Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration

Morad Ansari, Paul M. Mckeigue, Christine Skerka, Caroline Hayward, Igor Rudan, Veronique Vitart, Ozren Polasek, Ana-Maria Armbrecht, John R.W. Yates, Zoran Vatavuk, Goran Bencic, Ivana Kolcic, Ben A. Oostra, Cornelia M. Van Duijn, Susan Campbell, Chloe M. Stanton, Jennifer Huffman, Xinhua Shu, Jane C. Khan, Humma ShahidSimon P. Harding, Paul N. Bishop, Ian J. Deary, Anthony T. Moore, Baljean Dhillon, Pavao Rudan, Peter F. Zipfel, Robert B. Sim, Nicholas D. Hastie, Harry Campbell, Alan F. Wright

Research output: Contribution to journalArticle

Abstract

It is a longstanding puzzle why non-coding variants in the complement factor H (CFH) gene are more strongly associated with age-related macular degeneration (AMD) than functional coding variants that directly influence the alternative complement pathway. The situation is complicated by tight genetic associations across the region, including the adjacent CFH-related genes CFHR3 and CFHR1, which may themselves influence the alternative complement pathway and are contained within a common deletion (CNP147) which is associated with protection against AMD. It is unclear whether this association is mediated through a protective effect of low plasma CFHR1 concentrations, high plasma CFH or both. We examined the triangular relationships of CFH/CFHR3/CFHR1 genotype, plasma CFH or CFHR1 concentrations and AMD susceptibility in combined case–control (1256 cases, 1020 controls) and cross-sectional population (n = 1004) studies and carried out genome-wide association studies of plasma CFH and CFHR1 concentrations. A non-coding CFH SNP (rs6677604) and the CNP147 deletion were strongly correlated both with each other and with plasma CFH and CFHR1 concentrations. The plasma CFH-raising rs6677604 allele and raised plasma CFH concentration were each associated with AMD protection. In contrast, the protective association of the CNP147 deletion with AMD was not mediated by low plasma CFHR1, since AMD-free controls showed increased plasma CFHR1 compared with cases, but it may be mediated by the association of CNP147 with raised plasma CFH concentration. The results are most consistent with a regulatory locus within a 32 kb region of the CFH gene, with a major effect on plasma CFH concentration and AMD susceptibility.
Original languageEnglish
Pages (from-to)4857-4869
Number of pages13
JournalHuman Molecular Genetics
Volume22
Issue number23
DOIs
Publication statusPublished - 19 Jul 2013

Fingerprint

Complement Factor H
Macular Degeneration
Alternative Complement Pathway
Genes
Genome-Wide Association Study
Single Nucleotide Polymorphism

Keywords

  • genotype
  • plasma
  • single nucleotide polymorphism
  • genetics
  • age-related macular degeneration

