related macular degeneration

Mol Vis [serial online]

Progression of age-related macular degeneration: prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers

Arch Ophthalmol

Original article
C-Reactive Protein Levels and Complement Factor H Polymorphism Interaction in Age-related Macular Degeneration and Its Progression