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methodological and clinical standpoints including studies regarding its potential role as a tumor marker and/or prognostic factor. PRISMA method was used for study selection. The articles thus collected were examined and selected by two independent reviewers; any disagreement was resolved by a methodologist. A laboratory researcher reviewed the methods and laboratory techniques. Fifteen studies met the inclusion criteria and concerned the following cancer sites: the nervous system, bladder, breast, esophagus, stomach, liver, endometrium, thyroid, ovaries, pleura, lung and skin. Most articles described in vivo studies using a morphological approach and immunohistochemistry, whereas protein expression was quantified as staining intensity scored by two raters. Often the results were not comparable due to the different rating scales and study design. Current research on HtrA1 does not conclusively support its role as a tumor suppressor.

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o chemotherapy by modulating chemotherapy-induced cytotoxicity. Downregulation of HtrA1 attenuated cisplatin- and paclitaxel-induced cytotoxicity, while forced expression of HtrA1 enhanced cisplatin- and paclitaxel-induced cytotoxicity. HtrA1 expression was upregulated by both cisplatin and paclitaxel treatment. This upregulation resulted in limited autoproteolysis and activation of HtrA1. Active HtrA1 induces cell death in a serine protease-dependent manner. The potential role of HtrA1 as a predictive factor of clinical response to chemotherapy was assessed in both ovarian and gastric cancer patients receiving cisplatin-based regimens. Patients with ovarian or gastric tumors expressing higher levels of HtrA1 showed a higher response rate compared with those with lower levels of HtrA1 expression. These findings uncover what we believe to be a novel pathway by which serine protease HtrA1 mediates paclitaxel- and cisplatin-induced cytotoxicity and suggest that loss of HtrA1 in ovarian and gastric cancers may contribute to in vivo chemoresistance.

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used to determine the expression of HtrA1 in 50 hepatocellular carcinoma specimens and adjacent liver tissues. The correlation between the expression of HtrA1 and the clinico-pathologic data were analyzed.
RESULTS: The levels of HtrA1 were lower in tumor tissues than in their adjacent liver tissues. Moreover, an inverse relationship was found between HtrA1 expression and the differentiation of hepatocellular carcinoma. Loss of HtrA1 was more frequently found in tumors in Edmondson grade III-IV, especially in those with venous invasion, compared to tumors in Edmondson grade I-II. Most importantly, patients with higher HtrA1 expression had a better survival rate.
CONCLUSION: All these data suggest an important role of HtrA1 in hepatocellular carcinoma development and progression, which may be a new target for its treatment.

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EC cell lines and primary tumors, respectively. Migration, invasion assays and in vivo xenograft experiment were performed to compare the extent of metastasis between HtrA1 expressing and HtrA1 knocked down clones.
RESULTS: Western blot analysis of HtrA1 in 13 EC cell lines revealed complete loss of HtrA1 expression in all seven papillary serous EC cell lines. Downregulation of HtrA1 in Hec1A and Hec1B cell lines resulted in a three- to fourfold increase in the invasive potential. Exogenous expression of HtrA1 in Ark1 and Ark2 cells resulted in three- to fourfold decrease in both invasive and migration potential of these cells. There was an increased rate of metastasis to the lungs associated with HtrA1 downregulation in Hec1B cells compared to control cells with endogenous HtrA1 expression. Enhanced expression of HtrA1 in Ark2 cells resulted in significantly less tumor nodules metastasizing to the lungs compared to parental or protease deficient (SA mutant) Ark2 cells. Immunohistochemical analysis showed 57% (105/184) of primary EC tumors had low HtrA1 expression. The association of low HtrA1 expression with high-grade endometrioid tumors was statistically significant (P = 0.016).
CONCLUSIONS: Collectively, these data indicate loss of HtrA1 may contribute to the aggressiveness and metastatic ability of endometrial tumors.

