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. 2008 Jun;49(6):2357-65.
doi: 10.1167/iovs.07-1520. Epub 2008 Mar 3.

HTRA1 Variants in Exudative Age-Related Macular Degeneration and Interactions With Smoking and CFH

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Free PMC article

HTRA1 Variants in Exudative Age-Related Macular Degeneration and Interactions With Smoking and CFH

Pancy O S Tam et al. Invest Ophthalmol Vis Sci. .
Free PMC article

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.

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.

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.

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.

Figures

Figure 1
Figure 1
The association of exudative AMD with 41 variants across a 54-Mb region of chromosome 10 in the HTRA1 gene. The position of each SNP is given on a kilobase scale. (a) The location of exons of HTRA1 that map to the interval. (b) –Log (P) is plotted against the chromosomal location of the 41 variants.
Figure 2
Figure 2
Haploview plot depicting the haplotype block structure of the exudative AMD-associated region. Top diagram: the relative chromosomal position of each SNP.
Figure 3
Figure 3
Two-locus (HTRA1 and CFH) genotype-specific AMD risk.

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