共查询到20条相似文献,搜索用时 31 毫秒
1.
Sanna P. Seitsonen P?ivi Onkamo Gang Peng Momiao Xiong Petri V. Tommila P?ivi H. Ranta Juha M. Holopainen Jukka A. Moilanen Tapani Palosaari Kai Kaarniranta Seppo Meri Ilkka R. Immonen Irma E. J?rvel? 《PloS one》2008,3(12)
Background
Variants in the complement cascade genes and the LOC387715/HTRA1, have been widely reported to associate with age-related macular degeneration (AMD), the most common cause of visual impairment in industrialized countries.Methods/Principal Findings
We investigated the association between the LOC387715 A69S and complement component C3 R102G risk alleles in the Finnish case-control material and found a significant association with both variants (OR 2.98, p = 3.75×10−9; non-AMD controls and OR 2.79, p = 2.78×10−19, blood donor controls and OR 1.83, p = 0.008; non-AMD controls and OR 1.39, p = 0.039; blood donor controls), respectively. Previously, we have shown a strong association between complement factor H (CFH) Y402H and AMD in the Finnish population. A carrier of at least one risk allele in each of the three susceptibility loci (LOC387715, C3, CFH) had an 18-fold risk of AMD when compared to a non-carrier homozygote in all three loci. A tentative gene-gene interaction between the two major AMD-associated loci, LOC387715 and CFH, was found in this study using a multiplicative (logistic regression) model, a synergy index (departure-from-additivity model) and the mutual information method (MI), suggesting that a common causative pathway may exist for these genes. Smoking (ever vs. never) exerted an extra risk for AMD, but somewhat surprisingly, only in connection with other factors such as sex and the C3 genotype. Population attributable risks (PAR) for the CFH, LOC387715 and C3 variants were 58.2%, 51.4% and 5.8%, respectively, the summary PAR for the three variants being 65.4%.Conclusions/Significance
Evidence for gene-gene interaction between two major AMD associated loci CFH and LOC387715 was obtained using three methods, logistic regression, a synergy index and the mutual information (MI) index. 相似文献2.
Background
Age-related maculopathy (ARM) is a common cause of visual impairment in the elderly populations of industrialized countries and significantly affects the quality of life of those suffering from the disease. Variants within two genes, the complement factor H (CFH) and the poorly characterized LOC387715 (ARMS2), are widely recognized as ARM risk factors. CFH is important in regulation of the alternative complement pathway suggesting this pathway is involved in ARM pathogenesis. Two other complement pathway genes, the closely linked complement component receptor (C2) and complement factor B (CFB), were recently shown to harbor variants associated with ARM.Methods/Principal Findings
We investigated two SNPs in C2 and two in CFB in independent case-control and family cohorts of white subjects and found rs547154, an intronic SNP in C2, to be significantly associated with ARM in both our case-control (P-value 0.00007) and family data (P-value 0.00001). Logistic regression analysis suggested that accounting for the effect at this locus significantly (P-value 0.002) improves the fit of a genetic risk model of CFH and LOC387715 effects only. Modeling with the generalized multifactor dimensionality reduction method showed that adding C2 to the two-factor model of CFH and LOC387715 increases the sensitivity (from 63% to 73%). However, the balanced accuracy increases only from 71% to 72%, and the specificity decreases from 80% to 72%.Conclusions/Significance
C2/CFB significantly influences AMD susceptibility and although accounting for effects at this locus does not dramatically increase the overall accuracy of the genetic risk model, the improvement over the CFH-LOC387715 model is statistically significant. 相似文献3.