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roteins. During embryo development, mouse HtrA1 was expressed in specific areas where signaling by Tgfbeta family proteins plays important regulatory roles. The GST-pulldown assay showed that HtrA1 binds to a broad range of Tgfbeta family proteins, including Bmp4, Gdf5, Tgfbetas and activin. HtrA1 inhibited signaling by Bmp4, Bmp2, and Tgfbeta1 in C2C12 cells, presumably by preventing receptor activation. Experiments using a series of deletion mutants indicated that the binding activity of HtrA1 required the protease domain and a small linker region preceding it, and that inhibition of Tgfbeta signaling is dependent on the proteolytic activity of HtrA1. Misexpression of HtrA1 near the developing chick eye led to suppression of eye development that was indistinguishable from the effects of noggin. Taken together, these data indicate that HtrA1 protease is a novel inhibitor of Tgfbeta family members.

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sent study.
METHODS: The HtrA1 expression in human HCC tumor tissues and cells was determined by real-time PCR. SiRNA-HtrA1 and pcDNA-HtrA1 were respectively transfected into HepG2 and MHCC97H cells to observe their effects on cell migration and expression of EMT-associated markers Vimentin and E-cadherin. The relationship between HtrA1 and EMT in 60 HCC patients was also investigated.
RESULTS: HtrA1 expression of tumor tissues was down-regulated with the increasing of number in lymph nodes metastasis in HCC patients. HtrA1 down-regulation led to the significant increase of cell migration, Vimentin expression and decrease of E-cadherin expression, while HtrA1 overexpression resulted in an opposite function. The HtrA1 expression was positively related to the E-cadherin level (R(2) = 0.5903, P < 0.001) and negatively correlated with Vimentin level (R(2) = 0.6067, P < 0.001) in tumor tissues of HCC, respectively.
CONCLUSION: HtrA1 expression was closely related to EMT, which might be a potential mechanism underlying metastasis of HCC.

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PCR and Western-blotting methods, respectively. RESULTS: A statistically significant decrease of HtrA1 and HtrA3 expression in ovarian tumors comparing to normal tissues was observed. A dramatic decrease of HtrA3 mRNA and protein levels in all tumor tissue groups, and a loss of HtrA3 protein in 30% malignant tumors were found. A significant decrease of HtrA1 mRNA, and of HtrA3 mRNA and protein in malignant tumors compared to benign tumors was revealed. HtrA2 expression in tumor tissues was slightly decreased. Expression of TGF-beta1 in tumor tissues was not significantly different compared to control tissues. CONCLUSIONS: Our results show downregulation of HtrA1 and HtrA3 genes' expression in different types of ovarian tumors and give additional evidence that these genes may function as tumor suppressors.

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β-catenin, which binds to the T- cell factor/lymphoid enhancer factor (TCF/LEF) and triggers the activation of Wnt target genes. Here, we identify the serine protease High-Temperature Requirement A1 (HTRA1) as a novel component of the canonical Wnt pathway. We show that the HTRA1 protein inhibits the Wnt/β-catenin signaling, in both paracrine and autocrine manners, and affects the expression of several Wnt target genes. Moreover, HTRA1 forms a complex with β-catenin and reduces the proliferation rates of cells. Taken together, our findings indicate that HTRA1 functions as a novel suppressor of the canonical Wnt signaling pathway.

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ve 5-FU based adjuvant chemotherapy were included in our study. Chemotherapy was performed in 3 cycles for the patients. HtrA1 rs1049331 and rs11200638 polymorphisms were genotyped via polymerase chain reaction with sequencing method. The treatment response was estimated according to the RECIST guidelines. RESULTS The response rate of the eligible patients was 53.33%. For rs1049331, the presences of TT genotype and T allele indicted reduced chemotherapy sensitivity (adjusted TT: OR=1.736, 95%CI: 1.001-3.011, P=0.049; T: OR=1.801, 95%CI: 1.054-2.932, P=0.039). The rs11200638 polymorphism had no significant association with chemotherapy sensitivity in the study population (P>0.05 for all). CONCLUSIONS HtrA1 rs1049331 polymorphism, but not rs11200638 polymorphism, can influence individual sensitivity to 5-FU-based treatment in stage III colon cancer patients.

