Detailed analysis of allelic variation in the ABCA4 gene in age-related maculopathy.
OBJECTIVE
Age-related maculopathy (ARM) is one of the most common causes of blindness in older adults worldwide. Sequence variants in a gene coding for a retina-specific ATP-binding cassette (ABCA4) transporter protein, which is responsible for a phenotypically similar Mendelian form of retinal disease, were proposed to increase the risk of ARM. To examine the potential relationship of ABCA4 sequence variation and ARM risk in an independent data set, a clinically well-characterized population of 165 multiplex patients with ARM from 70 families, 33 unaffected relatives, and 59 unrelated control subjects with confirmed absence of ARM was screened for variants in any of the 50 exons and exon-intron boundaries of this gene.


METHODS
A combination of denaturing high-performance liquid chromatography (DHPLC) and bidirectional sequencing was used to detect ABCA4 sequence variants. The data set was analyzed with both case-control and family-based association analysis methods.


RESULTS
No evidence was found of significantly different allele frequencies of ABCA4 sequence variants in patients compared with control subjects, and no evidence for association or cosegregation with disease in family-based analyses.


CONCLUSIONS
This study confirmed the very high degree of ABCA4 sequence polymorphism in the general population, which makes the detection of potential disease-associated alleles particularly challenging. While this study does not definitively exclude ABCA4 from contributing to a small or moderate fraction of ARM, it adds to the body of evidence suggesting that ABCA4 is not a major susceptibility gene for this disorder.
Schmidt
Silke
S
Center for Human Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA.
Postel
Eric A
EA
Agarwal
Anita
A
Allen
I Coy
IC
Walters
Shaune N
SN
De la Paz
Monica A
MA
Scott
William K
WK
Haines
Jonathan L
JL
Pericak-Vance
Margaret A
MA
Gilbert
John R
JR
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012374:Rod Cell Outer Segment / Q000737:chemistry; D017422:Sequence Analysis, DNA
C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters