Contribution of copy number variation in the regulation of complement activation locus to development of age-related macular degeneration

Katharina E. Schmid-Kubista, Nirubol Tosakulwong, Yanhong Wu, Euijung Ryu, Laura A. Hecker, Keith Baratz, William L. Brown, Albert O. Edwards

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

PURPOSE. To develop an assay for determining the number of copies of the genes encoding complement factor H related 3 (CFHR3) and 1 (CFHR1) and determine the contribution of copy number variation (CNV) at CFHR3 and CFHR1 to the development of age-related macular degeneration (AMD). METHODS. A multiplex ligation-dependent probe amplification (MLPA) assay was developed to quantify the number of copies of CFHR3 and CFHR1 in humans. Subjects with (n = 252) and without (n = 249) AMD were genotyped using the assay, and the impact on AMD risk was evaluated. RESULTS. The MLPA assay provided a consistent estimate of the number of copies of CFHR3 and CFHR1 in 500 of the 501 samples. Four different combinations of CNVs were observed with frequencies as follows: both CFHR3 and CFHR1 deletion (14%), CFHR3-only deletion (0.4%), CFHR1-only deletion (1.1%), and CFHR1 duplication (0.1%). Deletion of both copies of CFHR3 and CFHR1 decreased the odds of having AMD eightfold (95% CI 2-36) and always occurred on a protective haplotype, never on the risk haplotype tagged by the Y402H risk allele in CFH. The protection conferred by deletion of CFHR3 and CFHR1 could not be distinguished from the absence of the risk haplotype. CONCLUSIONS. Both deletions and duplications of genes in the regulation of complement activation locus segregated in Caucasians. Deletion of CFHR3 and CFHR1 protected against the development of AMD at least in part because the deletion tagged a protective haplotype and did not occur on the riskhaplotype.

Original languageEnglish (US)
Pages (from-to)5070-5079
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Volume50
Issue number11
DOIs
StatePublished - Nov 1 2009

Fingerprint

Complement Factor H
Complement Activation
Macular Degeneration
Haplotypes
Multiplex Polymerase Chain Reaction
Gene Duplication
Gene Dosage
Gene Deletion
Alleles

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Contribution of copy number variation in the regulation of complement activation locus to development of age-related macular degeneration. / Schmid-Kubista, Katharina E.; Tosakulwong, Nirubol; Wu, Yanhong; Ryu, Euijung; Hecker, Laura A.; Baratz, Keith; Brown, William L.; Edwards, Albert O.

In: Investigative Ophthalmology and Visual Science, Vol. 50, No. 11, 01.11.2009, p. 5070-5079.

Research output: Contribution to journalArticle

Schmid-Kubista, Katharina E. ; Tosakulwong, Nirubol ; Wu, Yanhong ; Ryu, Euijung ; Hecker, Laura A. ; Baratz, Keith ; Brown, William L. ; Edwards, Albert O. / Contribution of copy number variation in the regulation of complement activation locus to development of age-related macular degeneration. In: Investigative Ophthalmology and Visual Science. 2009 ; Vol. 50, No. 11. pp. 5070-5079.
@article{e44c046672d94b0bbbba9e9e62aaba54,
title = "Contribution of copy number variation in the regulation of complement activation locus to development of age-related macular degeneration",
abstract = "PURPOSE. To develop an assay for determining the number of copies of the genes encoding complement factor H related 3 (CFHR3) and 1 (CFHR1) and determine the contribution of copy number variation (CNV) at CFHR3 and CFHR1 to the development of age-related macular degeneration (AMD). METHODS. A multiplex ligation-dependent probe amplification (MLPA) assay was developed to quantify the number of copies of CFHR3 and CFHR1 in humans. Subjects with (n = 252) and without (n = 249) AMD were genotyped using the assay, and the impact on AMD risk was evaluated. RESULTS. The MLPA assay provided a consistent estimate of the number of copies of CFHR3 and CFHR1 in 500 of the 501 samples. Four different combinations of CNVs were observed with frequencies as follows: both CFHR3 and CFHR1 deletion (14{\%}), CFHR3-only deletion (0.4{\%}), CFHR1-only deletion (1.1{\%}), and CFHR1 duplication (0.1{\%}). Deletion of both copies of CFHR3 and CFHR1 decreased the odds of having AMD eightfold (95{\%} CI 2-36) and always occurred on a protective haplotype, never on the risk haplotype tagged by the Y402H risk allele in CFH. The protection conferred by deletion of CFHR3 and CFHR1 could not be distinguished from the absence of the risk haplotype. CONCLUSIONS. Both deletions and duplications of genes in the regulation of complement activation locus segregated in Caucasians. Deletion of CFHR3 and CFHR1 protected against the development of AMD at least in part because the deletion tagged a protective haplotype and did not occur on the riskhaplotype.",
author = "Schmid-Kubista, {Katharina E.} and Nirubol Tosakulwong and Yanhong Wu and Euijung Ryu and Hecker, {Laura A.} and Keith Baratz and Brown, {William L.} and Edwards, {Albert O.}",
year = "2009",
month = "11",
day = "1",
doi = "10.1167/iovs.09-3975",
language = "English (US)",
volume = "50",
pages = "5070--5079",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "11",

