Haplotypes of HTRA1 rs1120638, TIMP3 rs9621532, VEGFA rs833068, CFI rs10033900, ERCC6 rs3793784, and KCTD10 rs56209061 Gene Polymorphisms in Age-Related Macular Degeneration.
ABSTRACT: Background:To determine the impact of HTRA1 rs1120638, TIMP3 rs9621532, VEGFA rs833068, CFI rs10033900, ERCC6 rs3793784, and KCTD10 rs56209061 genotypes on the development of age-related macular degeneration (AMD) in the Lithuanian population. Methods:A total of 916 subjects were examined: 309 patients with early AMD, 301 patients with exudative AMD, and 306 healthy controls. The genotyping of HTRA1 rs11200638, TIMP3 rs9621532, VEGFA rs833068, CFI rs10033900, ERCC6 rs3793784, and KCTD10 rs56209061 was carried out using the RT-PCR method. Results:Our study showed that single-nucleotide polymorphisms rs3793784 and rs11200638 were associated with increased odds of early and exudative AMD, and the variant in KCTD10 (rs56209061) was found to be associated with decreased odds of early and exudative AMD development after adjustments for age and gender in early AMD analysis and after adjustments only for age in exudative AMD. The haplotype containing two minor alleles C-A and the G-A haplotype in rs3793784-rs11200638 were statistically significantly associated with an increased risk of exudative AMD development after adjustment for age, while the G-G haplotype showed a protective role against early and exudative AMD and the haplotype C-G in rs3793784-rs11200638 was associated with a decreased risk only of exudative AMD development. Conclusions:Our study identified two markers, rs11200638 and rs3793784, as risk factors for early and exudative AMD, and one marker, rs56209061, as a protective factor for early and exudative AMD development. The haplotypes constructed of rs3793784-rs11200638 were found to be associated with AMD development, as well.
Project description: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.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.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.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.
Project description:Exudative age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) share similar abnormal choroidal vasculature, but responses to treatments are different. In this study, we sequenced the whole HTRA1 gene and its promoter by direct sequencing in a Hong Kong Chinese PCV cohort. We identified rs11200638, c.34delCinsTCCT, c.59C>T, rs1049331 and rs2293870 significantly associated with PCV. Notably, rs2672598 was significantly associated with exudative AMD (p?=?1.31?×?10(-4)) than PCV (p?=?0.11). Logistic regression indicated that rs2672598 (p?=?2.27?×?10(-3)) remained significant after adjusting for rs11200638 in exudative AMD. Moreover, the rs11200638-rs2672598 joint genotype AA-CC conferred higher risk to exudative AMD (43.11 folds) than PCV (3.68 folds). Promoter analysis showed that rs2672598 C-allele showed higher luciferase expression than wildtype T-allele (p?=?0.026), independent of rs11200638 genotype (p?=?0.621). Coherently, vitreous humor HTRA1 expression with rs2672598 CC genotype was significantly higher than that with TT genotype by 2.56 folds (p?=?0.02). Furthermore, rs2672598 C-allele was predicted to alter the transcription factor binding sites, but not rs11200638 A-allele. Our results revealed that HTRA1 rs2672598 is more significantly associated with exudative AMD than PCV in ARMS2/HTRA1 region, and it is responsible for elevated HTRA1 transcriptional activity and HTRA1 protein expression.
Project description:PURPOSE: To determine the genetic association of an inflammation-related gene, formyl peptide receptor 1 (FPR1), in exudative age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). METHODS: The coding region of FPR1 gene was sequenced in 554 unrelated Chinese individuals: 155 exudative AMD patients, 179 PCV patients, and 220 controls. Interactions and combined effects of FPR1 with complement factor H (CFH), high temperature requirement factor A1 (HTRA1), and smoking were also investigated. RESULTS: A total of 28 polymorphisms in FPR1 were identified. Single nucleotide polymorphisms (SNP) rs78488639 increased the risk to exudative AMD (P=0.043) and PCV (P=0.016), whereas SNP rs867229 decreased the risk to exudative AMD (P=0.0026), but not PCV. Homozygous G allele of rs1042229 was associated with exudative AMD (P=0.0394, odds ratio (OR)=2.27, 95% confident interval: 1.08-4.74), but not with PCV. Exudative AMD, but not PCV, was associated with the heterozygous genotypes of rs2070746 (P=0.019, OR=0.57) and rs867229 (P=0.0082, OR=0.54). Significantly, interactions were identified among FPR1 rs78488639, CFH rs800292, and HTRA1 rs11200638 in both exudative AMD and PCV. Combined heterozygous risk alleles of CFH rs800292 GA and FPR1 rs78488639 CA were posed to PCV (P=2.22 × 10(-4), OR=10.47), but not exudative AMD. Furthermore, FPR1 rs78488639 CA combining with HTRA1 rs11200638 and smoking was also predisposed risks to exudative AMD and PCV. CONCLUSION: FPR1 is associated with exudative AMD and PCV in a Hong Kong Chinese cohort. FPR1 rs78488639 interacted with CFH rs800292, HTRA1 rs11200638, and smoking, enhancing risk to exudative AMD and PCV.