Jennyfer Zerbib Johanna M. Seddon Florence Richard Robyn Reynolds Nicolas Leveziel Pascale Benlian Patrick Borel Josué Feingold Arnold Munnich Gisèle Soubrane Josseline Kaplan Jean-Michel Rozet Eric H. Souied 《PloS one》2009,4(10)
Major genetic factors for age-related macular degeneration (AMD) have recently been identified as susceptibility risk factors, including variants in the CFH gene and the ARMS2 LOC387715/HTRA1locus. Our purpose was to perform a case-control study in two populations among individuals who did not carry risk variants for CFHY402H and LOC387715 A69S (ARMS2), called “study” individuals, in order to identify new genetic risk factors. Based on a candidate gene approach, we analyzed SNP rs5888 of the SCARB1 gene, coding for SRBI, which is involved in the lipid and lutein pathways. This study was conducted in a French series of 1241 AMD patients and 297 controls, and in a North American series of 1257 patients with advanced AMD and 1732 controls. Among these individuals, we identified 61 French patients, 77 French controls, 85 North American patients and 338 North American controls who did not carry the CFH nor ARMS2 polymorphisms. An association between AMD and the SCARB1 gene was seen among the study subjects. The genotypic distribution of the rs5888 polymorphism was significantly different between cases and controls in the French population (p<0.006). Heterozygosity at the rs5888 SNP increased risk of AMD compared to the CC genotypes in the French study population (odds ratio (OR) = 3.5, CI95%: 1.4–8.9, p<0.01) and after pooling the 2 populations (OR = 2.9, 95% CI: 1.6–5.3, p<0.002). Subgroup analysis in exudative forms of AMD revealed a pooled OR of 3.6 for individuals heterozygous for rs5888 (95% CI: 1.7–7.6, p<0.0015). These results suggest the possible contribution of SCARB1, a new genetic factor in AMD, and implicate a role for cholesterol and antioxidant micronutrient (lutein and vitamin E) metabolism in AMD. 相似文献
4.
Age-related macular degeneration (AMD) is a complex disorder of the central retina with readily increasing socio-economic impact on the societies of industrialized countries. With a prevalence of about 12% in the population over 80 years of age, advanced forms of AMD are nowadays the most common cause of blindness in the elderly. The risk of developing AMD is influenced by exogenous and endogenous factors. Although smoking is a well-established environmental component, the first clues to genetic influences resulted from twin studies and familial aggregation analyses. Recent work has identified genetic variants in two genomic regions at 1q32 and 10q26, which independently confer high risks for developing AMD. While association signals at 1q32 were shown to culminate over the complement factor H (CFH) gene, implicating innate immunity and inflammation in the etiology of AMD, the functional contribution of the LOC387715/HTRA1 (HtrA serine peptidase 1) gene locus still remains to be elucidated. In coming years it is to be expected, however, that our knowledge of the genetic factors and their cellular roles in the retina will further deepen and therefore will fundamentally change patient management. 相似文献
5.
Albert O. Edwards Brooke L. Fridley Katherine M. James Anil S. Sharma Julie M. Cunningham Nirubol Tosakulwong 《PloS one》2008,3(11)
Genome-wide association studies (GWASs) assess correlation between traits and DNA sequence variation using large numbers of genetic variants such as single nucleotide polymorphisms (SNPs) distributed across the genome. A GWAS produces many trait-SNP associations with low p-values, but few are replicated in subsequent studies. We sought to determine if characteristics of the genomic loci associated with a trait could be used to identify initial associations with a higher chance of replication in a second cohort. Data from the age-related eye disease study (AREDS) of 100,000 SNPs on 395 subjects with and 198 without age-related macular degeneration (AMD) were employed. Loci highly associated with AMD were characterized based on the distribution of genotypes, level of significance, and clustering of adjacent SNPs also associated with AMD suggesting linkage disequilibrium or multiple effects. Forty nine loci were highly associated with AMD, including 3 loci (CFH, C2/BF, LOC387715/HTRA1) already known to contain important genetic risks for AMD. One additional locus (C3) reported during the course of this study was identified and replicated in an additional study group. Tag-SNPs and haplotypes for each locus were evaluated for association with AMD in additional cohorts to account for population differences between discovery and replication subjects, but no additional clearly significant associations were identified. Relying on a significant genotype tests using a log-additive model would have excluded 57% of the non-replicated and none of the replicated loci, while use of other SNP features and clustering might have missed true associations. 相似文献
6.
