Personalised management of Age Related Macular Degeneration by identification of high risk genetic variants in complement factor I.

通过识别补体因子 I 中的高风险遗传变异对年龄相关性黄斑变性进行个性化管理。

• 批准号: 1786288
• 金额: --
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1786288
• 关键词: Personalised; management; Age; Related; Macular

Keywords: Tissue disease & degenerationAbstract: Age related macular degeneration (AMD) is the most common cause of blindness in the developed world, affecting one in three people by age 75. A genetic role in the pathogenesis of AMD had been suggested by familial aggregation, segregation, linkage, and twin studies. In 2005 several land mark Genome Wide Association studies identified a genetic loci linked to AMD, including a major loci in the complement factor H (CFH) gene on 1q32. Factor H (FH), in concert with Factor I (FI) are the principle regulators of the "always switched on" alternative pathway of complement. Further evidence for the central role of the complement system in AMD has come to light via many additional studies of genes in the complement pathway and through animal modelling, such as the aged cfh+/- mice. Most known genetic AMD variants are common single nucleotide polymorphisms, without established disease mechanisms. Recently, with our collaborators (Seddon, Atkinson) we sequenced the exons of 681 genes within AMD-associated loci and pathways in ~2500 AMD cases and controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (OR=3.6, p=2x10-8) (Nat Genet 45:1366).To evaluate the functional impact we measured circulating serum factor I (FI) protein levels in individuals with and without rare CFI variants. In individuals with CFI variants which resulted in decreased FI levels, there was an increased risk of AMD (OR13.6) (Hum Mol Genet, 24:386). Enhancing FI activity may be therapeutic and measuring FI provides a screening tool for identifying patients who are most likely to benefit from complement inhibitory therapy.However, 58% of the rare genetic variants we identified in the AMD population were not associated with low FI levels and their functional significance is as yet unclear. It is critical to establish whether these rare genetic variants are functionally significant and therefore whether these individuals would benefit from FI supplementation. This project will examine the functional significance of these rare variants.

保留字：组织疾病和变性摘要：年龄相关性黄斑变性（AMD）是发达国家最常见的致盲原因，到75岁时，三分之一的人会受到影响。家族聚集、分离、连锁和双生子研究表明，遗传在AMD的发病机制中起作用。在2005年，几项里程碑式的全基因组协会研究确定了与AMD相关的遗传基因座，包括补体因子H（CFH）基因1 q32上的主要基因座。因子H（FH）与因子I（FI）一起是补体的“始终开启”替代途径的主要调节剂。补体系统在AMD中的中心作用的进一步证据已经通过补体途径中的基因的许多额外研究和通过动物建模（例如老年cfh+/-小鼠）而被发现。大多数已知的遗传性AMD变体是常见的单核苷酸多态性，没有确定的疾病机制。最近，与我们的合作者（Seddon，Atkinson）一起，我们对约2500例AMD病例和对照中AMD相关位点和通路内的681个基因的外显子进行了测序。我们发现7.8%的AMD病例与2.3%的对照相比是罕见错义CFI变体的携带者（OR=3.6，p= 2x 10 -8）（Nat Genet 45：1366）。为了评估功能影响，我们测量了具有和不具有罕见CFI变体的个体中的循环血清因子I（FI）蛋白水平。在具有导致FI水平降低的CFI变体的个体中，存在AMD（OR 13.6）的增加的风险（CIMMol Genet，24：386）。增强FI活性可能是治疗性的，测量FI提供了一种筛选工具，用于识别最有可能从补体抑制疗法中获益的患者。然而，我们在AMD人群中发现的58%的罕见遗传变异与低FI水平无关，其功能意义尚不清楚。关键是要确定这些罕见的遗传变异是否具有功能意义，因此这些个体是否会从FI补充中受益。本项目将研究这些罕见变异的功能意义。

项目成果

The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade.

• DOI: 10.1093/hmg/ddab086
• 发表时间: 2021-06-17
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: McMahon O;Hallam TM;Patel S;Harris CL;Menny A;Zelek WM;Widjajahakim R;Java A;Cox TE;Tzoumas N;Steel DHW;Shuttleworth VG;Smith-Jackson K;Brocklebank V;Griffiths H;Cree AJ;Atkinson JP;Lotery AJ;Bubeck D;Morgan BP;Marchbank KJ;Seddon JM;Kavanagh D
• 通讯作者: Kavanagh D

Functional Characterization of Rare Genetic Variants in the N-Terminus of Complement Factor H in aHUS, C3G, and AMD.

• DOI: 10.3389/fimmu.2020.602284
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Wong EKS;Hallam TM;Brocklebank V;Walsh PR;Smith-Jackson K;Shuttleworth VG;Cox TE;Anderson HE;Barlow PN;Marchbank KJ;Harris CL;Kavanagh D
• 通讯作者: Kavanagh D

Homodimeric Minimal Factor H: In Vivo Tracking and Extended Dosing Studies in Factor H Deficient Mice.

• DOI: 10.3389/fimmu.2021.752916
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Kamala O;Malik TH;Hallam TM;Cox TE;Yang Y;Vyas F;Luli S;Connelly C;Gibson B;Smith-Jackson K;Denton H;Pappworth IY;Huang L;Kavanagh D;Pickering MC;Marchbank KJ
• 通讯作者: Marchbank KJ