Association between complement factor H Val62Ile polymorphism and age-related macular degeneration susceptibility: A meta-analysis

Wang, Xin; Geng, Peiliang; Zhang, Ying; Zhang, Maonian

doi:10.1016/j.gene.2014.01.032

Cited by 5 publications

(5 citation statements)

References 35 publications

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“…Prevalence of the 402H risk variant varies across ethnicities [ 95 ], with an increased AMD risk of 2.5 times among heterozygous individuals and 6.0 times among homozygotes [ 96 ]. This finding was confirmed by pooled analysis in both Caucasians [ 95 ] and Asians [ 97 – 99 ]. A more recent meta-analysis stratified by stage of disease and ethnicity, including data of 27418 AMD patients and 32843 controls, stated that the polymorphism is significantly associated with AMD: in Caucasian the mutated allele confers a 1.44 risk of early AMD, a 2.90 risk of dry AMD and a 2.46 risk of wet AMD; in Asians, the mutated allele seems to be associated only with wet AMD [ 100 ].…”

Section: The Role Of Common Variants In the Pathogenesis And Treatmentioning

confidence: 53%

“…Conversely to this well-known genetic risk factor, the rs800292 polymorphism, a coding variant in the SCR1 domain, has been found to be protective against AMD in both Caucasians and Asians [ 99 , 102 ]. This polymorphism, which leads to an amino acid change at position 62 of the FH polypeptide (V62I), also conferred a better response to treatment of neovascular AMD [ 101 ].…”

Section: The Role Of Common Variants In the Pathogenesis And Treatmentioning

confidence: 99%

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Complement System and Age-Related Macular Degeneration: Implications of Gene-Environment Interaction for Preventive and Personalized Medicine

Maugeri

Barchitta

Mazzone³

et al. 2018

BioMed Research International

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Age-related macular degeneration (AMD) is the most common cause of visual loss in developed countries, with a significant economic and social burden on public health. Although genome-wide and gene-candidate studies have been enabled to identify genetic variants in the complement system associated with AMD pathogenesis, the effect of gene-environment interaction is still under debate. In this review we provide an overview of the role of complement system and its genetic variants in AMD, summarizing the consequences of the interaction between genetic and environmental risk factors on AMD onset, progression, and therapeutic response. Finally, we discuss the perspectives of current evidence in the field of genomics driven personalized medicine and public health.

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Section: The Role Of Common Variants In the Pathogenesis And Treatmentioning

confidence: 53%

Section: The Role Of Common Variants In the Pathogenesis And Treatmentioning

confidence: 99%

Complement System and Age-Related Macular Degeneration: Implications of Gene-Environment Interaction for Preventive and Personalized Medicine

Maugeri

Barchitta

Mazzone³

et al. 2018

BioMed Research International

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“…Consistent with the decreased sialylation, a significantly reduced binding of FH to platelets and leukocytes was observed in the proband. The proband did not show any rare or significant variants in the CFH gene encoding FH, including age-related macular degeneration (AMD) related polymorphisms (Val62Ile, Tyr402His and Glu936Asp) ( 35 – 37 ). Hence, the reduced FH binding was attributed to the decreased sialylation shown in platelets and leukocytes.…”

Section: Discussionmentioning

confidence: 97%

Severe Congenital Thrombocytopenia Characterized by Decreased Platelet Sialylation and Moderate Complement Activation Caused by Novel Compound Heterozygous Variants in GNE

et al. 2021

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BackgroundHereditary thrombocytopenias constitute a genetically heterogeneous cause of increased bleeding. We report a case of a 17-year-old boy suffering from severe macrothrombocytopenia throughout his life. Whole genome sequencing revealed the presence of two compound heterozygous variants in GNE encoding the enzyme UDP-N-acetyl-glucosamine-2-epimerase/N-acetylmannosamine kinase, crucial for sialic acid biosynthesis. Sialic acid is required for normal platelet life span, and biallelic variants in GNE have previously been associated with isolated macrothrombocytopenia. Furthermore, sialic acid constitutes a key ligand for complement factor H (FH), an important inhibitor of the complement system, protecting host cells from indiscriminate attack.MethodsSialic acid expression and FH binding to platelets and leukocytes was evaluated by flow cytometry. The binding of FH to erythrocytes was assessed indirectly by measuring the rate of complement mediated hemolysis. Complement activation was determined by measuring levels of C3bBbP (alternative pathway), C4d (classical/lectin pathway) and soluble terminal complement complex assays.ResultsThe proband exhibited markedly decreased expression of sialic acid on platelets and leukocytes. Consequently, the binding of FH was strongly reduced and moderate activation of the alternative and classical/lectin complement pathways was observed, together with an increased rate of erythrocyte lysis.ConclusionWe report two previously undescribed variants in GNE causing severe congenital macrothrombocytopenia in a compound heterozygous state, as a consequence of decreased platelet sialylation. The decreased sialylation of platelets, leukocytes and erythrocytes affects the binding of FH, leading to moderate complement activation and increased hemolysis.

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“…Furthermore, rare CFH mutations have been disclosed and they are presumed to create meaningful disease phenotype features and earlier onset disease [ 64 ]: rs121913059 [ 38 ] shows increased risk regardless of the common variants. Additionally, other frameshift variants were identified, also independently of CFH Tyr402His [ 65 , 66 , 67 ]. CFHI62V polymorphism is a protective haplotype [ 65 ].…”

Section: Resultsmentioning

confidence: 99%

Genetic Aspects of Age-Related Macular Degeneration and Their Therapeutic Potential

Stradiotto

Allegrini

Fossati

et al. 2022

IJMS

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Age-related macular degeneration (AMD) is a complex and multifactorial disease, resulting from the interaction of environmental and genetic factors. The continuous discovery of associations between genetic polymorphisms and AMD gives reason for the pivotal role attributed to the genetic component to its development. In that light, genetic tests and polygenic scores have been created to predict the risk of development and response to therapy. Still, none of them have yet been validated. Furthermore, there is no evidence from a clinical trial that the determination of the individual genetic structure can improve treatment outcomes. In this comprehensive review, we summarize the polymorphisms of the main pathogenetic ways involved in AMD development to identify which of them constitutes a potential therapeutic target. As complement overactivation plays a major role, the modulation of targeted complement proteins seems to be a promising therapeutic approach. Herein, we summarize the complement-modulating molecules now undergoing clinical trials, enlightening those in an advanced phase of trial. Gene therapy is a potential innovative one-time treatment, and its relevance is quickly evolving in the field of retinal diseases. We describe the state of the art of gene therapies now undergoing clinical trials both in the field of complement-suppressors and that of anti-VEGF.

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Association between complement factor H Val62Ile polymorphism and age-related macular degeneration susceptibility: A meta-analysis

Cited by 5 publications

References 35 publications

Complement System and Age-Related Macular Degeneration: Implications of Gene-Environment Interaction for Preventive and Personalized Medicine

Complement System and Age-Related Macular Degeneration: Implications of Gene-Environment Interaction for Preventive and Personalized Medicine

Severe Congenital Thrombocytopenia Characterized by Decreased Platelet Sialylation and Moderate Complement Activation Caused by Novel Compound Heterozygous Variants in GNE

Genetic Aspects of Age-Related Macular Degeneration and Their Therapeutic Potential

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