IOVS AJP: Regulatory, Integrative and Comparative Physiology
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Originally published In Press as doi:10.1167/iovs.07-1520 on March 3, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:2357-2365.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-1520
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HTRA1 Variants in Exudative Age-Related Macular Degeneration and Interactions with Smoking and CFH

Pancy O. S. Tam,1 Tsz Kin Ng,1 David T. L. Liu,1 Wai Man Chan,1 Sylvia W. Y. Chiang,1 Li Jia Chen,1 Andrew DeWan,2 Josephine Hoh,2 Dennis S. C. Lam,1 and Chi Pui Pang1

1From the Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; and the 2Department of Epidemiology and Public Health, Yale University, New Haven, Connecticut.

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.






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