Project description:AIM:To determine whether gene polymorphisms of the major genetic risk loci for age-related macular degeneration (AMD): ARMS2 (rs10490923), the complement factor H (CFH) (rs1410996) and HTRA1 (rs11200638) influence the response to a treatment regimen with ranibizumab for exudative AMD. METHODS:This study included 100 patients (100 eyes) with exudative AMD. Patients underwent a treatment with ranibizumab injections monthly during three months. Reinjections were made when the best corrected visual acuity (BCVA) decrease five letters (ETDRS) or central subfield retinal thickness gained 100 µm in optical coherence tomography image. Genotypes (rs10490923, rs1410996 and rs11200638) were analyzed using TaqMan probes or polymerase chain reaction-restricted fragment length polymorphisms analysis. RESULTS:There were no statistically significant differences in allelic distribution of CFH (rs1410996), ARMS2 (rs10490923) and HTRA1 (rs11200638) polymorphisms regarding to response to ranibizumab treatment. CONCLUSION:Ranibizumab treatment response is not related to CFH (rs1410996), ARMS2 (rs10490923) and HTRA1 (rs11200638) poymorphisms.
Project description:PURPOSE: Variants in complement factor H (CFH), the hypothetical LOC387715, and the high-temperature requirement A-1 (HTRA1) genes have been reported to be associated with age-related macular degeneration (AMD). The purpose of this study was to investigate the association of reported common single-nucleotide polymorphisms (SNPs) in CFH, LOC387715, and HTRA1 with exudative AMD in a northern Chinese population. METHODS: A cohort of 121 unrelated patients with exudative AMD and 132 control subjects were enrolled in this study. Genomic DNA was extracted from blood leukocytes. Genotyping for SNPs rs1061170:T>C in CFH (Y402H), rs10490924:G>T in LOC387715 (A69S), and rs11200638:G>A in the promoter of HTRA1 was performed using a polymerase chain reaction (PCR) method followed by allele-specific restriction enzyme digestion and direct sequencing. RESULTS: The Y402H variant in CFH was not associated with exudative AMD in our study population. Frequencies of Y402H was 10.3% in AMD cases and 8.0% in controls (p=0.353). Significant associations were detected for exudative AMD with SNPs rs10490924:G>T in LOC387715 (A69S), and rs11200638:G>A in the promoter of HTRA1. The risk T-allele frequency of rs10490924 in LOC387715 was 64.9% in cases versus 43.2% in controls (p<0.001). The odds ratio for risk of AMD was 1.56 (95% CI; 0.80-3.03) for the GT genotype and 5.45 (95% CI; 2.59-11.49) for the TT genotype. The A allele frequency of rs11200638 in the HTRA1 promoter was 67.8% in cases versus 42.4% in controls (p<0.001). The odds ratio was 2.75 (95% CI; 1.34-5.64) for the GA genotype and 7.90 (95% CI; 3.61-17.26) for the AA genotype. An odds ratio of 7.94 (95% CI; 3.49-18.04) was obtained for carriers with both TT genotype in LOC387715 and AA genotype in the HTRA1 promoter. CONCLUSIONS: Our data suggest that the LOC387715 and HTRA1 polymorphisms are associated with a higher risk of exudative AMD in northern Chinese. We found no association of CFH Y402H with exudative AMD. The low frequency of CFH Y402H variant was further confirmed in this study population.
Project description:To investigate the association of genetic and environmental factors, and their interactions in Korean patients with exudative age-related macular degeneration (AMD).A total of 314 robustly characterized exudative AMD patients, including 111 PCV (polypoidal choroidal vasculopathy) and 154 typical choroidal neovascularization (CNV), and 395 control subjects without any evidence of AMD were enrolled. Full ophthalmologic examinations including fluorescein angiography (FA), indocyanine green angiography (ICG) and optical coherence tomography (OCT) were done, according to which patients were divided into either PCV or typical CNV. Standardized questionnaires were used to collect information regarding underlying systemic diseases, dietary habits, smoking history and body mass index (BMI). A total of 86 SNPs from 31 candidate genes were analyzed. Genotype association and logistic regression analyses were done and stepwise regression models to best predict disease for each AMD subtype were constructed.Age, spherical equivalent, myopia, and ever smoking were associated with exudative AMD. Age, hypertension, hyperlipidemia, spherical equivalent, and myopia were risk factors for typical CNV, while increased education and ever smoking were significantly associated with PCV (p<.05 for all). Four SNPs, ARMS2/HTRA1 rs10490924, rs11200638, and rs2736911, and CFH rs800292, showed association with exudative AMD. Two of these SNPs, ARMS2/HTRA1 rs10490924 and rs11200638, showed significant association with typical CNV and PCV specifically. There were no significant interactions between environmental and genetic factors. The most predictive disease model for exudative AMD included age, spherical equivalent, smoking, CFH rs800292, and ARMS2 rs10490924 while that for typical CNV included age, hyperlipidemia, spherical equivalent, and ARMS2 rs10490924. Smoking, spherical equivalent, and ARMS2 rs10490924 were the most predictive variables for PCV. When comparing PCV cases to CNV cases, age, BMI, and education were the most predictive risk factors of PCV.Only one locus, the ARMS2/HTRA1 was a significant genetic risk factor for Korean exudative AMD, including its subtypes, PCV and typical CNV. Stepwise regression revealed that CFH was important to risk of exudative AMD in general but not to any specific subtype. While increased education was a unique risk factor to PCV when compared to CNV, this association was independent of refractive error in this homogenous population from South Korea. No significant interactions between environmental and genetic risk factors were observed.
