Correction: A 32 kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-Related Macular Degeneration.
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ABSTRACT:
SUBMITTER: Sivakumaran TA
PROVIDER: S-EPMC6301675 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Correction: A 32 kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-Related Macular Degeneration.
Sivakumaran Theru A TA Igo Robert P RP Kidd Jeffrey M JM Itsara Andy A Kopplin Laura J LJ Chen Wei W Hagstrom Stephanie A SA Peachey Neal S NS Francis Peter J PJ Klein Michael L ML Chew Emily Y EY Ramprasad Vedam L VL Tay Wan-Ting WT Mitchell Paul P Seielstad Mark M Stambolian Dwight E DE Edwards Albert O AO Lee Kristine E KE Leontiev Dmitry V DV Jun Gyungah G Wang Yang Y Tian Liping L Qiu Feiyou F Henning Alice K AK LaFramboise Thomas T Sen Parveen P Aarthi Manoharan M George Ronnie R Raman Rajiv R Das Manmath Kumar MK Vijaya Lingam L Kumaramanickavel Govindasamy G Wong Tien Y TY Swaroop Anand A Abecasis Goncalo R GR Klein Ronald R Klein Barbara E K BEK Nickerson Deborah A DA Eichler Evan E EE Iyengar Sudha K SK
PloS one 20181220 12
[This corrects the article DOI: 10.1371/journal.pone.0025598.]. ...[more]
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Project description:Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N?=?293) and AMD cases (White N?=?4210 Indian?=?134; Malay?=?140) and controls (White N?=?3229; Indian?=?117; Malay?=?2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI?=?[2.51, 3.01]; p?=?8.31×10(-109)); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p?=?3.52×10(-9)) and by 15.57-fold (P?=?0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ?CNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number.
| S-EPMC3192039 | biostudies-literature
Project description:The purpose of the study was to determine serum complement factor H (CFH) levels in patients of age related macular degeneration (AMD) and examine its association with CFH Y402H polymorphism. 115 AMD patients and 61 normal controls were recruited in this study. The single nucleotide polymorphism was assayed by real time PCR and serum CFH levels were measured by ELISA and standardized to total serum protein. Chi-square test was applied to polymorphism analysis while Mann Whitney U-statistic for CFH-levels. Mendelian randomization approach was used for determining causal relationship. The genotype frequency differed between the AMD patients (TT- 18.3%, TC-41.3% and CC-40.4%) and controls (TT-76.3%, TC-13.6%, and CC-10.1%) (p?=?0001). The frequency of alleles was also significantly different when AMD (T-39% and C-61%) was compared to controls (T-83% and C-17%) (p?=?0.0001). Level of serum CFH was significantly lower in AMD patients as compared to normal controls (p?=?0.001). Our data showed that the CFH Y402H polymorphism is a risk factor for AMD in the North Indian population. Mendelian randomization approach revealed that CFH Y402H polymorphism affects AMD risk through the modification of CFH serum levels.
| S-EPMC3726372 | biostudies-literature
Project description:In developed countries, age-related macular degeneration is a common cause of blindness in the elderly. A common polymorphism, encoding the sequence variation Y402H in complement factor H (CFH), has been strongly associated with disease susceptibility. Here, we examined 84 polymorphisms in and around CFH in 726 affected individuals (including 544 unrelated individuals) and 268 unrelated controls. In this sample, 20 of these polymorphisms showed stronger association with disease susceptibility than the Y402H variant. Further, no single polymorphism could account for the contribution of the CFH locus to disease susceptibility. Instead, multiple polymorphisms defined a set of four common haplotypes (of which two were associated with disease susceptibility and two seemed to be protective) and multiple rare haplotypes (associated with increased susceptibility in aggregate). Our results suggest that there are multiple disease susceptibility alleles in the region and that noncoding CFH variants play a role in disease susceptibility.
