Abstract
• Purpose: To compare plasma levels of oxidative stress biomarkers in patients with age-related macular degeneration (AMD) and controls and to evaluate a potential relationship between biochemical markers of oxidative stress and AMD susceptibility genotypes. • Design: Prospective case-control study. • Methods: Plasma levels of oxidative stress biomarkers were determined in 77 AMD patients and 75 controls recruited from a clinical practice. Cysteine, cystine (CySS), glutathione, isoprostane, and isofuran were measured, and participants were genotyped for polymorphisms in the complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genes. • Results: CySS was elevated in cases compared with controls (P =.013). After adjustment for age, sex, and smoking, this association was not significant. In all participants, CySS levels were associated with the CFH polymorphism rs3753394 (P =.028) as well as an 8-allele CFH haplotype (P =.029) after correction for age, gender, and smoking. None of the other plasma markers was related to AMD status in our cohort. • Conclusions: Our investigation of the geneenvironment interaction involved in AMD revealed a relationship between a plasma biomarker of oxidative stress, CySS, and CFH genotype. These data suggest a potential association between inflammatory regulators and redox status in AMD pathogenesis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 460-467.e1 |
| Journal | American Journal of Ophthalmology |
| Volume | 153 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2012 |
| Externally published | Yes |
ASJC Scopus subject areas
- Ophthalmology
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In: American Journal of Ophthalmology, Vol. 153, No. 3, 03.2012, p. 460-467.e1.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Plasma biomarkers of oxidative stress and genetic variants in age-related macular degeneration
AU - Brantley, Milam A.
AU - Osborn, Melissa P.
AU - Sanders, Barton J.
AU - Rezaei, Kasra A.
AU - Lu, Pengcheng
AU - Li, Chun
AU - Milne, Ginger L.
AU - Cai, Jiyang
AU - Sternberg, Paul
N1 - Funding Information: The results of the present study support the hypothesis that increased oxidative stress contributes to AMD. It seems that there is a relationship between this oxidative stress and innate immunity and inflammation, although the exact mechanism of this interaction remains to be defined. The detected association between plasma CySS and AMD suggests that the Cys/CySS pool is involved in AMD or linked with established AMD risk factors. Maintaining a physiologic Cys/CySS redox state is critical to proper cellular function, and oxidation of extracellular Cys/CySS has been shown to influence RPE vitality directly. 49 Interestingly, evaluation of plasma CySS levels in patients with AMD of varying severities revealed significant associations for neovascular and advanced AMD patients, but not for intermediate AMD patients, suggesting that the detected association between CySS and AMD is driven largely by the patients with advanced AMD. In this study, the difference in plasma CySS levels between AMD patients and controls was no longer significant after adjusting for age alone ( P = .130), and a positive linear correlation was observed between CySS levels and age ( P < .001), indicating that plasma CySS levels may be more related to aging than to AMD. In our cohort, plasma thiol metabolites or lipid peroxidation products alone were not sufficient biomarkers for identifying individuals at risk for AMD. The relationship between plasma CySS and CFH genotype seen in this study supports a link between oxidative stress and inflammation in AMD. Immunologic and inflammatory processes (eg, drusen formation, complement activation) have been linked independently to AMD pathogenesis. 39 To date, the most compelling evidence for genetic effects on AMD susceptibility have been demonstrated for complement genes, including CFH , complement factor B ( BF )/complement component 2 ( C2 ), complement component 3 ( C3 ), complement factor I ( CFI ), complement factor H-related 1( CFHR1 ), and complement factor H-related 3 ( CFHR3 ). 25–28,33–38 Furthermore, the complex interaction between oxidative stress and inflammation has been implicated in AMD pathogenesis by recent RPE cell culture and animal studies. 