Scholarlink

<p>Age-related macular degeneration (AMD) is a prevalent cause of vision loss in the elderly with limited therapeutic options. A single chromosomal region around the complement factor H gene (<i>CFH</i>) is reported to explain nearly 25% of genetic AMD risk. Here, we used association testing, statistical finemapping and conditional analyses in 12,495 AMD cases and 461,686 controls to deconvolute four major <i>CFH</i> haplotypes that convey protection from AMD. We show that beyond <i>CFH</i>, two of these are explained by Finn-enriched frameshift and missense variants in the <i>CFH</i> modulator <i>CFHR5</i>. We demonstrate through a FinnGen sample recall study that <i>CFHR5</i> variant carriers exhibit dose-dependent reductions in serum levels of the <i>CFHR5</i> gene product FHR-5 and two functionally related proteins at the locus. Genetic reduction in FHR-5 correlates with higher complement activation capacity and a thicker retinal photoreceptor layer. Our results propose therapeutic downregulation of FHR-5 as promising to prevent or treat AMD.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Loss of CFHR5 function reduces the risk for age-related macular degeneration

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月1日

查看全文
  • Mary Pat Reeve,
  • Stephanie Loomis,
  • Eija Nissilä,
  • Thomas W. Soare,
  • Tobias Rausch,
  • Zhili Zheng,
  • Pietro DELLA BRIOTTA PAROLO,
  • Daniel Ben-Isvy,
  • Elias Aho,
  • Emilia Cesetti,
  • Yoko Okunuki,
  • Helen McLaughlin,
  • Johanna Mäkelä,
  • Mitja Kurki,
  • Michael E. Talkowski,
  • Jan O. Korbel,
  • Kip Connor,
  • Seppo Meri,
  • Mark J. Daly,
  • Heiko Runz

摘要

Age-related macular degeneration (AMD) is a prevalent cause of vision loss in the elderly with limited therapeutic options. A single chromosomal region around the complement factor H gene (CFH) is reported to explain nearly 25% of genetic AMD risk. Here, we used association testing, statistical finemapping and conditional analyses in 12,495 AMD cases and 461,686 controls to deconvolute four major CFH haplotypes that convey protection from AMD. We show that beyond CFH, two of these are explained by Finn-enriched frameshift and missense variants in the CFH modulator CFHR5. We demonstrate through a FinnGen sample recall study that CFHR5 variant carriers exhibit dose-dependent reductions in serum levels of the CFHR5 gene product FHR-5 and two functionally related proteins at the locus. Genetic reduction in FHR-5 correlates with higher complement activation capacity and a thicker retinal photoreceptor layer. Our results propose therapeutic downregulation of FHR-5 as promising to prevent or treat AMD.