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ed in 228 colon tissue samples from patients with CRC, adenoma with high-grade dysplasia (AHD), adenoma with low-grade dysplasia (ALD), ulcerative colitis of >10 year duration (UCL), ulcerative colitis of <5 year duration (UCS) and colonic diverticulitis (D), and was compared with its expression in normal colon tissues (NCTs) collected 5 cm from the CRC lesion and in healthy colon mucosa (HC), to establish whether HtrA1 can serve as a biomarker for these conditions. All tissue specimens came from Italian Caucasian subjects. The main finding of the present study was that HtrA1 expression was significantly reduced in CRC and UCL tissues compared with that observed in both NCT and HC samples and with tissues from the other patients. In particular, a similar HtrA1 expression was detected in the stromal compartment of UCL and CRC samples. In contrast, the HtrA1 level was significantly lower (p=0.0008) in UCL compared with UCS tissues, suggesting an inverse relationship between HtrA1 expression and ulcerative colitis duration. HtrA1 immunostaining in the stromal compartment of AHD and ALD tissues showed no differences compared with the HC tissues. No data are available on the immunohistochemical localization of HtrA1 in CRC or IBD. The present findings suggest that HtrA1 could serve as a marker to identify UCL patients at high risk of developing CRC.

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nts with familial small vessel disease carry mutations in one of known small vessel disease genes. We used whole exome sequencing to identify candidate genes in an autosomal dominant small vessel disease family in which known small vessel disease genes had been excluded, and subsequently screened all candidate genes in 201 unrelated probands with a familial small vessel disease of unknown aetiology, using high throughput multiplex polymerase chain reaction and next generation sequencing. A heterozygous HTRA1 variant (R166L), absent from 1000 Genomes and Exome Variant Server databases and predicted to be deleterious by in silico tools, was identified in all affected members of the index family. Ten probands of 201 additional unrelated and affected probands (4.97%) harboured a heterozygous HTRA1 mutation predicted to be damaging. There was a highly significant difference in the number of likely deleterious variants in cases compared to controls (P = 4.2 × 10(-6); odds ratio = 15.4; 95% confidence interval = 4.9-45.5), strongly suggesting causality. Seven of these variants were located within or close to the HTRA1 protease domain, three were in the N-terminal domain of unknown function and one in the C-terminal PDZ domain. In vitro activity analysis of HTRA1 mutants demonstrated a loss of function effect. Clinical features of this autosomal dominant small vessel disease differ from those of CARASIL and CADASIL by a later age of onset and the absence of the typical extraneurological features of CARASIL. They are similar to those of sporadic small vessel disease, except for their familial nature. Our data demonstrate that heterozygous HTRA1 mutations are an important cause of familial small vessel disease, and that screening of HTRA1 should be considered in all patients with a hereditary small vessel disease of unknown aetiology.

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ovel mutation in the HTRA1 gene in a CARASIL pedigree and explore its pathogenesis at the protein level. Subcutaneous tissue biopsy and HTRA1 gene analysis were performed in a CARASIL patient, and HTRA1 and TGF-beta1 protein expression in subcutaneous tissue and cultured fibroblasts from the proband were detected by immunohistochemistry and western blotting. A 28-year-old male proband and his brother experienced recurrent stroke, hair loss and low back pain. Abnormalities in the proband were found in the elastic plate of subcutaneous small arteries, and a novel homozygous frameshift mutation (c.161_162insAG), leading to the formation of a stop codon 159 amino acids downstream of the insertion (p.Gly56Alafs*160) was detected. Reduced HTRA1 protein and increased TGF-beta1 expression were detected in subcutaneous tissue and in cultured fibroblasts. A frameshift mutation in the HTRA1 gene detected in a CARASIL pedigree resulted in reduced HTRA1 protein and increased TGF-beta1 expression, which may cause severe CARASIL and peripheral small arterial disease.

