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Biochemical Markers in Ophthalmology
Published in Ching-Yu Cheng, Tien Yin Wong, Ophthalmic Epidemiology, 2022
Abdus Samad Ansari, Pirro G. Hysi
One of the landmark achievements in the field of genomic research was in the field of ophthalmology. The first successful GWAS led to the identification of associations between polymorphisms within the complement factor H (CFH) and AMD [17], symbolically marking the transition of genetics into the era of 21st-century genomic research. Although the study used a small number of cases and controls and a low-resolution SNP array, its success was sealed because the SNP rs1061170, coding for a tyrosine to histidine amino acid change in the complement factor H protein, conferred an unusually high risk of AMD (odds ratio [OR] = 7.4).
The nervous system and the eye
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
James A.R. Nicoll, William Stewart, Fiona Roberts
Age-related macular degeneration (ARMD) is the most important cause of untreatable visual loss in the ageing Western population. The pathogenesis is poorly understood but recent studies have implicated local inflammation and activation of complement among the processes involved. In particular, a specific polymorphism (Y402H) in the gene encoding complement factor H is strongly associated with disease susceptibility. The disease results in atrophy of photoreceptors at the macula and is accompanied by degenerative changes in the retinal pigment epithelium (RPE) (dry ARMD). This degeneration in the RPE may be complicated by haemorrhage and fibrosis (wet ARMD; disciform degeneration). The overlying photoreceptor tissue is destroyed with loss of central vision. Early disciform degeneration may now be successfully treated by intraocular injection of anti-VEGF antibodies.
Introduction: Biomedical innovation and policy in the twenty-first century
Published in Priya Hays, Advancing Healthcare Through Personalized Medicine, 2017
In 2005, the genetic etiology of age-related macular degeneration (AMD) was revealed through genome-wide association studies: a variant complement factor H responsible for AMD. Fast-forward to today, and thousands of variants have been found for chronic disease and complex traits, a stunning accomplishment and underpinning of disease, even if these results have been accompanied by a disappointing odds ratio of less than 2.
New findings in preventing recurrence and improving renal function in AHUS patients after renal transplantation treated with eculizumab: a systemic review and meta-analyses
Published in Renal Failure, 2023
Zhen Chun Tang, Huang Hui, Chunru Shi, Xiangmei Chen
Atypical hemolytic uremic syndrome (AHUS) is a rare, chronic multisystem disease that is life-threatening. The latest (2020) systematic review is the first to report the epidemiology of AHUS. The incidence of AHUS in the 20-year age group ranges from 0.26 to 0.75 per million population per year and 0.23 to 1.9 per million population for all age groups [1]. In the past, the prognosis of patients with AHUS was poor. Prior to the introduction of eculizumab, a majority of patients (over 50%) with this condition developed end-stage renal disease or succumbed to the illness within a year of initial diagnosis [2]. Inadequate complement regulation is thought to be a secondary cause of AHUS, and plasma therapy was once considered a potential contributing factor [3–7]. Although plasma infusion (PI) and plasma exchange (PEX) are sometimes used to treat AHUS, their efficacy is limited, and they may not prevent progression to end-stage renal disease [8]. Kidney transplantation therapy for AHUS patients is also not successful due to the high recurrence rate, especially for patients with complement Factor H (CFH) mutations. Bresin et al. reported a poor relapse rate of 85.7% after 1 year of organ transplantation [9], and the British and Italian registries reported almost equally poor results [10,11].
Clinical features of children with anti-CFH autoantibody-associated hemolytic uremic syndrome: a report of 8 cases
Published in Renal Failure, 2022
Qian Li, Xinxin Kong, Minle Tian, Jing Wang, Zhenle Yang, Lichun Yu, Suwen Liu, Cong Wang, Xiaoyuan Wang, Shuzhen Sun
Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) with three major clinical features: microvascular hemolytic anemia, acute kidney injury, and thrombocytopenia. HUS is divided into infection-related HUS, secondary HUS, and atypical HUS (aHUS) [1,2]. aHUS is mainly caused by abnormal complement replacement pathways, including hereditary and acquired complement functional defects. Complement factor H (CFH) is the main fluid phase regulator of the complement alternative pathway, and inherited defects and autoantibody formation in CFH are the two main pathogenic mechanisms that cause aHUS. Acquired complement functional defects mainly refer to anti-CFH autoantibody (Ab)-associated HUS. Anti-CFH Ab-associated HUS has serious clinical manifestations, with a mortality rate of up to 25%, and 20–29% of survivors progress to kidney failure; the recurrence rate of anti-CFH Ab-associated HUS is approximately 20–25% [3]. At present, immunosuppressive therapy is recognized internationally as an effective treatment [4], but there is no uniform standard for the selection and treatment protocol of immunosuppressive agents.
Anti-complement factor H (CFH) antibodies and a novel CFH gene mutation in an atypical hemolytic uremic syndrome patient with complement activation of the classical pathway
Published in Immunological Medicine, 2021
Sonoko Minato, Hiroyuki Iijima, Hiro Nakao, Kentaro Nishi, Yoshihiko Hidaka, Norimitsu Inoue, Mitsuru Kubota, Akira Ishiguro
Several causative genetic variants for aHUS have been identified. Approximately 50% of aHUS patients have loss-of-function variants in complement regulatory genes (CFH, MCP, CFI) or gain-of-function variants of complement factors (C3, CFB). In our patient, a single novel missense mutation, p.Glu1172Ala in the CFH gene, was found in a heterozygous state. No other mutations were found in complement genes. The majority of the reported CFH mutations are heterozygous likely pathogenic variants [9]. Previous reports have shown that only 9.2% of aHUS patients with CFH mutation carried abnormalities in other complement genes, suggesting that a mutation in the CFH gene alone may be sufficient to cause aHUS [9]. In addition, in silico analysis algorithms suggested the pathogenicity of the mutation. This mutation (exon 22 of CFH gene) is located in the major functional region C-terminal SCR 20, which is the recognition region and binding sites for the surface of endothelial cells. The exon 20–22 of the CFH gene is known as a hotspot for mutations in aHUS [10]. Therefore, the heterozygous CFH mutation in our case may be a cause of aHUS. Further studies are needed to elucidate this association.