Complement Factor H Polymorphism in Age-Related Macular Degeneration

Klein, Robert J.; Zeiss, Caroline J.; Chew, Emily Y.; Tsai, Jen-Yue; Sackler, Richard S.; Haynes, Chad; Henning, Alice K.; SanGiovanni, John Paul; Mane, Shrikant; Mayne, Susan T.; Bracken, Michael B.; Ferris, Frederick L.; Ott, Jürg; Barnstable, Colin J.; Hoh, Josephine

doi:10.1126/science.1109557

Cited by 3,948 publications

(2,754 citation statements)

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“…Recent evidence suggests that CFH may play a significant role in the pathogenesis of AMD. [8][9][10][11] CFH is a single polypeptide chain with a molecular weight of 155 kD that is present in the plasma at a concentration of 110-615 mg/ml. It is constitutively produced by the liver.…”

Section: Complement Factor Hmentioning

confidence: 99%

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The complement system and age-related macular degeneration

Sivaprasad

Chong

2006

Eye

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Purpose Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world. There are increasing evidences to suggest the complement system may play a significant role on the pathogenesis of AMD. In this review, we summarise the current research in this area. Methods Review of literature. Results The complement system is a complex system with several activation pathways. Complement factor H (CFH) polymorphisms has been associated with increase risk of AMD. CFH is an inhibitor protein; the polymorphisms might cause uncontrolled activation by initiation events. Conclusion Further studies on the molecular basis of the complement-mediated pathogenesis of AMD may offer novel therapy to AMD Eye (2006) 20, 867-872.

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Section: Complement Factor Hmentioning

confidence: 99%

“…6 Recent studies have also identified multiple genetic variants of Complement factor H (CFH), a regulator protein that can confer elevated risk of AMD. [8][9][10][11] The complement system…”

Section: Introductionmentioning

confidence: 99%

The complement system and age-related macular degeneration

Sivaprasad

Chong

2006

Eye

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“…The mutations are composed of a coding SNP (rs10490924) that produces the A69S mutation in the putative Age‐Related Maculopathy Susceptibility 2 (ARMS2) gene, an insertion–deletion del443ins54 that deletes the polyadenylation signal sequences of the RNA transcript, and the SNP, rs11200638, in the promoter of High Temperature Requirement A Serine Peptidase 1 ( HTRA1 ; Yang et al., 2006). The other major genetic locus linked to AMD is at chromosome 1q31, where a single nucleotide polymorphism (SNP) rs1061170 causes a missense mutation Y402H in complement factor H (CFH; Edwards et al., 2005; Klein et al., 2005; Hageman et al., 2005; Haines et al., 2005). These two genetic loci, 1q31 and 10q26, were the first to be identified in human GWAS, and they confer the most significant genetic risk of AMD alleles.…”

Section: Introductionmentioning

confidence: 99%

“…These two genetic loci, 1q31 and 10q26, were the first to be identified in human GWAS, and they confer the most significant genetic risk of AMD alleles. The initial cohort studies showed the risk of developing AMD was 4.6 times that of wild type among people heterozygous and 7.4 times increased for those homozygous for the CFH risk allele (Klein et al., 2005). Those heterozygous for the ARMS2/HTRA1 risk allele were at ~2.7 times greater risk of AMD, whereas homozygotes had 8.2 times increased risk (Rivera et al., 2005).…”

Section: Introductionmentioning

confidence: 99%

HTRA1, an age‐related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1

et al. 2018

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SummaryHigh‐temperature requirement protein A1 (HTRA1) is a serine protease secreted by a number of tissues including retinal pigment epithelium (RPE). A promoter variant of the gene encoding HTRA1 is part of a mutant allele that causes increased HTRA1 expression and contributed to age‐related macular degeneration (AMD) in genomewide association studies. AMD is characterized by pathological development of drusen, extracellular deposits of proteins and lipids on the basal side of RPE. The molecular pathogenesis of AMD is not well understood, and understanding dysregulation of the extracellular matrix may be key. We assess the high‐risk genotype at 10q26 by proteomic comparison of protein levels of RPE cells with and without the mutation. We show HTRA1 protein level is increased in high‐risk RPE cells along with several extracellular matrix proteins, including known HTRA1 cleavage targets LTBP‐1 and clusterin. In addition, two novel targets of HTRA1 have been identified: EFEMP1, an extracellular matrix protein mutated in Doyne honeycomb retinal dystrophy, a genetic eye disease similar to AMD, and thrombospondin 1 (TSP1), an inhibitor of angiogenesis. Our data support the role of RPE extracellular deposition with potential effects in compromised barrier to neovascularization in exudative AMD.

