Association between genetic variation of complement C3 and the susceptibility to advanced age-related macular degeneration: a meta-analysis

Zhang, Jun; Li, Shuang; Hu, Shuqiong; Xiang, Yong‐Bing

doi:10.1186/s12886-018-0945-5

Cited by 19 publications

(19 citation statements)

References 60 publications

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“…The highest score of association was CFH (0.999), Harrison et al suggested the decreased heparin-binding affinity caused by the Y402H polymorphism (a common SNP in CFH gene) may recognize of SCR7 H402 , which may contribute to the pathogenesis of AMD [54]. C3 gene contains many SNPs, our previous meta and Zhang et al both detected some increased and decreased SNPs in AMD [19,55]. Wang et al performed a systematic analysis and suggested rs641153 in the CFB gene was a protective factor in advanced AMD both in Caucasians and Asians [17].…”

Section: Discussionmentioning

confidence: 70%

Complement family member CFI polymorphisms and AMD susceptibility from a comprehensive analysis

2020

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The complement factor I (CFI) gene polymorphisms have been reported to age-related macular degenerative (AMD) risk, nevertheless, above association is not consistent. We investigated a meta-analysis to evaluate the conclusions between CFI polymorphisms (rs10033900 and rs2285714) and AMD risk. An identification was covered with the PubMed and other databases through February 8, 2020. Odds ratios (OR) and 95% confidence intervals (CI) were used to assess the strength of associations. After a comprehensive search, 11 different articles (12 case–control studies for total AMD and 11 case–control studies about neovascular disease/geographic atrophy in AMD) were retrieved. Individuals carrying C-allele or CC genotype of rs10033900 polymorphism may have a decreased risk to be AMD disease. For example, there has a significantly decreased relationship between rs10033900 polymorphism and AMD both in the whole group, Caucasian population and population-based source of control. Moreover, a similar trend in subgroup of genotype method group by MALDI-TOF MS was detected. To classify the type of AMD in further, decreased association was also observed in both neovascular disease and geographic atrophy AMD. No association was found about rs2285714 polymorphism. Our present groundbreaking study suggests that the CFI rs10033900 polymorphism is potentially associated with the risk of AMD development.

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Section: Discussionmentioning

confidence: 70%

Complement family member CFI polymorphisms and AMD susceptibility from a comprehensive analysis

2020

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“…We found a variant of ADAMTS13 (rs2301612, missense) in 49 (51%) of patients, previously described in congenital TTP [ 42 ]. We also detected two missense risk factor variants, previously described in complement-related diseases: rs2230199 in C3 (21 patients) [ 43 ]; and rs800292 in CFH (34 patients) [ 44 ]. Among them, 31 (32%) patients had a combination of these characterized variants (18 in the discovery and 13 in the validation cohort).…”

Section: Resultsmentioning

confidence: 95%

Genetic justification of severe COVID-19 using a rigorous algorithm

Gavriilaki

Asteris

Touloumenidou

et al. 2021

Clinical Immunology

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Recent studies suggest excessive complement activation in severe coronavirus disease-19 (COVID-19). The latter shares common characteristics with complement-mediated thrombotic microangiopathy (TMA). We hypothesized that genetic susceptibility would be evident in patients with severe COVID-19 (similar to TMA) and associated with disease severity. We analyzed genetic and clinical data from 97 patients hospitalized for COVID-19. Through targeted next-generation-sequencing we found an ADAMTS13 variant in 49 patients, along with two risk factor variants ( C3 , 21 patients; CFH ,34 patients). 31 (32%) patients had a combination of these, which was independently associated with ICU hospitalization ( p = 0.022). Analysis of almost infinite variant combinations showed that patients with rs1042580 in thrombomodulin and without rs800292 in complement factor H did not require ICU hospitalization. We also observed gender differences in ADAMTS13 and complement-related variants. In light of encouraging results by complement inhibitors, our study highlights a patient population that might benefit from early initiation of specific treatment.

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“…C3 is the most abundant complement component, is involved in all three complement cascade pathways and certain single nucleotide polymorphisms are associated with higher risk of developing AMD [22,23,[50][51][52][53][54][55][56][57][58][59]. Furthermore, elevated plasma levels of C3 have been reported in AMD patients [27,28,60,61].…”

Section: Discussionmentioning

confidence: 99%

Acadesine suppresses TNF-α induced complement component 3 (C3), in retinal pigment epithelial (RPE) cells

et al. 2020

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Rationale Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness in the developed world. Aging, inflammation and complement dysregulation affecting the retinal pigment epithelium (RPE), are considered significant contributors in its pathogenesis and several evidences have linked tumor necrosis factor alpha (TNF-α) and complement component 3 (C3) with AMD. Acadesine, an analog of AMP and an AMP-activated protein kinase (AMPK) activator, has been shown to have cytoprotective effects in human clinical trials as well as having anti-inflammatory and anti-vascular exudative effects in animals. The purpose of this study was to evaluate if acadesine is able to suppress TNF-α induced C3 in RPE cells. Methods ARPE-19 and human primary RPE cells were cultured and allowed to grow to confluence. TNF-α was used for C3 induction in the presence or absence of acadesine. Small molecule inhibitors and siRNA were used to determine if acadesine exerts its effect via the extracellular or intracellular pathway and to evaluate the importance of AMPK for these effects. The expression level of C3 was determined by immunoblot analysis. Results Acadesine suppresses TNF-α induced C3 in a dose dependent manner. When we utilized the adenosine receptor inhibitor dipyridamole (DPY) along with acadesine, acadesine’s effects were abolished, indicating the necessity of acadesine to enter the cell in order to exert it’s action. However, pretreatment with 5-iodotubericidin (5-Iodo), an adenosine kinase (AK) inhibitor, didn’t prevent acadesine from decreasing TNF-α induced C3 expression suggesting that acadesine does not exert its effect through AMP conversion and subsequent activation of AMPK. Consistent with this, knockdown of AMPK α catalytic subunit did not affect the inhibitory effect of acadesine on TNF-α upregulation of C3. Conclusions Our results suggest that acadesine suppresses TNF-α induced C3, likely through an AMPK-independent pathway, and could have potential use in complement over activation diseases.

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Association between genetic variation of complement C3 and the susceptibility to advanced age-related macular degeneration: a meta-analysis

Cited by 19 publications

References 60 publications

Complement family member CFI polymorphisms and AMD susceptibility from a comprehensive analysis

Complement family member CFI polymorphisms and AMD susceptibility from a comprehensive analysis

Genetic justification of severe COVID-19 using a rigorous algorithm

Acadesine suppresses TNF-α induced complement component 3 (C3), in retinal pigment epithelial (RPE) cells

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