}

TY - JOUR

T1 - Contribution of copy number variation in the regulation of complement activation locus to development of age-related macular degeneration

AU - Schmid-Kubista, Katharina E.

AU - Tosakulwong, Nirubol

AU - Wu, Yanhong

AU - Ryu, Euijung

AU - Hecker, Laura A.

AU - Baratz, Keith

AU - Brown, William L.

AU - Edwards, Albert O.

PY - 2009/11/1

Y1 - 2009/11/1

N2 - PURPOSE. To develop an assay for determining the number of copies of the genes encoding complement factor H related 3 (CFHR3) and 1 (CFHR1) and determine the contribution of copy number variation (CNV) at CFHR3 and CFHR1 to the development of age-related macular degeneration (AMD). METHODS. A multiplex ligation-dependent probe amplification (MLPA) assay was developed to quantify the number of copies of CFHR3 and CFHR1 in humans. Subjects with (n = 252) and without (n = 249) AMD were genotyped using the assay, and the impact on AMD risk was evaluated. RESULTS. The MLPA assay provided a consistent estimate of the number of copies of CFHR3 and CFHR1 in 500 of the 501 samples. Four different combinations of CNVs were observed with frequencies as follows: both CFHR3 and CFHR1 deletion (14%), CFHR3-only deletion (0.4%), CFHR1-only deletion (1.1%), and CFHR1 duplication (0.1%). Deletion of both copies of CFHR3 and CFHR1 decreased the odds of having AMD eightfold (95% CI 2-36) and always occurred on a protective haplotype, never on the risk haplotype tagged by the Y402H risk allele in CFH. The protection conferred by deletion of CFHR3 and CFHR1 could not be distinguished from the absence of the risk haplotype. CONCLUSIONS. Both deletions and duplications of genes in the regulation of complement activation locus segregated in Caucasians. Deletion of CFHR3 and CFHR1 protected against the development of AMD at least in part because the deletion tagged a protective haplotype and did not occur on the riskhaplotype.

AB - PURPOSE. To develop an assay for determining the number of copies of the genes encoding complement factor H related 3 (CFHR3) and 1 (CFHR1) and determine the contribution of copy number variation (CNV) at CFHR3 and CFHR1 to the development of age-related macular degeneration (AMD). METHODS. A multiplex ligation-dependent probe amplification (MLPA) assay was developed to quantify the number of copies of CFHR3 and CFHR1 in humans. Subjects with (n = 252) and without (n = 249) AMD were genotyped using the assay, and the impact on AMD risk was evaluated. RESULTS. The MLPA assay provided a consistent estimate of the number of copies of CFHR3 and CFHR1 in 500 of the 501 samples. Four different combinations of CNVs were observed with frequencies as follows: both CFHR3 and CFHR1 deletion (14%), CFHR3-only deletion (0.4%), CFHR1-only deletion (1.1%), and CFHR1 duplication (0.1%). Deletion of both copies of CFHR3 and CFHR1 decreased the odds of having AMD eightfold (95% CI 2-36) and always occurred on a protective haplotype, never on the risk haplotype tagged by the Y402H risk allele in CFH. The protection conferred by deletion of CFHR3 and CFHR1 could not be distinguished from the absence of the risk haplotype. CONCLUSIONS. Both deletions and duplications of genes in the regulation of complement activation locus segregated in Caucasians. Deletion of CFHR3 and CFHR1 protected against the development of AMD at least in part because the deletion tagged a protective haplotype and did not occur on the riskhaplotype.

UR - http://www.scopus.com/inward/record.url?scp=73949086785&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73949086785&partnerID=8YFLogxK

U2 - 10.1167/iovs.09-3975

DO - 10.1167/iovs.09-3975

M3 - Article

C2 - 19553609

AN - SCOPUS:73949086785

VL - 50

SP - 5070

EP - 5079

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 11

ER -