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HTRA1 variants in exudative age-related macular degeneration and interactions with smoking and CFH.
- Source :
-
Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2008 Jun; Vol. 49 (6), pp. 2357-65. Date of Electronic Publication: 2008 Mar 03. - Publication Year :
- 2008
-
Abstract
- Purpose: Mapping the genes for age-related macular degeneration (AMD) had not been successful until recent genome-wide association studies revealed Tyr402His in CFH and rs11200638 in HTRA1 as AMD-related genetic variants. This study was conducted to identify other critical factors in HTRA1 that are associated with exudative AMD.<br />Methods: The promoter, splice regions, and coding exons of HTRA1 were sequenced in 163 patients with exudative AMD and 183 sex- and age-matched control subjects. Also documented were the CFH genotype and smoking status.<br />Results: Four significant SNPs were found in the promoter and the first exon of HTRA1: rs11200638 (-625G>A), rs2672598 (-487T>C), rs1049331 (102C>T, Ala34Ala), and rs2293870 (108G>T, Gly36Gly) with respective P = 1.7 x 10(-14), 3.0 x 10(-10), 3.7 x 10(-12), and 3.7 x 10(-12). Among them, rs11200638 is the most significant associated SNP with a high odds ratio (OR) of 7.6 (95% CI: 3.94-14.51). One risk haplotype block across the promoter and exon 1, ACCTT, significantly predisposes to AMD (P = 6.68 x 10(-14)). In both models, significant independent additive effects were identified with smoking and rs800292 (184G>A, Val62Ile) of CFH. Smoking and rs11200638 (HTRA1) combined caused a 15.7-fold increased risk, whereas combined rs800292 and rs11200638 caused a 23.3-fold increased risk. An extremely high population attributable risk (PAR) of 78% was also found.<br />Conclusions: A high impact of the additive effect of CFH and HTRA1 in the development of exudative AMD was shown. The HTRA1-smoking additive effect found in this study further suggests the importance of this environmental risk factor in AMD.
- Subjects :
- Aged
Aged, 80 and over
Complement Factor H genetics
Exons genetics
Exudates and Transudates
Female
Haplotypes
High-Temperature Requirement A Serine Peptidase 1
Humans
Male
Middle Aged
Polymerase Chain Reaction
Promoter Regions, Genetic genetics
Risk Factors
Sequence Analysis, DNA
Macular Degeneration genetics
Polymorphism, Single Nucleotide
Serine Endopeptidases genetics
Smoking genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0146-0404
- Volume :
- 49
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Investigative ophthalmology & visual science
- Publication Type :
- Academic Journal
- Accession number :
- 18316707
- Full Text :
- https://doi.org/10.1167/iovs.07-1520