| S-EPMC1941700 | biostudies-literature
Project description:To examine if the gene encoding C-reactive protein (CRP), a biomarker of inflammation, confers risk for neovascular age-related macular degeneration (AMD) in the presence of other modifiers of inflammation, including body mass index (BMI), diabetes, smoking, and complement factor H (CFH) Y402 genotype. Additionally we examined the degree to which CRP common variation was in linkage disequilibrium (LD) within our cohort.We ascertained 244 individuals from 104 families where at least one member had neovascular AMD, and a sibling had normal maculae and was past the age of the index patient's diagnosis of neovascular AMD. We employed a direct sequencing approach to analyze the 5'-promoter region as well as the entire coding region and the 3'-untranslated region of the CRP gene. CFH Y402 genotype data was available for all participants. Lifestyle and medical factors were obtained via administration of a standardized questionnaire. The family-based association test, haplotype analysis, McNemar's test, and conditional logistic regression were used to determine significant associations and interactions. Haploview was used to calculate the degree of LD (r2) between all CRP variants identified.Six single nucleotide polymorphisms (SNPs; rs3091244, rs1417938, rs1800947, rs1130864, rs1205, and rs3093068) comprised one haplotype block of which only rs1130864 and rs1417938 were in high LD (r2=0.94). SNP rs3093068 was in LD but less so with rs3093059 (r2=0.83), which is not part of the haplotype block. Six SNPs made up six different haplotypes with > or = 5% frequency, none of which were significantly associated with AMD risk. No statistically significant association was detected between any of the nine common variants in CRP and neovascular AMD when considering disease status alone or when controlling for smoking exposure, BMI, diabetes, or CFH genotype. Significant interactions were not found between CRP genotypes and any of the risk factors studied. No novel CRP variation was identified.We provide evidence that if elevated serum/plasma levels of CRP are associated with neovascular AMD, it is likely not due to genetic variation within CRP, but likely due to variations in some other genetic as well as epidemiological factors.
| S-EPMC2515825 | biostudies-literature
Project description:PurposeTo investigate the association between polymorphism rs1061170 (T1277C, Y402H) in age-related macular degeneration (AMD) susceptibility gene Complement Factor H (CFH) and treatment response of neovascular AMD.MethodsWe performed a literature-based meta-analysis including 10 published association studies involving 1,510 patients. Treatments included anti-VEGF (bevacizumab and ranibizumab) or photodynamic therapy. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed- and random-effects models. Q-statistic test was used to assess heterogeneity.ResultsPolymorphism rs1061170 showed a significant summary OR of 1.68 (95% CI, 1.09 to 2.60; P = 0.020; CC versus TT; random-effects) for treatment response of neovascular AMD with heterogeneity of 0.09. In subgroup analysis, rs1061170 was more likely to be a predictor of response to anti-VEGF therapy (P = 0.011). However, heterozygous TC genotype was not associated with altered treatment response (OR = 1.18, 95% CI, 0.95 to 1.47; P = 0.145; fixed-effects). Influence analysis indicated the robustness of our findings.Conclusionsrs1061170 might be associated with treatment response of neovascular AMD, especially for the anti-VEGF agents. It might be the first meta-analytically confirmed genetic marker predictive for AMD treatment response though a further validation in larger studies is needed.