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, to define the haplotype structure of these six loci, and to confirm their genetic association with the disease. Methods. Caucasian patients (n = 482) were stratified into categories based on AREDS (Age-Related Eye Disease Study) grading criteria (groups 0 and 1 served as the control, groups 3 and 4 contained subjects with AMD, and group 2 was excluded from the analysis). The six genetic variants in the ARMS2-HTRA1 region were genotyped and analyzed both independently and as a joint haplotype for association in subjects with disease (n = 291) compared with the control (n = 191). Results. The six high-risk alleles all showed a statistically significant association with AMD (the most significant SNP was rs10490924 [P < or = 3.31 x 10(-5), OR = 1.86]; the least significant SNP was rs932275 [P < or = 9.15 x 10(-5), OR = 1.78]). Multimarker analysis revealed that all six markers were in strong linkage disequilibrium with each other, and the two major haplotypes that captured >98% of the genetic variation in the region were both significantly associated with the disease: One increased the risk of AMD and contained only risk alleles (P < or = 2.20 x 10(-5)), and the other haplotype decreased the risk of AMD and contained only wild-type alleles (P < or = 6.81 x 10(-5)). Furthermore, 36 individuals comprising both cases and controls were identified outside of these two major haplotypes, with at least one discordant marker. Conclusions. The results replicate the previously reported association between the high-risk alleles and AMD and independently confirm, for the first time, an association with AMD and the indel (del443ins54) polymorphism in a Caucasian population. Two major haplotypes that are associated with AMD and many minor novel haplotypes were identified. The novel haplotypes, identified from 36 cases and controls with discordant alleles spanning the ARMS2-HTRA1 region provide unique opportunities to gauge the relative phenotypic contributions of each of these genetic risk factors. With the identification of more discordant patients in the future, it may be possible to resolve the ongoing controversy as to which of the risk alleles and genes (ARMS2 vs. HTRA1) has the greatest impact on disease susceptibility. Future work should include the analysis of larger and more diverse populations, to further define the linkage structure of the region with a focus on phenotypic effects on AMD of the various haplotypes involving 10q26, as well as a functional analysis of the normal ARMS2 protein.

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ese. Variants in the C2 and BF genes have been found to confer a significantly reduced risk of AMD. This study was undertaken to determine whether these associations occur in Chinese patients with PCV. METHODS: Patients of Chinese ethnicity with clinically and angiographically diagnosed PCV and normal control subjects were recruited from the Singapore National Eye Centre. Five single-nucleotide polymorphisms (SNPs) in the CFH gene, two each within the C2 and BF genes and two variants located in the LOC387715 and HTRA1 genes, were screened in all patients and control subjects. RESULTS: Seventy-two patients with PCV and 93 normal control subjects were studied. A significant association was noted with CFH variants rs3753394 and rs800292 among the PCV cases (P = 0.0015 and P = 0.0045, respectively). Individuals homozygous for the TT genotype of rs3753394 had a significantly higher risk (P = 0.0076) of PCV (OR = 4.29; 95% CI: 1.47-12.50) than those carrying a single copy of the T allele (P = 0.3210; OR = 1.69; 95% CI: 0.60-4.78), after adjustment for such risk factors as age and sex. The genotype frequencies of rs11200638 and rs10490924 in HTRA1 and LOC387715, respectively, were also found to be significantly different between patients with PCV and normal control subjects (P = 0.00032 and P = 0.003, respectively). The AA genotype of rs11200638 and TT genotype of rs10490924 conferred a 4.9-fold (95% CI: 1.85-12.95) and 4.89-fold (95% CI: 1.85-12.90) increased risk of PCV, respectively, after adjustment for age and sex. The Y402H variant of CFH (rs1061170) and the BF and C2 variants were not significantly different in patients and normal control subjects. CONCLUSIONS: The SNPs rs3753394 and rs800292 of CFH and rs11200638 of HTRA1 are significantly associated with the risk of PCV in Chinese patients.

