HTRA1 Polymorphisms Research Articles

Association of ARMS2, HTRA1 and CFH genes polymorphisms in patients with age-related macular degeneration in the Malaysian population

BackgroundDespite extensive research efforts, understanding the precise causes and molecular underpinnings of age-related macular degeneration (AMD) remains elusive. Exploring different populations becomes crucial to establish conclusive insights into the role of genetic factors in AMD.MethodologyThis study aimed to investigate the association between the well-documented major risk alleles in the HTRA1, ARMS2 and CFH genes with AMD in the Malaysian multi-ethnic population. A total of 205 subjects were enrolled in this study, 103 were diagnosed with AMD while 102 represented the control subjects. Genomic DNA was extracted from peripheral blood mononuclear cells and gene amplification was performed by polymerase chain reaction. Subsequently, genotyping for the HTRA1, ARMS2 and CFH genes was performed using direct DNA sequencing analysis.ResultsSignificant associations (p < 0.05) were detected with AMD for both SNP rs11200638: G > A in the promoter of HTRA1 and rs10490924: G > T in ARMS2 but not for variant Y402H in CFH gene (p > 0.05) in our study population. The A allele frequency of rs11200638 in the HTRA1 promoter was 51.9% in cases versus 39.2% in controls (p = 0.010). The frequency of AA genotype was 28.2% for AMD cases, compared to 17.6% in controls (OR 2.58, 95% CI 1.19–5.58; p = 0.043). The frequency of the TT genotype of rs10490924 in ARMS2 was 25.2% in cases versus 8.8% in controls (OR 2.23, 95% CI 0.83–5.99; p = 0.002).ConclusionThe study reveals an association between specific genetic variants in the HTRA1 and ARMS2 genes and the occurrence of AMD in the Malaysian population. However, contrary to expectations, the study did not identify a substantial correlation between AMD and the Y402H variant of the CFH gene in this specific population.

Association of the HtrA1 rs11200638 Polymorphism with Neovascular Age-Related Macular Degeneration in Indonesia.

IntroductionThe aim of this study was to investigate the association of the HtrA1 rs11200638 polymorphism with neovascular age-related macular degeneration (nAMD) in Indonesia.MethodsThis case–control study included 80 patients with nAMD and 85 controls. Demographic parameters and whole blood were collected from each participant. Genomic DNA was extracted and used to assess the rs11200638 genotype by PCR and restriction enzyme digestion. Associations between the HtrA1 rs11200638 polymorphism and other risk factors for susceptibility to nAMD were assessed using the logistic regression model.ResultsSignificant allelic associations between the HtrA1 polymorphism and nAMD were detected (odds ratio [OR] 8.67; 95% confidence interval [CI] 4.88–15.41; P < 0.001). Genotype analysis showed a statistical difference between the nAMD group and the control group (P < 0.001). In the multiple adjusted logistic regression model, people with the AA genotype were more likely to have nAMD although there was a wide confidence interval (OR 19.65; 95% CI 4.52–85.38; P < 0.001).ConclusionOur findings show that the risk of nAMD increased in the presence of risk alleles of HtrA1 rs11200638.

Correlation Analysis of Intervertebral Disc Degeneration with HTRA1 and HAPLN1 Gene Polymorphisms

The lumbar spine, an important part of the body's motor mechanism, is more susceptible to damage as it bears most of the body's load. Age can cause clinical manifestations such as neurological impairment, back and leg pain in the lumbar spine. External forces result in nucleus pulposus out, destruction of the intervertebral disc fibrous ring, and gradual aging and damage. Lumbar degenerative change is a common middle-aged and old-aged disease, and its clinical symptoms on the initial stage are not obvious, but it becomes more and more serious as they get older. Patients with severe lumbar degenerative changes will appear symptoms such as urinary and fecal incontinence, lower extremity numbness, back pain, and sexual dysfunction. The main reason for back pain and leg pain is the degenerative changes in the lumbar intervertebral discs, at the same time which also leads to patients' lumbar instability. This study focuses on the correlation analysis of intervertebral disc degeneration with HTRA1 and HAPLN1 gene polymorphisms.

Effect of HtrA1 Polymorphism on Sensitivity to Chemotherapy in Patients with Colon Cancer.