| S-EPMC3419212 | biostudies-literature
Project description:Age-related macular degeneration (AMD) remains the leading cause of blindness in elderly people, but the pathophysiology of this disease is still largely unknown. We investigated the systemic expression of angiogenesis-regulating growth factors and selected miRNAs known to regulate angiogenesis in AMD patients. We also focused on possible correlations of their expression with the presence of CFH Y402H or ARMS A69S risk variants. A total of 354 AMD patients and 121 controls were enrolled in this study. The levels of angiogenesis-regulating factors were analyzed in plasma samples using Luminex technology. The expression of selected miRNAs was analyzed in peripheral blood plasma using real-time qPCR. The genetic analysis was performed with an Illumina NextSeq500 system. AMD was an independent factor associated with lower levels of angiogenin (? = -0.29, p < 0.001), endostatin (? = -0.18, p < 0.001), FGF-basic (? = -0.18, p < 0.001), PlGF (? = -0.24, p < 0.001), miRNA-21-3p (? = -0.13, p = 0.01) and miRNA-155-5p (? = -0.16, p = 0.002); and with higher levels of FGF-acidic (? = 0.11, p = 0.03), miRNA-23a-3p (? = 0.17, p < 0.001), miRNA-126-5p (? = 0.13, p = 0.009), miRNA-16-5p (? = 0.40, p < 0.001), miRNA-17-3p (? = 0.13, p = 0.01), miRNA-17-5p (? = 0.17, p < 0.001), miRNA-223-3p (? = 0.15, p = 0.004), and miRNA-93 (? = 0.11, p = 0.04). The expression of analyzed miRNA molecules significantly correlated with the levels of tested angiogenesis-regulating factors and clinical parameters in AMD patients, whereas such correlations were not observed in controls. We also found an association between the CFH Y402H polymorphism and miRNA profiles, whereby TT homozygotes showed evidently higher expression of miRNA-16-5p than CC homozygotes or TC heterozygotes (p = 0.0007). Our results suggest that the balance between systemic pro- and anti-angiogenic factors and miRNAs is vital in multifactorial AMD pathogenesis.
| S-EPMC6887747 | biostudies-literature
Project description:Pharmacogenetic studies indicate that a variable response to anti-vascular endothelial growth factor (VEGF) therapy in patients with neovascular form of AMD (nAMD) may be due to polymorphisms in the complement factor H gene (CFH). This study is the first to investigate the association between CFH Y402H polymorphism and the response to ranibizumab therapy in Malaysian patients with nAMD. We included 134 patients with nAMD, examined between September 2014 and February 2016. The diagnosis of nAMD was confirmed by ophthalmologic examination, before ranibizumab therapy was started. Each patient received an intravitreal injection of 0.5 mg/0.05 ml ranibizumab following a treat-and-extend (TE) regimen. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were recorded after 3 and 6 months following the first injection and compared with the baseline values. Genotyping of Y402H (rs1061170) polymorphism was performed using PCR-RFLP and the amplified product was digested with MluCI restriction enzyme. Association between the Y402H genotypes and response to treatment was determined by a logistic regression analysis of responder (n = 49) and non-responder (n = 84) group. Significantly worse mean BCVA was observed for the CC genotype compared to the TT + CT genotype in the total sample after 6-month follow-up (p = 0.018). Comparing the baseline and 6-month point measurements, improved mean BCVA was observed in responder group, while worse mean BCVA was recorded for non-responder group. However, our regression analysis, adjusted for confounding factors, showed no significant association between the Y402H genotypes and response to treatment in nAMD patients under the recessive model (p > 0.05). Overall, our results suggest that factors other than Y402H polymorphism may be involved in the progression of nAMD after treatment with anti-VEGF agents, in Malaysian population.