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eractions. DESIGN: Case-control study. PARTICIPANTS: Subjects with AMD (n = 244) or no or minimal maculopathy (n = 209) in the Age Related Eye Disease Ancillary Study. METHODS: Risk factors, genotypes, and biomarkers were assessed by questionnaire, direct measurement, and analyses of blood specimens. The independent and joint effects of serum CRP and CFH (rs1061170) and ARMS2/HTRA1 (rs10490924) genotypes were assessed using logistic regression analyses, adjusting for age, gender, education, smoking, body mass index, and vitamin/mineral supplementation. MAIN OUTCOME MEASURES: We defined AMD as large drusen, geographic atrophy, or neovascular disease. RESULTS: Higher CRP levels were associated with a higher risk of AMD, controlling for genotype and demographic and behavioral risk factors, with odds ratio 2.6 for levels of 3.0 mg/L and above versus below 1.0 mg/L (95% confidence interval, 1.01-6.7). Single nucleotide polymorphisms (SNPs) in both genes were also independently associated with risk of AMD, controlling for the level of CRP and other factors. Presence of both highest level of CRP together with risk genotypes for both SNPs, conferred the highest risk of AMD (OR 5.4, 95% CI 1.4-21.1). CONCLUSIONS: High-sensitivity CRP and polymorphisms in the CFH and ARMS2/HTRA1 genes are independently associated with risk of AMD. Higher CRP level tends to confer a higher risk of AMD within most genotype groups.

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resistance.
METHODS: A gene microarray was used to screen for genes related to cisplatin resistance in NSCLC cell lines. Subsequently, the correlation between the HDAC, RXR and HtrA1 genes, in NSCLC, were verified using gene manipulation. Immunohistochemical staining was used to detect HDAC, RXR and HtrA1 expression in NSCLC specimens. Proliferation, migration and invasion assays were performed in vitro and in vivo to determine the role of the HDAC/RXR/HtrA1 signaling axis in cisplatin resistance, and luciferase reporter analysis and ChIP assays were performed to ascertain the mechanisms by which HDAC and RXR regulate the expression of HtrA1. Furthermore, in vitro and in vivo experiments were conducted in NSCLC cisplatin-resistant NSCLC to elucidate the effect of the low molecular weight compound, DW22, which targets the NSCLC cisplatin resistance HDAC/RXR/HtrA1 signaling pathway.
RESULTS: HtrA1 was identified as a cisplatin resistance-related gene in NSCLC cells. The regulation of HtrA1 by HDAC and RXR significantly decreased the efficacy of cisplatin in NSCLC cells resistant to cisplatin. Immunohistochemistry results showed a negative relationship between HDAC1 and HtrA1, and a positive relationship between RXRα and HtrA1 in NSCLC patients' tissues. Notably, the expression of HDAC1 and HtrA1 can be considered as biomarkers for the efficacy of platinum-based drugs and prognosis in NSCLC patients. Mechanistically, the heterodimers of the nuclear receptor RXR, in combination with the enzyme, HDAC, regulate the transcription of HtrA1 in NSCLC cells. The rescue of HtrA1 expression by dual targeting of HDAC and RXR with the compound, DW22, significantly inhibited the proliferation, migration and invasion of NSCLC cells resistant to cisplatin, and induced NSCLC cell apoptosis.
CONCLUSION: Our results indicate that HtrA1, a cisplatin resistance-related gene, is synergistically regulated by HDAC and RXR in NSCLC. Targeting the HDAC/RXR/HtrA1 signaling axis can rescue HtrA1 expression and reverse cisplatin resistance in NSCLC.