Age-related macular degeneration (AMD) is a disease with multifactorial etiology characterized by irreversible loss of central visual acuity. The discovery of susceptive single-nucleotide polymorphisms (SNPs) has progressed our understanding of AMD. Complement factor H (CFH) gene Y402H polymorphism and high-temperature requirement A-1 (HTRA1) LOC387715 gene A69S polymorphisms are the most important SNPs reported in the literature. Determination of genetic risk factors and genotype-phenotype relationship in AMD may result in rapid and cost-effective therapeutic applications for young and old population. In this study, we hypothesized a potential association between CFH gene Y402H and HTRA1 LOC387715 gene A69S polymorphism in Turkish AMD patients. In blood samples from a total of 252 individuals, 147 clinically diagnosed as AMD and the others control, polymorphic sites in CFH, Y402H (Tsp509I T/C), and HTRA1, LOC387715 A69S (FnuHI G/T), were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. There was significant difference between CFH genotypes in the AMD group, TT 21.8%, TC 48.3%, and CC 29.9%, and in the control subjects, TT 45% (p=0.003), TC 41% (p=0.0001), and CC 14% (p=0.0001). Further, the A69S polymorphism of LOC387715 was investigated and found to be significantly associated with AMD. LOC387715 genotypes in the AMD group were GG 30.6%, GT 38.1%, and TT 31.3% and in the control subjects were GG 59% (p=0.027), GT 39% (p=0.0001), and TT 2% (p=0.0001), respectively. We also found that Y402H C and A69S T allele were associated with AMD. This is the first study showing that Y402H and LOC387715 are associated with AMD in Turkish population. 相似文献
7.
Asako Goto Masakazu Akahori Haru Okamoto Masayoshi Minami Naoki Terauchi Yuji Haruhata Minoru Obazawa Toru Noda Miki Honda Atsushi Mizota Minoru Tanaka Takaaki Hayashi Masaki Tanito Naoko Ogata Takeshi Iwata 《Journal of ocular biology, diseases, and informatics》2009,2(4):164-175
Age-related macular degeneration (AMD) is a common cause of blindness in the elderly. Caucasian patients are predominantly affected by the dry form of AMD, whereas Japanese patients have predominantly the wet form of AMD and/or polypoidal choroidal vasculopathy (PCV). Although genetic association in the 10q26 (ARMS2/HTRA1) region has been established in many ethnic groups for dry-type AMD, typical wet-type AMD, and PCV, the contribution of the 1q32 (CFH) region seem to differ among these groups. Here we show a single nucleotide polymorphism (SNP) in the ARMS2/HTRA1 locus is associated in the whole genome for Japanese typical wet-type AMD (rs10490924: , OR = 4.16) and PCV (rs10490924: , OR = 2.72) followed by CFH (rs800292: , OR = 2.08; , OR = 2.00), which differs from previous studies in Caucasian populations. Moreover, a SNP (rs2241394) in complement component C3 gene showed significant association with PCV (, OR = 3.47). We conclude that dry-type AMD, typical wet-type AMD, and PCV have both common and distinct genetic risks that become apparent when comparing Japanese versus Caucasian populations.
Electronic supplementary material
The online version of this article (doi:10.1007/s12177-009-9047-1) contains supplementary material, which is available to authorized users. 相似文献8.
Yanagisawa S Kondo N Miki A Matsumiya W Kusuhara S Tsukahara Y Honda S Negi A 《PloS one》2011,6(12):e28847
Background
Genetic variants in the complement component 3 gene (C3) have been shown to be associated with age-related macular degeneration (AMD) in Caucasian populations of European descent. In particular, a nonsynonymous coding variant, rs2230199 (R102G), is presumed to be the most likely causal variant in the C3 locus based on strong statistical evidence for disease association and mechanistic functional evidence. However, the risk allele is absent or rare (<1%) in Japanese and Chinese populations, and the association of R102G with AMD has not been reported in Asian populations. Genetic heterogeneity of disease-associated variants among different ethnicities is common in complex diseases. Here, we sought to examine whether other common variants in C3 are associated with wet AMD, a common advanced-stage manifestation of AMD, in a Japanese population.Methodology/Principal Findings
We genotyped 13 tag single nucleotide polymorphisms (SNPs) that capture the majority of common variations in the C3 locus and tested for associations between these SNPs and wet AMD in a Japanese population comprising 420 case subjects and 197 controls. A noncoding variant in C3 (rs2241394) exhibited statistically significant evidence of association (allelic P = 8.32×10−4; odds ratio = 0.48 [95% CI = 0.31–0.74] for the rs2241394 C allele). Multilocus logistic regression analysis confirmed that the effect of rs2241394 was independent of the previously described loci at ARMS2 and CFH, and that the model including variants in ARMS2 and CFH plus C3 rs2241394 provided a better fit than the model without rs2241394. We found no evidence of epistasis between variants in C3 and CFH, despite the fact that they are involved in the same biological pathway.Conclusions
Our study provides evidence that C3 is a common AMD-associated locus that transcends racial boundaries and provides an impetus for more detailed genetic characterization of the C3 locus in Asian populations. 相似文献9.