BackgroundThis study was performed to estimate the genetic effects of HtrA1 polymorphisms rs1049331 and rs11200638 on treatment response in stage III colon cancer patients receiving 5-FU-based chemotherapy.Material/MethodsA total of 105 stage III colon cancer patients who received postoperative 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.ResultsThe 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).ConclusionsHtrA1 rs1049331 polymorphism, but not rs11200638 polymorphism, can influence individual sensitivity to 5-FU-based treatment in stage III colon cancer patients.

Association of HTRA1 and ARMS2 gene polymorphisms with response to intravitreal ranibizumab among neovascular age-related macular degenerative subjects

BackgroundThe association of HTRA1 rs11200638 and ARMS2 rs10490924 gene polymorphisms with response to intravitreal ranibizumab therapy among neovascular AMD (nAMD) subjects in Malaysia was determined in this study, followed by the expression of HTRA1 and ARMS2 genes.ResultsBoth single nucleotide polymorphisms (SNPs) recorded a significant association between nAMD and controls with HTRA1 rs11200638 at P = 0.018 (OR = 1.52, 95% CI = 1.07–215) and ARMS2 rs10490924 at P < 0.001 (OR = 2.44, 95% CI = 1.75–3.42). An association was also observed in response to ranibizumab for both SNPs in a logistic regression analysis (P < 0.001). The mRNA levels in the HTRA1 variant between responder and non-responder groups were significantly different for the homozygous non-risk GG genotype (P = 0.032).ConclusionsThe HTRA1 rs11200638 and ARMS2 rs10490924 gene polymorphisms are associated with nAMD among Malaysians. Both gene polymorphisms were also correlated with response to intravitreal ranibizumab therapy based on visual and anatomical outcomes especially the HTRA1 rs11200638 variant.

Influence of CFH, HTRA1 and ARMS2 polymorphisms in the response to intravitreal ranibizumab treatment for wet age-related macular degeneration in a Spanish population.

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. 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. There were no statistically significant differences in allelic distribution of CFH (rs1410996), ARMS2 (rs10490923) and HTRA1 (rs11200638) polymorphisms regarding to response to ranibizumab treatment. Ranibizumab treatment response is not related to CFH (rs1410996), ARMS2 (rs10490923) and HTRA1 (rs11200638) poymorphisms.

The presence of CFH, HTRA1, ARMS2, VEGF-A and VEGF-R and the appearance of age-related macular degeneration sub-types

ObjectiveTo demonstrate the genetic influence in the onset of the different age-related macular disease (AMD) subtypes by analysing the genotype distribution of CFH, ARMS2, HTRA1, VEGF-A and VEGF-R polymorphisms in patients with neovascular and atrophic AMD. Materials and methodsThe study was conducted on 101 consecutive patients with AMD diagnosis (74 exudative, 27 atrophic) following Wisconsin international classification criteria. The CFH rs1410996, ARMS2 rs10940923, VEGF-A rs833061, rs699947, and VEGF-R rs2071559 polymorphisms were analyzed using real time PCR with taqman probes, and HTRA1 rs112000638 using restriction endonucleases digestion.A study was made of the genotype distribution of the different polymorphisms in our group of patients with neovascular AMD and those with the atrophic type, and a comparison was made of the results for each one of the genes studied. ResultsNo statistically significant differences (p>.05) were found in the genotype distribution of the different polymorphisms between patients with neovascular AMD and patients with atrophic AMD in our population, although the “risk” genotypes tended to appear more frequently in patients with neovascular AMD, despite the lack of statistical significance. ConclusionsAllelic variants of CFH, ARMS2, HTRA1, VEGF-A or VEGF-R genes are not associated with the different AMD subtypes. This suggests that, although the polymorphisms seem to be associated with the disease susceptibility, they are not involved in the onset of the different clinical variants of AMD. Further studies in different populations, and with a larger cohort of patients, are needed to confirm these results.