| S-EPMC6087554 | biostudies-literature
Project description:PurposeGenetic susceptibility could be modified by environmental factors and may also influence differential responses to treatments for age-related macular degeneration (AMD). We investigated whether genotype could influence response to docosahexaenoic acid (DHA)-supplementation in the occurrence of choroidal new vessels (CNV).MethodsThe Nutritional AMD Treatment 2 (NAT2) study was a randomized, placebo-controlled, double-blind, parallel, comparative study, including 250 patients aged 55 to 85 years with early lesions of age-related maculopathy, visual acuity better than 0.4 Logarithm of Minimum Angle of Resolution units in the study eye and neovascular AMD in the fellow eye. Patients were randomized at baseline to receive either 3 daily fish-oil capsules, each containing 280 mg DHA, 90 mg EPA and 2 mg Vitamin E, or placebo.ResultsPatients carrying the risk allele (C) for CFH Y402H had no statistically significant increased risk for developing CNV in the study eye (Hazard Ratio (HR)=0.97; 95% Confidence Interval (CI): 0.54-1.76 for heterozygous and HR=1.29; 95%CI: 0.69-2.40 for homozygous). Patients carrying the risk allele (T) for ARMS2 A69S had no statistically significant increased risk for developing CNV in the study eye (HR=1.68; 95%CI: 0.91-3.12) for heterozygous and HR=1.78; 95%CI: 0.90-3.52 for homozygous). A significant interaction was observed between CFH Y402H and DHA-supplementation (p=0.01). We showed a protective effect of DHA-supplementation among homozygous non-risk patients. Among these patients, occurrence of CNV was 38.2% in placebo group versus 16.7% in DHA group (p=0.008).ConclusionsThese results suggest that a genetic predisposition to AMD conferred by the CFH Y402H variant limits the benefit provided by DHA supplementation.Trial registrationISRCTN registry 98246501.
| S-EPMC4489493 | biostudies-literature
Project description:BackgroundThe wet form of age-related macular degeneration (ARMD) is a leading cause of irreversible blindness in Caucasians. Our purpose was to assess influence of gene polymorphisms A69S (rs10490924) and R38X (rs2736911) ARMS2 and Y402 (rs1061170) CFH on wet ARMD risk in a Polish population.Material/methods130 unrelated patients (90 with wet ARMD and 40 controls) took part in the study. Dry blood was used for DNA isolation. PCR amplification and gene sequencing were performed. In subjects with R38X and A69S, SNP gene cloning was used to exclude the possible combined variant.ResultsHomozygous Y402H and A69S conferred a significance risk of wet ARMD in Poland: Y402H odds ratio (OR) was 5.57 (95% confidence interval: 1.58-19.6), p=0.002; and A69S OR was 7.72 (95% confidence interval: 1.73-34.36), p=0.001. R38X is probably more common in healthy subjects: OR was 0.45 (95% confidence interval: 0.19-1.05), p=0.053.ConclusionsThe etiologic role in ARMD of A69S ARMS2 and Y402H CFH gene variants were confirmed in a Polish population for the first time. R38X variant of ARMS2 seems to be protective from wet ARMD.
| S-EPMC3560583 | biostudies-literature
Project description:A single nucleotide polymorphism, tyrosine at position 402 to histidine (Y402H), within the gene encoding complement factor H (FH) predisposes individuals to acquiring age-related macular degeneration (AMD) after aging. This polymorphism occurs in short consensus repeat (SCR) 7 of FH and results in decreased binding affinity of SCR6-8 for heparin. As FH is responsible for regulating the complement system, decreased affinity for heparin results in decreased regulation on surfaces of self. To understand the involvement of the Y402H polymorphism in AMD, we leverage methods from bioinformatics and computational biophysics to quantify structural and dynamical differences between SCR7 isoforms that contribute to decreased pattern recognition in SCR7H402. Our data from molecular and Brownian dynamics simulations suggest a revised mechanism for decreased heparin binding. In this model, transient contacts not observed in structures for SCR7 are predicted to occur in molecular dynamics simulations between coevolved residues Y402 and I412, stabilizing SCR7Y402 in a conformation that promotes association with heparin. H402 in the risk isoform is less likely to form a contact with I412 and samples a larger conformational space than Y402. We observe energy minima for sidechains of Y402 and R404 from SCR7Y402 that are predicted to associate with heparin at a rate constant faster than energy minima for sidechains of H402 and R404 from SCR7H402. As both carbohydrate density and degree of sulfation decrease with age in Bruch's membrane of the macula, the decreased heparin recognition of SCR7H402 may contribute to the pathogenesis of AMD.
| S-EPMC6350009 | biostudies-literature