40–42 The CySS-associated SNP in this study, rs3753394, is a C-to-T polymorphism near the 5′ region of the CFH gene. This SNP previously was associated with neovascular AMD or polypoidal choroidal vasculopathy in Chinese and Japanese study populations. 50–55 The CySS-associated haplotype identified in this study seems to be driven largely by the effects of this SNP (rs3753394). Our findings add to the body of work demonstrating interactions between plasma biomarkers of AMD and AMD risk genotypes. Specifically, elevated plasma levels of the inflammatory marker C-reactive protein in combination with the CFH Y402H risk genotype conferred an additive risk of developing AMD. 56 Also, increased plasma markers of carboxyethylpyrrole, a product of lipid peroxidation, were associated with AMD-associated risk genotypes in ARMS2 and HTRA1. 7 The potential association of IsoPs and IsoFs with AMD seemed plausible, because the retina–RPE complex is highly vulnerable to oxidative damage by radical-catalyzed lipid peroxidation. 2,23,57 Altered levels of these lipid peroxidation products have been associated with a range of human diseases, including other neurodegenerative diseases such as Parkinson and Alzheimer disease. 20,21,23,24,58,59 Although mean plasma IsoF levels were 47% greater in AMD patients (0.22 ng/mL) compared with controls (0.15 ng/mL) in our study population, this difference was not significant given the high variation among individuals ( P = .087, Wilcoxon rank sum test). In contrast, the isoprostane measurements clearly were unaffected by AMD status (0.051 ng/mL in AMD patients and 0.059 ng/mL in controls; P = .372 by t test and P = .850 by Wilcoxon rank sum test). The observed trend of increased IsoFs (but not IsoPs) in AMD patients suggests a possible role for oxygen tension in AMD pathogenesis. We found no linear correlation between CySS and IsoF levels in the study cohort ( R 2 = 0.01), indicating that any contribution of IsoF and CySS to AMD risk likely act by independent mechanisms. This study was limited by its sample size. Because plasma biomarker levels often vary considerably among normal individuals, it is challenging to obtain enough power to identify small but clinically significant differences between cases and controls. Future longitudinal studies comparing biomarker levels in the same individuals at different time points may minimize variation in biomarker levels and may yield interesting results. The sample size also limited the power of the SNP analysis. We did not correct for multiple comparisons because it would have been difficult to achieve an accurate correction given the various levels of correlation among SNPs. The calculated effect size for variant alleles in rs3753394 suggests that the influence of this genetic variant on plasma CySS levels may be clinically meaningful. In conclusion, it seems that these biomarkers may be associated more closely with AMD risk factors than with AMD itself. We previously reported that long-term zinc supplementation decreased plasma CySS levels in a subset of the AREDS study population. 60 The results of this study suggest that the positive response of AMD patients to zinc treatment may be the result of offsetting increased oxidative stress caused by aging. Additionally, our investigation of the gene–environment interaction involved in AMD revealed a relationship between a blood plasma biomarker of redox status, CySS, and CFH genotype. These data suggest a potential relationship between inflammatory regulators and the role of redox status in the pathogenesis of AMD and should be added to the body of evidence linking oxidative stress and inflammation to AMD. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest, and none were reported. Publication of this article was supported by Grants EY007892 (P.S.), P30 EY08126 , and P30 ES000267 (G.L.M.) from the National Institutes of Health , Bethesda, Maryland; the Jahnigen Career Development Award from the American Geriatrics Society, New York, New York (M.A.B.); the Carl M. & Mildred A. Reeves Foundation, Columbus, Indiana (M.A.B.); and an unrestricted departmental grant from Research to Prevent Blindness, Inc , New York, New York. Involved in Study design and conduct (M.A.B., J.C., P.S.); Data collection (B.J.S., K.A.R., G.L.M., J.C.); Data management, analysis, and interpretation (M.A.B., M.P.O., P.L., C.L., G.L.M., J.C., P.S.); Manuscript preparation (M.A.B., M.P.O., J.C., P.S.); and Manuscript review