Relación de la presencia de polimorfismos de CFH, HTRA1, ARMS2, VEGF-A y VEGF-R con la aparición de los subtipos de degeneración macular asociada a la edad

ObjectiveTo demonstrate the genetic influence in the onset of the different age-related macular disease (AMD) subtypes by analysing the genotype distribution of CFH, ARMS2, HTRA1, VEGF-A and VEGF-R polymorphisms in patients with neovascular and atrophic AMD. Materials and methodsThe study was conducted on 101 consecutive patients with AMD diagnosis (74 exudative, 27 atrophic) following Wisconsin international classification criteria. The CFH rs1410996, ARMS2 rs10940923, VEGF-A rs833061, rs699947, and VEGF-R rs2071559 polymorphisms were analysed using real time PCR with taqman probes, and HTRA1 rs112000638 using restriction endonucleases digestion.A study was made of the genotype distribution of the different polymorphisms in our group of patients with neovascular AMD and those with the atrophic type, and a comparison was made of the results for each one of the genes studied. ResultsNo statistically significant differences (P>.05) were found in the genotype distribution of the different polymorphisms between patients with neovascular AMD and patients with atrophic AMD in our population, although the “risk” genotypes tended to appear more frequently in patients with neovascular AMD, despite the lack of statistical significance. ConclusionsAllelic variants of CFH, ARMS2, HTRA1, VEGF-A or VEGF-R genes are not associated with the different AMD subtypes. This suggests that, although the polymorphisms seem to be associated with the disease susceptibility, they are not involved in the onset of the different clinical variants of AMD. Further studies in different populations, and with a larger cohort of patients, are needed to confirm these results.

CFH (rs1410996), HTRA1 (rs112000638) and ARMS2 (rs10490923) Gene Polymorphisms are Associated with AMD Risk in Spanish Patients

ABSTRACTPurpose: Age-related macular degeneration (AMD) is the main cause of legal blindness in the western adult population. We investigated the association between SNPs located in CFH, ARMS2 and HTRA1 and AMD in Spanish patients.Patients and Methods: We obtained peripheral blood samples from 121 patients with a diagnosis of AMD (84 exudative and 37 atrophic) at the Department of Ophthalmology of the University Hospital of Salamanca. We took 91 subjects as a control group. We studied a single nucleotide polymorphism (SNP) in each patient for each of the genes associated with high susceptibility to developing AMD using Real-time PCR with TaqMan probes for CFH and ARMS2 polymorphisms and PCR-RFLP for HTRA1 polymorphism.Results: We observed a statistically significant difference between patients and controls in the distribution of CFH rs1410996 genotypes, patients homozygous for the C-allele have twice the risk of developing the disease (p = 0.010; OR = 2,176 (1.194–3.964)). The analysis of ARMS2 rs10490923 polymorphism also showed differences in allelic distribution between the case and control groups (p < 0.001). Carriers of the T-allele appear more frequently in the group of patients (p < 0.001; OR = 3.340 (1.848–6.060)). Our results also confirm significant differences in the distribution of HTRA1 rs112000638 polymorphism with an increased representation of the G-allele in the patient’s group (p < 0.001; OR = 6.254(3.463–12.280)). Our study also indicates that TTGG ARMS2/HTRA1 (rs10490923/rs112000638) haplotype increases the risk of developing AMD by 9 times.Conclusions: Our results show that genotypes of ARMS2 (rs10490923), HTRA1 (rs112000638) and CFH (rs1410996) polymorphisms are related to an increased risk of suffering AMD in Spanish patients.

Influence of CFH, HTRA1 and ARMS2 haplotype polymorphisms in the development of age-related macular disease

ObjectiveTo demonstrate genetic influence on the onset of age-related macular disease (AMD), analyzing genotype distribution of haplotypes, including polymorphisms of genes with proved relationships with AMD risk (CFH, ARMS2, HTRA1) in patients with AMD and in healthy people. MethodsWe took 101 consecutive patients with an AMD diagnosis following Wisconsin international classification. For our control group, we took 91 patients without AMD or any significant macular changes. We analyzed CFH rs 1410996, ARMS2 rs 10940923 polymorphisms using real time PCR with Taqman probes, and HTRA1-625 using restriction endonuclease digestion.We studied haplotypes by simultaneously combining genotypes which, in previous studies, had been shown to have relationship with AMD (CFH, ARMS2, HTRA1) in patients with AMD and healthy people. ResultsThere was a statistically significant higher proportion of patients with AMD simultaneously expressing CFH GG (rs 1410996) and ARMS2 TT (rs 10940923) (p=.037; OR: 7.742 [1.010–63.156]); ARMS2 TT (rs 10940923) and HTRA 1-625 TT (p=.001; OR: 9.006 [2.019–40.168]) and CFH GG (rs 1410996), ARMS2 TT (rs 1040923) and HTRA1-625 GG (p=.043; OR: 6.702 [1.003–55.565]) genotypes. ConclusionsHaplotypes which combine “risk genotypes”, demonstrated in previous studies, of our analyzed polymorphisms are more frequent in patients with AMD than in the control group, and they seem to increase the risk of suffering the disease in our population.

