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Variation of Codons 1961 and 2177 of the Stargardt Disease Gene Is Not Associated With Age-Related Macular Degeneration
Robyn H. Guymer, MD, PhD;
Elise Héon, MD;
Andrew J. Lotery, MD, FRCOphth;
Francis L. Munier, MD;
Daniel F. Schorderet, PhD;
Paul N. Baird, PhD;
Robyn J. McNeil, BSc;
Heidi Haines, MS;
Val C. Sheffield, MD, PhD;
Edwin M. Stone, MD, PhD
Arch Ophthalmol. 2001;119:745-751.
Objectives To investigate the role of 2 specific alleles of the Stargardt disease
gene (ABCA4) in the pathogenesis of age-related macular
degeneration (AMD). Secondary objectives were to investigate differences in
frequency of the G1961E allele in selected ethnic
groups as well as to examine the segregation of both G1961E and D2177N alleles in 5 multiplex families
with AMD.
Methods Five hundred forty-four patients with AMD and 689 controls were ascertained
from 3 continents. Blood samples from 62 normal individuals of Somalian ancestry
were also obtained. Participants were screened for the presence of these ABCA4 alleles with a combination of restriction digestion
and single-strand conformation polymorphism analysis of polymerase chain reaction
amplification products. Detected alleles were confirmed by DNA sequencing.
The number of subjects exhibiting the G1961E or D2177N variants were compared between AMD and control groups
using a 2-tailed Fisher exact test.
Results There was no significant difference (P>.1)
in the frequency of the G1961E and D2177N alleles in patients with AMD (2.2%) vs controls (1.0%). In contrast,
there was a significant difference (P<.001) in
the frequency of the G1961E alleles between normal
individuals of Somali ancestry (11.3%) and normal individuals from other populations
(0.4%). There was no evidence of cosegregation of these alleles and the AMD
phenotype in the 5 multiplex families with AMD examined. These two ABCA4 alleles were slightly more frequent in patients with AMD with
choroidal neovascularization (2.7%) than those without this complication (2.5%).
Conclusions Somali ancestry is more than 100 times more strongly associated with
presence of the G1961E allele than the AMD phenotype.
This study did not find any statistically significant evidence for involvement
of the G1961E or D2177N
alleles of the ABCA4 gene in AMD.
Clinical Relevance The ABCA4 gene is definitively involved in
the pathogenesis of Stargardt disease and some cases of photoreceptor degeneration.
However, it does not seem to be involved in a statistically significant fraction
of AMD cases.
From the Centre for Eye Research Australia (Drs Guymer and Baird and
Ms McNeil), University of Melbourne, and Royal Victorian Eye and Ear Hospital
(Dr Guymer), Melbourne, Victoria; Department of Ophthalmology (Dr Héon),
University of Toronto, Toronto, Canada; Vision Science Research Program (Dr
Héon), University Health Network, Toronto; Departments of Ophthalmology
(Drs Lotery and Stone and Ms Haines) and Pediatrics (Dr Sheffield), University
of Iowa College of Medicine, Iowa City; Hôpital Jules Gonin (Dr Munier),
Lausanne, Switzerland; Division de Génétique Médicale
(Drs Munier and Schorderet), Centre Hospitalier Universitaire Vaudois, Lausanne;
and the Howard Hughes Medical Institute (Dr Sheffield), Chevy Chase, Md.
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