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“…Our understanding of the important role that genetic background plays in the pathogenesis of AMD was greatly enhanced in 2005, with several independent reports associating the complement factor H (CFH) gene, located on chromosome 1q31, with this disease (Edwards et al, 2005;Hageman et al, 2005;Haines et al, 2005;Klein et al, 2005). The strong association of the CFH Y402H variant allele with increased risk for AMD suggested an important role for the alternative complement pathway and the involvement of inflammation in the pathogenesis of AMD (Anderson et al, 2002;Hageman et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

The association between macular pigment optical density and CFH, ARMS2, C2/BF, and C3 genotype

Loane

Nolan

McKay

et al. 2011

Experimental Eye Research

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Keywords: age-related macular degeneration age-related maculopathy susceptibility 2 gene carotenoids Complement factor H lutein macular pigment zeaxanthin a b s t r a c t Age-related macular degeneration (AMD) is the most common cause of blindness in older people in developed countries, and risk for this condition may be classified as genetic or environmental, with an interaction between such factors predisposing to this disease. This study investigated the relationship between AMD risk genes, macular pigment optical density (MPOD), which may protect against AMD, and serum concentrations of the macular carotenoids, lutein (L) and zeaxanthin (Z). This was a cross-sectional study of 302 healthy adult subjects. Dietary intake of L and Z was assessed by food frequency questionnaire, and MPOD was measured by customized heterochromatic flicker photometry. We also calculated MPOD Area as the area of MP under the spatial profile curve, to reflect MP across the macula. Serum L and Z were measured by HPLC. Genotyping of tag SNPs in the genes CFH, ARMS2, C3, C2 and BF was undertaken with multiplex polymerase chain reaction (PCR) and primer extension methodology (ABI Snapshot, ABI Warrington UK) on DNA extracted from peripheral blood. The mean AE SD (range) age of the subjects in this study was 48 AE 11 (21e66) years. There was a statistically significant association between CFH genotype and family history of AMD, with subjects having two non-risk CFH haplotypes (n ¼ 35), or one non-risk and one protective CFH haplotype (n ¼ 33), being significantly more likely to have a negative family history of AMD (Pearson Chi square: p ¼ 0.001). There was no significant association between the AMD risk genes investigated and either MPOD (One way ANOVA: p > 0.05) or serum concentrations of L or Z (One way ANOVA: p > 0.05, for both). Subjects who were homozygous for risk alleles of both CFH and ARMS2 (n ¼ 4) had significantly lower MPOD at 0.5 and 1 retinal eccentricity (Independent samples t test: p < 0.05) and lower MPOD Area which approached statistical significance (Independent samples t test: p ¼ 0.058), compared to other subjects (n ¼ 291). In conclusion, this study did not detect an association between individual AMD risk genotypes and the putatively protective MP, or serum concentrations of its constituent carotenoids. However, the combination of homozygous risk alleles at both CFH and ARMS2 loci was associated with significantly lower MPOD centrally, despite comparable serum concentrations of the macular carotenoids. These findings suggest that the maculae of subjects at very high genetic risk of AMD represent a hostile environment for accumulation and/or stabilization of MP.

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Complement Factor H Polymorphism in Age-Related Macular Degeneration

Cited by 3,948 publications

References 30 publications

The complement system and age-related macular degeneration

The complement system and age-related macular degeneration

HTRA1, an age‐related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1

The association between macular pigment optical density and CFH, ARMS2, C2/BF, and C3 genotype

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