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 Pang 3*
1 Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
2 Department of Epidemiology and Public Health, Yale University, New Haven, Connecticut, United States
3 Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
* To whom correspondence should be addressed. E-mail: cppang{at}cuhk.edu.hk.
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Abstract |
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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-susceptible genetic variants. In this study, we aim to identify other critical factors in HTRA1 that is associated with exudative AMD.
Methods: The promoter, splice regions and coding exons of HTRA1 were sequenced in 163 exudative AMD patients and 183 sex and age-matched control subjects. Also documented were the CFH genotype and smoking status.
Results: We found 4 significant SNPs 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-values = 1.7x10-14, 3.0x10-10, 3.7x10-12 and 3.7x10-12. Among them, rs11200638 is the most significant associated SNP with a high 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= 6.68x10-14). Significant independent additive effects were identified in either model with smoking and rs800292 (184G>A, Val62Ile) of CFH. The combined OR for disease of smoking and rs11200638 (HTRA1) caused a 15.7 fold increased risk whereas that of combined rs800292 and rs11200638 showed 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 in our study. HTRA1-smoking additive effect found in this study further suggests the importance of this environmental risk factor in AMD.
Key Words:
HTRA1, age-related macular degeneration, 10q26