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ors. However, its precise functions and molecular mechanisms in esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we detected HtrA1 level in ESCC tissues and cells and investigated the biological roles of HtrA1 in ESCC. We found that expressions of HtrA1 mRNA and protein in ESCC tissues and cells were significantly lower than those in normal esophageal epithelial tissues and cells (P < 0.05). Expressions of HtrA1 mRNA and protein were closely associated with TNM staging and lymph node metastasis (P < 0.05). Additionally, the survival rate of patients with low HtrA1 level was lower than those patients with high HtrA1 level (P < 0.05). Elevated HtrA1 level markedly inhibited cell proliferation in vitro and in vivo, reduced cell invasion in vitro, and induced cell apoptosis. Notably, HtrA1 overexpression inhibited phosphorylation levels of IκBα and p65 subunit of the NF-κB signaling pathway, but increased total IκBα level, coupled with decreases of Ki-67, Bcl-2, Bcl-xL, cyclin D1, and MMP-9 proteins and increase of caspase-3 activity. Overall, these data suggest that HtrA1 may play critical roles in the tumorgenesis and progression of ESCC, and HtrA1 overexpression exerts its anti-tumor effect by blocking the NF-κB signaling pathway; thus, manipulation of HtrA1 may be an effective molecular target for ESCC treatment.

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:700;'>HTRA1 has been reported to interact with members of the transforming growth factor-beta (TGF-beta) family and regulate their signaling pathways. Growth differentiation factor 6 (GDF6), a member of the TGF-beta family, is involved in ectoderm patterning and eye development. Mutations in GDF6 have been associated with abnormal eye development that may result in microphthalmia and anophthalmia. In this report, we identified a single nucleotide polymorphism (SNP) rs6982567 A/G near the GDF6 gene that is significantly associated with AMD (p value = 3.54 x 10(-8)). We demonstrated that the GDF6 AMD risk allele (rs6982567 A) is associated with decreased expression of the GDF6 and increased expression of HTRA1. Similarly, the HTRA1 AMD risk allele (rs10490924 T) is associated with decreased GDF6 and increased HTRA1 expression. We observed decreased vascular development in the retina and significant up-regulation of GDF6 gene in the RPE layer, retinal and brain tissues in HTRA1 knock-out (htra1(-/-)) mice as compared with the wild-type counterparts. Furthermore, we showed enhanced SMAD signaling in htra1(-/-) mice. Our data suggests a critical role of HTRA1 in the regulation of angiogenesis via TGF-beta signaling and identified GDF6 as a novel disease gene for AMD.

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in A549/CDDP cells correlates with acquirement of cancer stem cell-like properties (increased percentage of CD133-expressing subpopulation, sphere formation and levels of some pluripotency-associated markers). HtrA1 expression at both mRNA and protein levels was reduced in CDDP-resistant A549/CDDP cells compared with that in A549 cells. Ectopic expression of HtrA1 in A549/CDDP cells reversed cancer stem cell-like properties and CDDP resistance. In A549 cells, stable knockdown of HtrA1 expression promoted cancer stem cell-like properties and CDDP insensitivity, however, these effects were blocked by inhibition of PI3K/Akt pathway using LY294002. Furthermore, HtrA1 knockdown could significantly stimulate PI3K/Akt signaling in A549 cells. In vivo studies, HtrA1 knockdown promoted tumorigenesis and conferred CDDP resistance in xenograft A549 tumors, which were reversed by intraperitoneal injection of LY294002. In conclusion, these results indicate that HtrA1 downregulation confers CDDP resistance by inducing cancer stem cell-like properties via PI3K/Akt-dependent pathway in A549 cells. Therefore, HtrA1 may be a potential target for overcoming CDDP resistance in LAC.