Cite this

Ansari, M., Mckeigue, P. M., Skerka, C., Hayward, C., Rudan, I., Vitart, V., ... Wright, A. F. (2013). Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration. Human Molecular Genetics, 22(23), 4857-4869. https://doi.org/10.1093/hmg/ddt336
Ansari, Morad ; Mckeigue, Paul M. ; Skerka, Christine ; Hayward, Caroline ; Rudan, Igor ; Vitart, Veronique ; Polasek, Ozren ; Armbrecht, Ana-Maria ; Yates, John R.W. ; Vatavuk, Zoran ; Bencic, Goran ; Kolcic, Ivana ; Oostra, Ben A. ; Van Duijn, Cornelia M. ; Campbell, Susan ; Stanton, Chloe M. ; Huffman, Jennifer ; Shu, Xinhua ; Khan, Jane C. ; Shahid, Humma ; Harding, Simon P. ; Bishop, Paul N. ; Deary, Ian J. ; Moore, Anthony T. ; Dhillon, Baljean ; Rudan, Pavao ; Zipfel, Peter F. ; Sim, Robert B. ; Hastie, Nicholas D. ; Campbell, Harry ; Wright, Alan F. . / Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 23. pp. 4857-4869.
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abstract = "It is a longstanding puzzle why non-coding variants in the complement factor H (CFH) gene are more strongly associated with age-related macular degeneration (AMD) than functional coding variants that directly influence the alternative complement pathway. The situation is complicated by tight genetic associations across the region, including the adjacent CFH-related genes CFHR3 and CFHR1, which may themselves influence the alternative complement pathway and are contained within a common deletion (CNP147) which is associated with protection against AMD. It is unclear whether this association is mediated through a protective effect of low plasma CFHR1 concentrations, high plasma CFH or both. We examined the triangular relationships of CFH/CFHR3/CFHR1 genotype, plasma CFH or CFHR1 concentrations and AMD susceptibility in combined case–control (1256 cases, 1020 controls) and cross-sectional population (n = 1004) studies and carried out genome-wide association studies of plasma CFH and CFHR1 concentrations. A non-coding CFH SNP (rs6677604) and the CNP147 deletion were strongly correlated both with each other and with plasma CFH and CFHR1 concentrations. The plasma CFH-raising rs6677604 allele and raised plasma CFH concentration were each associated with AMD protection. In contrast, the protective association of the CNP147 deletion with AMD was not mediated by low plasma CFHR1, since AMD-free controls showed increased plasma CFHR1 compared with cases, but it may be mediated by the association of CNP147 with raised plasma CFH concentration. The results are most consistent with a regulatory locus within a 32 kb region of the CFH gene, with a major effect on plasma CFH concentration and AMD susceptibility.",
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Ansari, M, Mckeigue, PM, Skerka, C, Hayward, C, Rudan, I, Vitart, V, Polasek, O, Armbrecht, A-M, Yates, JRW, Vatavuk, Z, Bencic, G, Kolcic, I, Oostra, BA, Van Duijn, CM, Campbell, S, Stanton, CM, Huffman, J, Shu, X, Khan, JC, Shahid, H, Harding, SP, Bishop, PN, Deary, IJ, Moore, AT, Dhillon, B, Rudan, P, Zipfel, PF, Sim, RB, Hastie, ND, Campbell, H & Wright, AF 2013, 'Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration', Human Molecular Genetics, vol. 22, no. 23, pp. 4857-4869. https://doi.org/10.1093/hmg/ddt336

Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration. / Ansari, Morad; Mckeigue, Paul M.; Skerka, Christine ; Hayward, Caroline ; Rudan, Igor ; Vitart, Veronique ; Polasek, Ozren ; Armbrecht, Ana-Maria ; Yates, John R.W. ; Vatavuk, Zoran ; Bencic, Goran ; Kolcic, Ivana ; Oostra, Ben A. ; Van Duijn, Cornelia M. ; Campbell, Susan; Stanton, Chloe M. ; Huffman, Jennifer ; Shu, Xinhua; Khan, Jane C. ; Shahid, Humma ; Harding, Simon P. ; Bishop, Paul N. ; Deary, Ian J. ; Moore, Anthony T. ; Dhillon, Baljean ; Rudan, Pavao ; Zipfel, Peter F.; Sim, Robert B. ; Hastie, Nicholas D. ; Campbell, Harry ; Wright, Alan F. .

In: Human Molecular Genetics, Vol. 22, No. 23, 19.07.2013, p. 4857-4869.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration

AU - Ansari, Morad

AU - Mckeigue, Paul M.

AU - Skerka, Christine

AU - Hayward, Caroline

AU - Rudan, Igor

AU - Vitart, Veronique

AU - Polasek, Ozren

AU - Armbrecht, Ana-Maria

AU - Yates, John R.W.

AU - Vatavuk, Zoran

AU - Bencic, Goran

AU - Kolcic, Ivana

AU - Oostra, Ben A.

AU - Van Duijn, Cornelia M.

