Association of CRP levels with ARMS2 and CFH variants in age-related macular degeneration

Shijo, Taiyo; Sakurada, Yoichi; Fukuda, Yoshiko; Yoneyama, Seigo; Sugiyama, Atsushi; Matsubara, Mio; Kikushima, Wataru; Tanabe, Naohiko; Parikh, Ravi; Kashiwagi, Kenji

doi:10.1007/s10792-020-01460-y

Cited by 11 publications

(8 citation statements)

References 18 publications

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“…Both have been highly associated with increased AMD risk [ 95 , 223 , 305 , 308 , 309 , 315 , 316 , 317 ] and a younger onset of the disease [ 304 ]. ARMS2 rs10490924 is correlated with elevated C-reactive protein levels [ 318 ], suggesting an inflammatory mechanism at play. Interestingly, while the ARMS2 rs10490924 G allele is associated with an increased risk of progression to advanced stages of disease [ 296 ], the G allele is also associated with a higher likelihood of MNV response to anti-VEGF therapy in patients who have progressed to neovascular disease [ 98 , 317 , 319 , 320 , 321 , 322 ], particularly in East Asian populations [ 321 ].…”

Section: Genes Implicated In Multiple Pathwaysmentioning

confidence: 99%

Molecular Genetic Mechanisms in Age-Related Macular Degeneration

Shughoury

Sevgi

Ciulla

2022

Genes

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Age-related macular degeneration (AMD) is among the leading causes of irreversible blindness worldwide. In addition to environmental risk factors, such as tobacco use and diet, genetic background has long been established as a major risk factor for the development of AMD. However, our ability to predict disease risk and personalize treatment remains limited by our nascent understanding of the molecular mechanisms underlying AMD pathogenesis. Research into the molecular genetics of AMD over the past two decades has uncovered 52 independent gene variants and 34 independent loci that are implicated in the development of AMD, accounting for over half of the genetic risk. This research has helped delineate at least five major pathways that may be disrupted in the pathogenesis of AMD: the complement system, extracellular matrix remodeling, lipid metabolism, angiogenesis, and oxidative stress response. This review surveys our current understanding of each of these disease mechanisms, in turn, along with their associated pathogenic gene variants. Continued research into the molecular genetics of AMD holds great promise for the development of precision-targeted, personalized therapies that bring us closer to a cure for this debilitating disease.

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Section: Genes Implicated In Multiple Pathwaysmentioning

confidence: 99%

Molecular Genetic Mechanisms in Age-Related Macular Degeneration

Shughoury

Sevgi

Ciulla

2022

Genes

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“…Age-related macular degeneration (AMD), the leading cause of moderate and severe irreversible vision loss in people over 50 years of age worldwide, is a chronic inflammatory disease with a multifactorial etiology including the combined effects of multiple genes and environmental factors [ 1 , 2 ]. Of the implicated genetic factors, variants of ARMS2 and CFH are major contributors to AMD pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Association between Polygenic Risk Score and One-Year Outcomes Following As-Needed Aflibercept Therapy for Exudative Age-Related Macular Degeneration

et al. 2020

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We investigated whether polygenic risk score (PRS) was associated with one-year outcome of as-needed aflibercept therapy for exudative age-related macular degeneration (AMD), including AMD (n = 129) and polypoidal choroidal vasculopathy (n = 132). A total of 261 patients were treated with as-needed intravitreal aflibercept injection (IAI) after three monthly IAIs and the completion of a one-year follow-up. One hundred and seventy-two healthy volunteers served as controls. Genotyping of ARMS2 A69S (rs10490924), CFH I62V (rs800292), SKIV2L-C2-CFB (rs429608), C3 (rs2241394), ADAMTS-9 (rs6795735) and CETP (rs3764261) was performed for all participants. A total of 63 PRSs were quantified. There was a positive association between the PRS involving ARMS2, CFH, C3, and ADAMTS-9 and best-corrected visual acuity at twelve months (p = 0.046, multiple regression analysis). When comparing PRSs of patients requiring retreatment and of patients without retreatment, 35 PRSs were significantly greater in patients requiring retreatment than in patients without requiring retreatment, with the PRS involving ARMS2 and CFH being most significantly associated (p = 1.6 × 10−4). The number of additional injections was significantly associated with 40 PRSs and the PRS involving ARMS2 and CFH showed a most significant p-value (p = 2.42 × 10−6). Constructing a PRS using a combination with high-risk variants might be informative for predicting the response to IAI for exudative AMD.

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“…Plasma samples from individuals with exudative AMD have higher CRP levels than samples from controls, independent of ARMS2 and CFH genotype status. 54 Therefore, investigations of other members and ligands of the complement pathway should be performed for CFH P503A to determine if there are broader effects of the risk allele independent of CFH expression.…”

Section: Discussionmentioning

confidence: 99%

Consequences of a Rare Complement Factor H Variant for Age-Related Macular Degeneration in the Amish

Waksmunski

Miskimen

Song

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose Genetic variants in the complement factor H gene ( CFH ) have been consistently implicated in age-related macular degeneration (AMD) risk. However, their functional effects are not fully characterized. We previously identified a rare, AMD-associated variant in CFH (P503A, rs570523689) in 19 Amish individuals, but its functional consequences were not investigated. Methods We performed genotyping for CFH P503A in 1326 Amish individuals to identify additional risk allele carriers. We examined differences for age at AMD diagnosis between carriers and noncarriers. In blood samples from risk allele carriers and noncarriers, we quantified (i) CFH RNA expression, (ii) CFH protein expression, and (iii) C-reactive protein (CRP) expression. Potential changes to the CFH protein structure were interrogated computationally with Phyre 2 and Chimera software programs. Results We identified 39 additional carriers from Amish communities in Ohio and Indiana. On average, carriers were younger than noncarriers at AMD diagnosis, but this difference was not significant. CFH transcript and protein levels in blood samples from Amish carriers and noncarriers were also not significantly different. CRP levels were also comparable in plasma samples from carriers and noncarriers. Computational protein modeling showed slight changes in the CFH protein conformation that were predicted to alter interactions between the CFH 503 residue and other neighboring residues. Conclusions In total, we have identified 58 risk allele carriers for CFH P503A in the Ohio and Indiana Amish. Although we did not detect significant differences in age at AMD diagnosis or expression levels of CFH in blood samples from carriers and noncarriers, we observed modest structural changes to the CFH protein through in silico modeling. Based on our functional and computational observations, we hypothesize that CFH P503A may affect CFH binding or function rather than expression, which would require additional research to confirm.

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Association of CRP levels with ARMS2 and CFH variants in age-related macular degeneration

Cited by 11 publications

References 18 publications

Molecular Genetic Mechanisms in Age-Related Macular Degeneration

Molecular Genetic Mechanisms in Age-Related Macular Degeneration

Association between Polygenic Risk Score and One-Year Outcomes Following As-Needed Aflibercept Therapy for Exudative Age-Related Macular Degeneration

Consequences of a Rare Complement Factor H Variant for Age-Related Macular Degeneration in the Amish

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