and approval (M.A.B., M.P.O., B.J.S., K.A.R., P.L., C.L., G.L.M., J.C., P.S.). All procedures were approved prospectively by the local institutional review board, the Vanderbilt University Human Research Protection Program. Research adhered to the tenets of the Declaration of Helsinki and was conducted in accordance with Health Insurance Portability and Accountability Act regulations. Informed consent was obtained from all participants on study enrollment. The authors thank the staff of the Eicosanoid Core Laboratory for the measurements of isoprostanes and isofurans, as well as Jonathan Haines, Jeffrey Canter, and the DNA Resources Core of the Center for Human Genetics Research at Vanderbilt University for assistance with genotyping. Milam A. Brantley Jr is an Assistant Professor and Director of the Center for Ocular Pharmacogenomics at the Vanderbilt Eye Institute, Nashville, Tennessee. He earned a BA from Austin College, Sherman, Texas, and an MD/PhD in Molecular and Human Genetics from Baylor College of Medicine, Houston, Texas. He completed his Ophthalmology training at Washington University School of Medicine, St. Louis, Missouri, and Moorfields Eye Hospital, London, United Kingdom. His clinical specialty is inherited retinal diseases, and his research investigates how genetics influences disease susceptibility and response to treatment.
PY - 2012/3
Y1 - 2012/3
N2 - • Purpose: To compare plasma levels of oxidative stress biomarkers in patients with age-related macular degeneration (AMD) and controls and to evaluate a potential relationship between biochemical markers of oxidative stress and AMD susceptibility genotypes. • Design: Prospective case-control study. • Methods: Plasma levels of oxidative stress biomarkers were determined in 77 AMD patients and 75 controls recruited from a clinical practice. Cysteine, cystine (CySS), glutathione, isoprostane, and isofuran were measured, and participants were genotyped for polymorphisms in the complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genes. • Results: CySS was elevated in cases compared with controls (P =.013). After adjustment for age, sex, and smoking, this association was not significant. In all participants, CySS levels were associated with the CFH polymorphism rs3753394 (P =.028) as well as an 8-allele CFH haplotype (P =.029) after correction for age, gender, and smoking. None of the other plasma markers was related to AMD status in our cohort. • Conclusions: Our investigation of the geneenvironment interaction involved in AMD revealed a relationship between a plasma biomarker of oxidative stress, CySS, and CFH genotype. These data suggest a potential association between inflammatory regulators and redox status in AMD pathogenesis.
AB - • Purpose: To compare plasma levels of oxidative stress biomarkers in patients with age-related macular degeneration (AMD) and controls and to evaluate a potential relationship between biochemical markers of oxidative stress and AMD susceptibility genotypes. • Design: Prospective case-control study. • Methods: Plasma levels of oxidative stress biomarkers were determined in 77 AMD patients and 75 controls recruited from a clinical practice. Cysteine, cystine (CySS), glutathione, isoprostane, and isofuran were measured, and participants were genotyped for polymorphisms in the complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genes. • Results: CySS was elevated in cases compared with controls (P =.013). After adjustment for age, sex, and smoking, this association was not significant. In all participants, CySS levels were associated with the CFH polymorphism rs3753394 (P =.028) as well as an 8-allele CFH haplotype (P =.029) after correction for age, gender, and smoking. None of the other plasma markers was related to AMD status in our cohort. • Conclusions: Our investigation of the geneenvironment interaction involved in AMD revealed a relationship between a plasma biomarker of oxidative stress, CySS, and CFH genotype. These data suggest a potential association between inflammatory regulators and redox status in AMD pathogenesis.
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U2 - 10.1016/j.ajo.2011.08.033
DO - 10.1016/j.ajo.2011.08.033
M3 - Article
C2 - 22035603
AN - SCOPUS:84857456680
SN - 0002-9394
VL - 153
SP - 460-467.e1
JO - American Journal of Ophthalmology
JF - American Journal of Ophthalmology
IS - 3
ER -