Effect of the Gas6 c.834+7G&gt;A Polymorphism and the Interaction of Known Risk Factors on AMD Pathogenesis in Hungarian Patients

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. Numerous genetic factors contribute to the development of the multifactorial disease. We performed a case-control study to assess the risk conferred by known and candidate genetic polymorphisms on the development of AMD. We searched for genetic interactions and for differences in dry and wet AMD etiology. We enrolled 213 patients with exudative, 67 patients with dry AMD and 106 age and ethnically matched controls. Altogether 12 polymorphisms in Apolipoprotein E, complement factor H, complement factor I, complement component 3, blood coagulation factor XIII, HTRA1, LOC387715, Gas6 and MerTK genes were tested. No association was found between either the exudative or the dry form and the polymorphisms in the Apolipoprotein E, complement factor I, FXIII and MerTK genes. Gas6 c.834+7G>A polymorphism was found to be significantly protective irrespective of other genotypes, reducing the odds of wet type AMD by a half (OR = 0.50, 95%CI: 0.26–0.97, p = 0.04). Multiple regression models revealed an interesting genetic interaction in the dry AMD subgroup. In the absence of C3 risk allele, mutant genotypes of both CFH and HTRA1 behaved as strongly significant risk factors (OR = 7.96, 95%CI: 2.39 = 26.50, p = 0.0007, and OR = 36.02, 95%CI: 3.30–393.02, p = 0.0033, respectively), but reduced to neutrality otherwise. The risk allele of C3 was observed to carry a significant risk in the simultaneous absence of homozygous CFH and HTRA1 polymorphisms only, in which case it was associated with a near-five-fold relative increase in the odds of dry type AMD (OR = 4.93, 95%CI: 1.98–12.25, p = 0.0006). Our results suggest a protective role of Gas6 c.834+7G>A polymorphism in exudative AMD development. In addition, novel genetic interactions were revealed between CFH, HTRA1 and C3 polymorphisms that might contribute to the pathogenesis of dry AMD.

The effect of a Gas6 c.834+7G&gt;a polymorphism and the interaction of known risk factors on AMD pathogenesis in Hungarian patients

AbstractPurpose We performed a case‐control study to search for genetic interactions and for differences in dry and wet age‐related macular degeneration (AMD) pathogenesis.Methods We enrolled 213 patients with exudative, 67 patients with dry AMD and 106 age and ethnically matched controls. Altogether 12 polymorphisms in Apolipoprotein E, complement factor H, complement factor I, complement component 3, blood coagulation factor XIII, HTRA1, LOC387715, Gas6 and MerTK genes were tested.Results No association was found between either the exudative or the dry form and the genetic backround in the case of Apolipoprotein E, complement factor I, FXIII and MerTK polymorphisms. Gas6 c.834+7G&gt;A polymorphism was found to be significantly protective irrespective of other genotypes, reducing the odds of wet type AMD by a half (OR=0.50, 95%CI: 0.26‐0.97, p=0.04). Multiple regression models revealed a genetic interaction in the dry AMD subgroup. In the absence of a C3 risk allele, mutated alleles of both CFH and HTRA1 behaved as strongly significant risk factors (OR=7.96, 95%CI: 2.39=26.50, p=0.0007, and OR=36.02, 95%CI: 3.30‐393.02, p=0.0033, respectively), but reduced to neutrality otherwise. The risk allele of C3 was observed to carry a significant risk in the simultaneous absence of homozygous CFH and HTRA1 polymorphisms only, in which case it was associated with a near‐five‐fold relative increase in the odds of dry type AMD(OR=4.93, 95%CI: 1.98‐12.25, p=0.0006)Conclusion Our results shed light on the protective role of Gas6 c.834+7G&gt;A polymorphism in exudative AMD development. In addition, novel genetic interactions were revealed in dry AMD pathogenesis.