AU - Campbell, Susan

AU - Stanton, Chloe M.

AU - Huffman, Jennifer

AU - Shu, Xinhua

AU - Khan, Jane C.

AU - Shahid, Humma

AU - Harding, Simon P.

AU - Bishop, Paul N.

AU - Deary, Ian J.

AU - Moore, Anthony T.

AU - Dhillon, Baljean

AU - Rudan, Pavao

AU - Zipfel, Peter F.

AU - Sim, Robert B.

AU - Hastie, Nicholas D.

AU - Campbell, Harry

AU - Wright, Alan F.

PY - 2013/7/19

Y1 - 2013/7/19

N2 - It is a longstanding puzzle why non-coding variants in the complement factor H (CFH) gene are more strongly associated with age-related macular degeneration (AMD) than functional coding variants that directly influence the alternative complement pathway. The situation is complicated by tight genetic associations across the region, including the adjacent CFH-related genes CFHR3 and CFHR1, which may themselves influence the alternative complement pathway and are contained within a common deletion (CNP147) which is associated with protection against AMD. It is unclear whether this association is mediated through a protective effect of low plasma CFHR1 concentrations, high plasma CFH or both. We examined the triangular relationships of CFH/CFHR3/CFHR1 genotype, plasma CFH or CFHR1 concentrations and AMD susceptibility in combined case–control (1256 cases, 1020 controls) and cross-sectional population (n = 1004) studies and carried out genome-wide association studies of plasma CFH and CFHR1 concentrations. A non-coding CFH SNP (rs6677604) and the CNP147 deletion were strongly correlated both with each other and with plasma CFH and CFHR1 concentrations. The plasma CFH-raising rs6677604 allele and raised plasma CFH concentration were each associated with AMD protection. In contrast, the protective association of the CNP147 deletion with AMD was not mediated by low plasma CFHR1, since AMD-free controls showed increased plasma CFHR1 compared with cases, but it may be mediated by the association of CNP147 with raised plasma CFH concentration. The results are most consistent with a regulatory locus within a 32 kb region of the CFH gene, with a major effect on plasma CFH concentration and AMD susceptibility.

AB - It is a longstanding puzzle why non-coding variants in the complement factor H (CFH) gene are more strongly associated with age-related macular degeneration (AMD) than functional coding variants that directly influence the alternative complement pathway. The situation is complicated by tight genetic associations across the region, including the adjacent CFH-related genes CFHR3 and CFHR1, which may themselves influence the alternative complement pathway and are contained within a common deletion (CNP147) which is associated with protection against AMD. It is unclear whether this association is mediated through a protective effect of low plasma CFHR1 concentrations, high plasma CFH or both. We examined the triangular relationships of CFH/CFHR3/CFHR1 genotype, plasma CFH or CFHR1 concentrations and AMD susceptibility in combined case–control (1256 cases, 1020 controls) and cross-sectional population (n = 1004) studies and carried out genome-wide association studies of plasma CFH and CFHR1 concentrations. A non-coding CFH SNP (rs6677604) and the CNP147 deletion were strongly correlated both with each other and with plasma CFH and CFHR1 concentrations. The plasma CFH-raising rs6677604 allele and raised plasma CFH concentration were each associated with AMD protection. In contrast, the protective association of the CNP147 deletion with AMD was not mediated by low plasma CFHR1, since AMD-free controls showed increased plasma CFHR1 compared with cases, but it may be mediated by the association of CNP147 with raised plasma CFH concentration. The results are most consistent with a regulatory locus within a 32 kb region of the CFH gene, with a major effect on plasma CFH concentration and AMD susceptibility.

KW - genotype

KW - plasma

KW - single nucleotide polymorphism

KW - genetics

KW - age-related macular degeneration

U2 - 10.1093/hmg/ddt336

DO - 10.1093/hmg/ddt336

M3 - Article

VL - 22

SP - 4857

EP - 4869

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

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