Beyond Factor H: the impact of genetic risk variants for age-related macular degeneration on circulating Factor H-Like 1 and Factor H-Related protein levelsCitation formats

  • External authors:
  • Valentina Cipriani
  • Anna Tierney
  • John Griffiths
  • Verena Zuber
  • John R. W. Yates
  • Anthony T. Moore

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Beyond Factor H: the impact of genetic risk variants for age-related macular degeneration on circulating Factor H-Like 1 and Factor H-Related protein levels. / Cipriani, Valentina; Tierney, Anna; Griffiths, John; Zuber, Verena; Sergouniotis, Panos; Yates, John R. W. ; Moore, Anthony T.; Bishop, Paul; Clark, Simon; Unwin, Richard.

In: American Journal of Human Genetics, 13.07.2021.

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Cipriani, Valentina ; Tierney, Anna ; Griffiths, John ; Zuber, Verena ; Sergouniotis, Panos ; Yates, John R. W. ; Moore, Anthony T. ; Bishop, Paul ; Clark, Simon ; Unwin, Richard. / Beyond Factor H: the impact of genetic risk variants for age-related macular degeneration on circulating Factor H-Like 1 and Factor H-Related protein levels. In: American Journal of Human Genetics. 2021.

Bibtex

@article{5873222912464095b88eec163bede8cd,
title = "Beyond Factor H: the impact of genetic risk variants for age-related macular degeneration on circulating Factor H-Like 1 and Factor H-Related protein levels",
abstract = "Age-related macular degeneration (AMD) is a leading cause of vision loss, with a strong genetic susceptibility at the complement factor H (CFH) locus. This locus encodes a series of complement regulators: factor H (FH), a splice variant factor H-like 1 (FHL-1), and five factor H-related proteins (FHR-1 to FHR-5), all involved in the regulation of complement factor C3b turnover. Little is known about the influence of AMD associated variants at this locus on FHL- 1 and FHR protein levels. We have used a bespoke targeted mass spectrometry assay to measure the circulating levels of all seven complement regulators, and demonstrated elevated levels in 352 advanced AMD individuals for all FHR proteins (FHR-1, P=2.4x10-10; FHR-2, P=6.0x10-10; FHR-3, P=1.5x10-5; FHR-4, P=1.3x10-3; FHR-5, P=1.9x10-4) and FHL-1 (P=4.9x10-4) compared to 252 controls, while no difference was seen for FH (P=0.94). Genome-wide association analyses in controls revealed genome-wide significant signals at the CFH locus for all five FHR proteins, and univariate Mendelian randomization analyses strongly supported the association of FHR-1, FHR-2, FHR-4 and FHR-5 with AMD susceptibility. These findings provide a strong biochemical explanation for how geneticallydriven alterations in circulating FHR proteins could be major drivers of AMD and highlight the need for research into FHR protein modulation as a viable therapeutic avenue for AMD.",
author = "Valentina Cipriani and Anna Tierney and John Griffiths and Verena Zuber and Panos Sergouniotis and Yates, {John R. W.} and Moore, {Anthony T.} and Paul Bishop and Simon Clark and Richard Unwin",
year = "2021",
month = jul,
day = "13",
doi = "10.1016/j.ajhg.2021.05.015",
language = "English",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",

}

RIS

TY - JOUR

T1 - Beyond Factor H: the impact of genetic risk variants for age-related macular degeneration on circulating Factor H-Like 1 and Factor H-Related protein levels

AU - Cipriani, Valentina

AU - Tierney, Anna

AU - Griffiths, John

AU - Zuber, Verena

AU - Sergouniotis, Panos

AU - Yates, John R. W.

AU - Moore, Anthony T.

AU - Bishop, Paul

AU - Clark, Simon

AU - Unwin, Richard

PY - 2021/7/13

Y1 - 2021/7/13

N2 - Age-related macular degeneration (AMD) is a leading cause of vision loss, with a strong genetic susceptibility at the complement factor H (CFH) locus. This locus encodes a series of complement regulators: factor H (FH), a splice variant factor H-like 1 (FHL-1), and five factor H-related proteins (FHR-1 to FHR-5), all involved in the regulation of complement factor C3b turnover. Little is known about the influence of AMD associated variants at this locus on FHL- 1 and FHR protein levels. We have used a bespoke targeted mass spectrometry assay to measure the circulating levels of all seven complement regulators, and demonstrated elevated levels in 352 advanced AMD individuals for all FHR proteins (FHR-1, P=2.4x10-10; FHR-2, P=6.0x10-10; FHR-3, P=1.5x10-5; FHR-4, P=1.3x10-3; FHR-5, P=1.9x10-4) and FHL-1 (P=4.9x10-4) compared to 252 controls, while no difference was seen for FH (P=0.94). Genome-wide association analyses in controls revealed genome-wide significant signals at the CFH locus for all five FHR proteins, and univariate Mendelian randomization analyses strongly supported the association of FHR-1, FHR-2, FHR-4 and FHR-5 with AMD susceptibility. These findings provide a strong biochemical explanation for how geneticallydriven alterations in circulating FHR proteins could be major drivers of AMD and highlight the need for research into FHR protein modulation as a viable therapeutic avenue for AMD.

AB - Age-related macular degeneration (AMD) is a leading cause of vision loss, with a strong genetic susceptibility at the complement factor H (CFH) locus. This locus encodes a series of complement regulators: factor H (FH), a splice variant factor H-like 1 (FHL-1), and five factor H-related proteins (FHR-1 to FHR-5), all involved in the regulation of complement factor C3b turnover. Little is known about the influence of AMD associated variants at this locus on FHL- 1 and FHR protein levels. We have used a bespoke targeted mass spectrometry assay to measure the circulating levels of all seven complement regulators, and demonstrated elevated levels in 352 advanced AMD individuals for all FHR proteins (FHR-1, P=2.4x10-10; FHR-2, P=6.0x10-10; FHR-3, P=1.5x10-5; FHR-4, P=1.3x10-3; FHR-5, P=1.9x10-4) and FHL-1 (P=4.9x10-4) compared to 252 controls, while no difference was seen for FH (P=0.94). Genome-wide association analyses in controls revealed genome-wide significant signals at the CFH locus for all five FHR proteins, and univariate Mendelian randomization analyses strongly supported the association of FHR-1, FHR-2, FHR-4 and FHR-5 with AMD susceptibility. These findings provide a strong biochemical explanation for how geneticallydriven alterations in circulating FHR proteins could be major drivers of AMD and highlight the need for research into FHR protein modulation as a viable therapeutic avenue for AMD.

U2 - 10.1016/j.ajhg.2021.05.015

DO - 10.1016/j.ajhg.2021.05.015

M3 - Article

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

ER -