The HtrA1 Promoter Polymorphism, Smoking, and Age-related Macular Degeneration in Multiple Case-control Samples

Abstract

Purpose-To assess the association and combined effect on the risk of age-related macular degeneration (AMD) by the HtrA1 and complement factor H (CFH) polymorphisms, smoking and serum cholesterol. Design-Clinic-based and population-based case-control.Participants-Eight hundred and five AMD cases and 921 controls from The Eye Clinic of National Eye Institute, Age-Related Eye Diseases Study (AREDS), Blue Mountain Eye Study Cohort, and Minnesota Lions Eye Bank.Methods-DNA Samples were genotyped for polymorphisms of rs11200638 in HtrA1 promotor and rs380390 in CFH. HtrA1 protein in ocular tissue was measured. Interactions of the HtrA1 risk allele with the CFH risk variant, smoking status and cholesterol were assessed.Main Outcome Measures-AMD was evaluated by retinal specialists and AMD subtypes (geographic atrophy and neovascularization) were determined.Results-Strong associations of the HtrA1 risk allele (A) with AMD were present in all sample sets. A similar magnitude of association was observed for central geographic atrophy and neovascular AMD. The combination of the HtrA1 and CFH risk alleles increased AMD susceptibility, as did the combination of the HtrA1 risk allele with smoking. No combined effect of HtrA1 risk allele and cholesterol level was found. Enhanced expression of HtrA1 protein was detected in retina with AMD. †Corresponding to Chi-Chao Chan: Bldg. 10, Rm. 10N103, 10 Center Dr., NIH/NEI, Bethesda, MD 20892−1857, Phone: (301) 496 −0417, Fax: (301) 402−8664, Email: chanc@nei.nih.gov.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Précis:The genetic variant of HtrA1 confers increased risk for developing age-related macular degeneration (AMD). AMD risk increases further when the risk alleles from HtrA1 are combined with either CFH risk alleles or history of smoking. NIH Public Access Materials and Methods Patient PopulationEach participant provided written informed consent according to protocols approved by the Institutional Review/Ethics Boards of NEI Institutional Review Board, AREDS clinical site, University of Minnesota, or University of Sydney, respectively. This research followed the tenets of the Helsinki Declaration.The clinic-based NEI case-control study included diagnosed advanced AMD cases and controls from the greater Washington, D.C. area, who had been evaluated by AREDS ophthalmologists at the NEI. Venous whole blood (10 mL) was collected from NEI study subjects. Genomic DNA was extracted and isolated using a QIAamp DNA Blood Maxi kit (Qiagen, Valencia, CA). 7,14 In addition, DNA samples from the AREDS Genetic Repository were obtained and...

In-depth analyses unveil the association and possible functional involvement of novel RAD51B polymorphisms in age-related macular degeneration

“…Growing evidence of the involvement of oxidative stress and DNA repair in AMD pathogenesis alongside recent report of SNP rs8017304 A>G association with AMD by the International AMD Genomics Consortium The call rate of the China set is 85.3 % led us to analyze the influence of RAD51B on AMD in the well-established NEI sample set (Tuo et al 2006(Tuo et al , 2008Ross et al 2007;Ardeljan et al 2013). Looking at allelic frequencies in the reported rs8017304 A>G and six additional tag-SNPs across the RAD51B gene, we found significant AMD-association with the reported rs8017304 A>G and two novel RAD51B SNPs, rs17105278 T>C and rs4902566 C>T. Our data indicate substantial risk association with the minor alleles of rs17105278 T>C and rs4902566 C>T under the dominant model.…”

“…Categorizing the genotypes of these two SNPs in control subjects and AMD cases in the NEI sample set revealed a strong combination effect of minor C allele homozygosity at rs17105278 T>C and minor T allele homozygosity at rs4902566 C>T toward AMD susceptibility ( We also attempted SNP-SNP interaction analysis between the RAD51B and well-known AMD SNPs such as CFH, HTRA1, and ARMS2, for which we have data published on our sample set (Tuo et al 2008;Ross et al 2007;Chan et al 2007). The results did not reveal any interactions between rs17105278 T>C or rs4902566 C>T and these previously identified SNPs (data not shown).…”

Interactive Expressions of HtrA1 and VEGF in Human Vitreous Humors and Fetal RPE Cells

“…2) might be related to inflammatory and stress responses. [37][38][39] HtrA1 is associated with geographic atrophy 29 and drusen, 30,31 and is upregulated in response to estrogeninduced oxidative stress. 40 We also found that human fetal RPE cells responded to chemical-induced stress by simultaneous upregulations of HTRA1 and VEGFA after treatments with tunicamycin and DTT (Figs.…”

Age-related macular degeneration and the complement system

“…Patients homozygous for both the CFH Y402 andARMS2 A69S SNPs have a substantially increased risk of AMD (50 times higher), with an even higher risk when smoking and obesity are taken into account (Schaumberg et al 2007). Tuo et al (2008) reported that presence of both ARMS2 and CFH risk SNPs have an additive effect on AMD susceptibility (Tuo et al 2008), but this was not replicated in other studies (Weger et al 2007;Francis et al 2008). Dinu et al (2007) reported patients with either the heterozygous or homozygous CFH Y402H allele and a haplotype of the C7 gene were associated with a reduced risk of developing wet AMD, compared to dry AMD.…”