Use of buccal swab as a source of genomic DNA for genetic screening in patients with age-related macular degeneration

The collection of buccal cells with swabs provides a noninvasive method for obtaining genomic DNA for genetic screening. We aimed to study the feasibility of using buccal swabs for genetic screening in patients with exudative age-related macular degeneration (AMD). Blood and buccal swabs were collected for genetic analysis from 65 patients with exudative AMD. Genomic DNA was isolated from either blood or buccal swabs. The yield of genomic DNA from both sources was determined by spectrophotometer. Genotyping for CFH, LOC387715, and HTRA1 Polymorphisms was performed using a method of polymerase chain reaction (PCR) followed by restriction enzyme digestion. Results using genomic DNA from blood or buccal swabs were compared. Three swabs were obtained from each patient, 2 from each side of buccal mucosa, and 1 from both upper and inferior gingival mucosa. From swabs with genomic DNA extracted within a week after sample collection, an average of (3.17 ± 1.46) µg genomic DNA was obtained from swab collected from the left or right side buccal mucosa, and (3.94 ± 1.04) µg from swab collected from the upper and inferior gingival mucosa, with relatively higher yield of genomic DNA from the upper and inferior gingival mucosa (t = 6.79, P < 0.05). From swabs of the left or right side buccal mucosa after being stored at -20°C for 12 months, an average of (3.10 ± 1.17) µg genomic DNA was obtained, which showed no statistically significant difference as compared to the yield of genomic DNA extracted from newly collected swabs (t = 0.59, P > 0.05). In all 65 patients, genomic DNA isolated from either buccal swabs or blood samples showed exactly the same results regarding the genotypes of CFH, LOC387715, and HTRA1 Polymorphisms. Buccal swab is a simple, noninvasive, and reliable source for obtaining genomic DNA. Swabs stored for 12 months at -20°C provide similar amount of genomic DNA as the freshly collected swabs.

Association of ARMS2/HTRA1 variants with polypoidal choroidal vasculopathy phenotype in a Korean population

To investigate whether ARMS2 (rs10490924)/HTRA1 (rs11200638) variants are associated with polypoidal choroidal vasculopathy (PCV) in a Korean population and with various PCV phenotypes. A case-control study comprised of 103 patients with PCV and 112 control subjects. The PCV and control groups were genotyped for ARMS2 (rs10490924) and HTRA1 (rs11200638) polymorphisms. Clinical characteristics were evaluated, including best-corrected visual acuity (BCVA), fundus findings, and angiographic findings, at first visit. Two single nucleotide polymorphisms generated highly significant allelic associations with PCV. The frequency of vitreous hemorrhage (VH) was different among the genotypes with respect to both rs10490924 and rs11200638. The frequency of the T allele of rs10490924 was higher in PCV patients with VH than in PCV patients without VH. The frequency of the A allele of rs11200638 was higher in PCV patients with VH than in PCV patients without VH. In rs10490924, the mean BCVA of the GG genotype group was better than that of the TT and TG genotype groups. In rs11200638, the mean BCVA of the GG genotype group was better than that of the AA and AG genotype groups. The ARMS2 (rs10490924)/HTRA1 (rs11200638) variants are significantly associated with the risk of PCV in a Korean population. ARMS2/HTRA1 variants contribute significantly to the PCV phenotypes, including frequency of VH and mean BCVA at baseline.