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f central vision. Soft confluent drusen, characterized by deposits in macula without visual loss are considered a precursor of advanced AMD. A single nucleotide polymorphism, rs11200638, in the promoter of HTRA1 has been shown to increases the risk for wet AMD. However, its impact on soft confluent drusen and GA or the relationship between them is unclear. To better understand the role the HTRA1 polymorphism plays in AMD subtypes, we genotyped an expanded Utah population with 658 patients having advanced AMD or soft confluent drusen and 294 normal controls and found that the rs11200638 was significantly associated with GA. This association remains significant conditional on LOC387715 rs10490924. In addition, rs11200638 was significantly associated with soft confluent drusen, which are strongly immunolabeled with HTRA1 antibody in an AMD eye with GA similar to wet AMD. Two-locus analyses were performed for CFH Y402H variant at 1q31 and the HTRA1 polymorphism. Together CFH and HTRA1 risk variants increase the odds of having AMD by more than 40 times. These findings expand the role of HTRA1 in AMD. Understanding the underlying molecular mechanism will provide an important insight in pathogenesis of AMD.

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n studies have linked a multifunctional serine protease, HTRA1, to AMD. However, the precise role of HTRA1 in AMD remains elusive. By transgenically expressing human HTRA1 in mouse retinal pigment epithelium, we showed that increased HTRA1 induced cardinal features of PCV, including branching networks of choroidal vessels, polypoidal lesions, severe degeneration of the elastic laminae, and tunica media of choroidal vessels. In addition, HTRA1 mice displayed retinal pigment epithelium atrophy and photoreceptor degeneration. Senescent HTRA1 mice developed occult CNV, which likely resulted from the degradation of the elastic lamina of Bruch's membrane and up-regulation of VEGF. Our results indicate that increased HTRA1 is sufficient to cause PCV and is a significant risk factor for CNV.

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reditary cerebral small vessel diseases and is mainly observed in the Japanese population. Even though this pathology is inherited in an autosomal recessive manner, recent studies have described symptomatic carriers with heterozygous HTRA1 mutations who have milder symptoms than patients with biallelic HTRA1 mutations. We present the case of a Lithuanian male patient who had a stroke at the age of 36, experienced several transient ischemic attacks, and developed an early onset, progressing dementia. These clinical symptoms were associated with extensive leukoencephalopathy, lacunar infarcts, and microbleeds based on brain magnetic resonance imaging (MRI). A novel heterozygous in-frame HTRA1 gene deletion (NM_002775.5:c.533_535del; NP_002766.1:p.(Lys178del)) was identified by next generation sequencing. The variant was consistent with the patient's phenotype, which could not be explained by alternative causes, appeared highly deleterious after in silico analysis, and was not reported in the medical literature or population databases to date.

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87715 and HTRA1 in an AMD cohort from India. METHODS: The coding region of LOC387715 (exon 1) and the promoter of HTRA1 were screened by resequencing in AMD cases and normal controls. Odds ratios were calculated to assess the risk of individual genotypes. Linkage disequilibrium (LD) and haplotype frequencies were estimated with Haploview software. Population attributable risk (PAR %) for the associated SNPs and their combined effects were calculated. RESULTS: Resequencing revealed seven different SNPs in these genes, of which significant associations were noted with the risk alleles of rs10490924 (T allele; P = 5.34 x 10(-12)) in LOC387715, and rs11200638 (A allele; P = 4.32 x 10(-12)) and rs2672598 (C allele; P = 3.39 x 10(-11)) in HTRA1 among the cases. Correspondingly, the homozygous risk genotypes TT, AA, and CC in these SNPs exhibited higher disease odds and PAR %. rs10490924 and rs11200638 were in tight LD (D', 0.90; 95% CI, 0.84-0.93). G-C-T-A-C was the risk haplotype (P = 8.04 x 10(-15)), whereas the G-C-G-G-T haplotype was protective (P = 2.01 x 10(-4)). The combined effect of the CFH (CC) and LOC387715 (TT) risk genotypes exhibited a PAR of 93.7% (OR, 73.89; 95% CI, 8.69-628.13). CONCLUSIONS: The present data provided an independent validation of the association of LOC387715 and HTRA1 SNPs, along with their risk estimates among Indian patients with AMD. These associations underscore their significant involvement in AMD susceptibility, which may be useful for predictive testing.