Project description:BACKGROUND:This study aimed to demonstrate the phenotypic and genotypic factors associated with photodynamic therapy (PDT) for age-related macular degeneration (AMD). METHODS:The study included 149 patients with exudative AMD treated by PDT. Eight phenotypic factors and ten genotypic factors for three single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996) in the complement factor H (CFH) gene, rs 11200638-SNP in the high temperature requirement A-1 (HTRA1) gene, two SNPs (rs699947, rs2010963) in the vascular endothelial growth factor (VEGF) gene, and four SNPs (rs12948385, rs12150053, rs9913583, rs1136287) in the pigment epithelium-derived factor (PEDF) gene were evaluated. RESULTS:A significant association with best-corrected visual acuity change was demonstrated in the greatest linear dimension, presence or absence of pigment epithelial detachment, and HTRA1-rs11200638 genotype statistically (P=3.67×10(-4), 1.95×10(-2), 1.24×10(-3), respectively). Best-corrected visual acuity in patients with AA genotype of HTRA1-rs11200638 significantly decreased compared with that in patients with GG genotype (P=1.33×10(-3)). Logistic regression analyses demonstrated HTRA1-rs11200638 genotype was most strongly associated with best-corrected visual acuity outcome from baseline at 12 months after photodynamic therapy (P=4.60×10(-3); odds ratio 2.363; 95% confidence interval 1.303-4.285). CONCLUSION:The HTRA1-rs11200638 variant showed the most significant association. Therefore, this variant may be used as a prognostic factor to estimate the PDT response with significant predictive power.
Project description:Variations in a locus at chromosome 10q26 are strongly associated with the risk of age-related macular degeneration (AMD). The most significantly associated haplotype includes a nonsynonymous SNP rs10490924 in the exon 1 of ARMS2 and rs11200638 in the promoter region of HTRA1. It is under debate which gene(s), ARMS2, HTRA1 or some other genes are functionally responsible for the genetic association. To verify whether the associated variants correlate with a higher HTRA1 expression level as previously reported, HTRA1 mRNA and protein were measured in a larger human retina-RPE-choroid samples (n = 82). Results show there is no significant change of HTRA1 mRNA level among genotypes at rs11200638, rs10490924 or an indel variant of ARMS2. Furthermore, two AMD-associated synonymous SNPs rs1049331 and rs2293870 in HTRA1 exon 1 do not change its protein level either. These results suggest that the AMD-associated variants in the chromosome 10q26 locus do not significantly affect the expression of HTRA1.
Project description:A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits.
Project description:Anti-angiogenesis treatments are the most commonly used treatments for the vision loss caused by exudative age-related macular degeneration (AMD), in which the anti-vascular endothelial growth factor (VEGF) drugs with ranibizumab and bevacizumab are current standard treatments. However, the outcome of anti-VEGF therapeutics is not uniform in all patients.We performed a literature-based meta-analysis including, five published studies relevant to HTRA1 and response to anti-VEGF treatment (bevacizumab or ranibizumab). Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed- and random-effects models. Sensitivity analysis and meta-regression were also performed. Q-statistic test and Egger's test was used to evaluate heterogeneity and publication bias respectively.Overall, no association between the rs11200638 polymorphism in HTRA1 gene and the anti-VEGF treatment response was found in the genotype GG versus AA (OR = 1.06; 95% CI: 0.77 to 1.48; P = 0.98), genotype GA versus AA (OR = 1.11; 95% CI: 0.83 to 1.47; P = 0.93), genotype GG + GA versus AA (OR = 1.22; 95% CI: 0.94 to 1.57; P = 0.09), and allele G versus A (OR = 0.92; 95% CI: 0.78 to 1.08; P = 0.14). In the subgroup analysis by ethnicity Caucasian population, and a significant association was still not observed in all genetic models. Sensitivity analysis indicated the robustness of our findings, and no publication bias was observed in our meta-analysis.This study shows that there was no association between the polymorphism rs11200638 in HTRA1 gene and response to anti-VEGF treatment of exudative AMD. However, more studies are needed to further prove the conclusion of present study, especially well-designed and high quality randomised controlled trials or intervention studies.