Analysis of complement factor H Y402H, LOC387715, HTRA1 polymorphisms and ApoE alleles with susceptibility to age‐related macular degeneration in Hungarian patients

Recent studies strongly support the role of genetic factors in the aetiology of age-related macular degeneration (AMD). We investigated the frequency of Tyr402His polymorphism of the complement factor H (CFH) gene, Ser69Ala polymorphism at LOC387715, rs11200638 polymorphism of the HTRA1 gene and different apolipoprotein E (ApoE) alleles in Hungarian patients with AMD in order to determine the disease risk conferred by these factors. In a case-control study, we performed clinical and molecular genetic examination of 105 AMD patients (48 patients in the early and 57 in the late subgroup) and 95 unrelated healthy controls. Detailed patient histories were recorded with the use of a questionnaire focusing on known risk factors for AMD. In the early AMD subgroup, homozygous CFH, LOC387715 or HTRA1 polymorphisms conferred a 4.9-fold (95% confidence interval [CI] 1.7-14.2), 7.4-fold (95% CI 2.1-26.2) or 10.1-fold (95% CI 2.5-40.8) risk of disease, respectively. In the late AMD subgroup, carriers of two CFH, LOC387715 or HTRA1 risk alleles were at 10.7-fold (95% CI 3.7-31.0), 11.3-fold (95% CI 3.2-40.4) or 13.5-fold (95% CI 3.3-55.4) greater disease risk, respectively. Two CFH and one LOC387715 risk alleles in combination conferred a 15.0-fold (95% CI 3.2-71.0) increase in risk, whereas two LOC387715 risk alleles combined with one CFH risk allele was associated with a 14.0-fold (95% CI 2.1-95.1) increased risk for late AMD. ApoE alleles neither increased disease risk nor proved to be protective. The CFH, LOC387715 and HTRA1 polymorphisms are strongly associated with the development of AMD in the Hungarian population. The association is particularly pronounced when homozygous risk alleles are present and in the late stages of the disease.

Genetic influences on biomarkers in AMD

Abstract Purpose To describe the genetic influences on biomarkers in age‐related macular degeneration (AMD). Methods We have previously demonstrated that AMD is associated with systemic activation of complement factors, alternation of cytokine levels, and changes in the matrix protein level. In this study, we examine the association of these changes with the genotype of the common "AMD" genes. Results Activation of complement factors were closely associated with "at risk" complement factor polymorphisms. Plasma cytokine levels were not associated with complement factor H polymorphisms, but were associated with the "at risk" HTRA1 polymorphisms. Plasma matrix protein showed a trend association with the "at risk" HTRA1 polymorphisms. Conclusion Traditional genotype‐phenotype correlation is based on clinical phenotype. Biomarker research is leading to a new area of genotype‐phenotype correlation research. It is unclear at this stage, how important these correlations are. Further studies are required.

Meta-analysis of the association of the HTRA1 polymorphisms with the risk of age-related macular degeneration

HTRA1 was considered as one of important age-related macular degeneration (AMD) candidate genes. However, due to population heterogeneity and bias from case–control study, the association between HTRA1 and AMD needs further confirmation across different studies in different population. In this study, a meta-analysis was performed in 14 case–control studies which were published before August 31, 2008. Effect of HTRA1 polymorphism with AMD was synthetically evaluated. The pooled odds ratio (OR) for heterozygous genotype GA versus wild homozygous genotype GG is 2.13 (95% CI: 1.90, 2.39), the OR of homozygous genotype AA versus GG is 6.92 (95% CI: 5.74, 8.34) and the OR of allele A carrier (GA + AA) versus GG is 3.02 (95% CI: 2.57, 3.53). Sub-analysis indicated that the risk of HTRA1 rs11200638 on wet AMD was stronger than dry AMD, and it seems that HTRA1 rs11200638 could increase the risk of AMD in all races. This study strengthens the hypothesis of association between rs11200638 in the promoter of HTRA1 polymorphism and AMD. The variant of HTRA1/625G → A could be a potentially promising genetic biomarker of AMD.

Rhesus monkeys and humans share common susceptibility genes for age-related macular disease

Age-related macular degeneration (AMD), a complex multigenic disorder and the most common cause of vision loss in the elderly, is associated with polymorphisms in the LOC387715/ARMS2 and HTRA1 genes on 10q26. Like humans, macaque monkeys possess a macula and develop age-related macular pathologies including drusen, the phenotypic hallmark of AMD. We genotyped a cohort of 137 unrelated rhesus macaques with and without macular drusen. As in humans, one variant within LOC387715/ARMS2 and one in HTRA1 were significantly associated with affected status. HTRA1 and the predicted LOC387715/ARMS2 gene were both transcribed in rhesus and human retina and retinal pigment epithelium. Among several primate species, orthologous exons for the human LOC387715/ARMS2 gene were present only in Old World monkeys and apes. In functional analyses, the disease-associated HTRA1 polymorphism resulted in a 2-fold increase in gene expression, supporting a role in pathogenesis. These results demonstrate that two genes associated with AMD in humans are also associated with macular disease in rhesus macaques and that one of these genes is specific to higher primates. This is the first evidence that humans and macaques share the same genetic susceptibility factors for a common complex disease.

Genotype–Phenotype Correlations for Exudative Age-Related Macular Degeneration Associated with HomozygousHTRA1andCFHGenotypes

Major genetic factors for age-related macular degeneration (AMD) have recently been identified as susceptibility risk factors, including polymorphisms of HTRA1 and CFH genes. The purpose was to analyze the angiographic features of patients harboring homozygous genotypes for HTRA1 and CFH genes in a French exudative AMD population. Two hundred patients affected with exudative AMD were genotyped for the polymorphisms rs11200638 of the HTRA1 gene and rs10611710 of the CFH gene. Four homozygous groups were extracted from the entire cohort: double homozygous for wild-type alleles of both genes (group 1), homozygous for the polymorphism of the HTRA1 gene only (group 2), homozygous for the polymorphism of the CFH gene only (group 3), and double homozygous carriers for both polymorphisms (group 4). Choroidal neovascularization (CNV) was graded as classic and predominantly classic (PC), occult, minimally classic (MC), or retinal angiomatosis proliferation (RAP). Group 1 (n = 9) presented 44.4% classic and PC, 33.3% occult, 11.1% MC, and 11.1% RAP. Group 2 (n = 12) presented 50.0% classic and PC, 33.3% occult, no MC CNV and 16.7% RAP. Group 3 (n = 28) presented 10.7% classic and PC, 67.9% occult, 14.3% MC, and 7.1% RAP. Group 4 (n = 17) presented 29.4% classic and PC, 52.9% occult, 11.8% MC, and 5.9% RAP. Occult CNV or MC CNV was more frequently observed in group 3 than in group 2 (82.1% vs 33.3%; P < 0.02). Classic and PC CNV were more frequently observed in group 2 than in group 3 (50% vs. 10.7%; P < 0.03). This attempt at a genotypic-angiographic correlation in an exudative AMD sample suggests an association between occult or MC CNV and the CFH polymorphism and between classic and PC CNV and the HTRA1 polymorphism.

HTRA1 POLYMORPHISM IN DRY AND WET AGE-RELATED MACULAR DEGENERATION

To investigate HTRA1 polymorphisms in unrelated Taiwan Chinese patients with age-related macular degeneration (AMD) and control subjects without AMD. A total of 95 unrelated Taiwan Chinese patients with AMD and 90 age- and sex-matched control subjects were enrolled in the study. Genomic DNA was prepared from peripheral blood obtained from all patients with AMD and control subjects. Polymerase chain reactions were used to analyze two HTRA1 single-nucleotide polymorphisms (rs11200638 [G/A] and rs10490924 [G/T]). Of the 95 participants with AMD, dry AMD was diagnosed in 52 patients and wet AMD in 43 patients. Both rs11200638 (G/A) and rs10490924 (G/T) were significantly associated with all AMD (rs11200638: P = 6.7 x 10(-7) for an additive allele-dosage model, OR(het) = 1.97 [0.81, 4.81], OR(hom) = 8.59 [3.28, 22.49], A allele: 73% in all AMD versus 47% in controls; rs10490924: P = 9.2 x 10(-6), OR(het) = 1.86 [0.79, 4.35], OR(hom) = 5.08 [2.21, 11.70], T allele: 73% in all AMD versus 50% in controls). In terms of significance of association, rs11200638 was the most significantly associated variant. Subtype analysis including dry and wet AMD also revealed similar results. Haplotype analysis demonstrated that AT was significantly associated with wet and all AMD (P = 0.011 and 0.004, respectively), whereas GG was significantly associated with the control group when compared with all AMD (P = 0.035). The study demonstrated that both single-nucleotide polymorphisms were significantly associated with dry and wet AMD and rs11200638 was the most significantly associated variant in a Taiwan Chinese population.