Jiayin Gu Gayle J. T. Pauer Xiuzhen Yue Umadevi Narendra Gwen M. Sturgill James Bena Xiaorong Gu Neal S. Peachey Robert G. Salomon Stephanie A. Hagstrom John W. Crabb Clinical Genomic Proteomic AMD Study Group 《Molecular & cellular proteomics : MCP》2009,8(6):1338-1349
Age-related macular degeneration (AMD) is a progressive disease and major cause of severe visual loss. Toward the discovery of tools for early identification of AMD susceptibility, we evaluated the combined predictive capability of proteomic and genomic AMD biomarkers. We quantified plasma carboxyethylpyrrole (CEP) oxidative protein modifications and CEP autoantibodies by ELISA in 916 AMD and 488 control donors. CEP adducts are uniquely generated from oxidation of docosahexaenoate-containing lipids that are abundant in the retina. Mean CEP adduct and autoantibody levels were found to be elevated in AMD plasma by ∼60 and ∼30%, respectively. The odds ratio for both CEP markers elevated was 3-fold greater or more in AMD than in control patients. Genotyping was performed for AMD risk polymorphisms associated with age-related maculopathy susceptibility 2 (ARMS2), high temperature requirement factor A1 (HTRA1), complement factor H, and complement C3, and the risk of AMD was predicted based on genotype alone or in combination with the CEP markers. The AMD risk predicted for those exhibiting elevated CEP markers and risk genotypes was 2–3-fold greater than the risk based on genotype alone. AMD donors carrying the ARMS2 and HTRA1 risk alleles were the most likely to exhibit elevated CEP markers. The results compellingly demonstrate higher mean CEP marker levels in AMD plasma over a broad age range. Receiver operating characteristic curves suggest that CEP markers alone can discriminate between AMD and control plasma donors with ∼76% accuracy and in combination with genomic markers provide up to ∼80% discrimination accuracy. Plasma CEP marker levels were altered slightly by several demographic and health factors that warrant further study. We conclude that CEP plasma biomarkers, particularly in combination with genomic markers, offer a potential early warning system for assessing susceptibility to this blinding, multifactorial disease.Age-related macular degeneration (AMD)1 is the most common cause of legal blindness in the elderly in developed countries (1). It is a complex, progressive disease involving multiple genetic and environmental factors that can result in severe visual loss. Early risk factors include the macular deposition of debris (drusen) on Bruch membrane, the extracellular matrix separating the choriocapillaris from the retinal pigment epithelium (RPE). Later stages of “dry” AMD involve the degeneration of photoreceptor and RPE cells resulting in geographic atrophy. In “wet” AMD, abnormal blood vessels grow from the choriocapillaris through Bruch membrane (choroidal neovascularization (CNV)). CNV occurs in 10–15% of AMD cases yet accounts for over 80% of debilitating visual loss in AMD. Anti-vascular endothelial growth factor treatments can effectively inhibit the progression of CNV (1), and antioxidant vitamins and zinc can slow dry AMD progression for select individuals (2). However, there are no universally effective therapies for the prevention of dry AMD or the progression from dry to wet AMD nor are there therapies to repair retinal damage in advanced AMD. The prevalence of advanced AMD in the United States is projected to increase by 50% to ∼3 million by the year 2020 largely because of the rapidly growing elderly population (3). Accordingly early identification of AMD susceptibility and implementation of preventive measures are important therapeutic strategies (1).The molecular mechanisms causing AMD remain unknown, although inflammatory processes have been implicated by the identification of AMD susceptibility genes encoding complement factors (4–10) and the presence of complement proteins in drusen (11–13). Oxidative stress has long been associated with AMD pathology as shown by the finding that smoking significantly increases the risk of AMD (14) and that antioxidant vitamins can selectively slow AMD progression (2). A direct molecular link between oxidative damage and AMD was established by the finding that carboxyethylpyrrole (CEP), an oxidative protein modification generated from docosahexaenoate (DHA)-containing phospholipids, was elevated in Bruch membrane and drusen from AMD patients (11). Subsequently CEP adducts as well as CEP autoantibodies were found to be elevated in plasma from AMD donors (15), and CEP adducts were found to stimulate neovascularization in vivo, suggesting a role in the induction of CNV (16). From such observations, oxidative protein modifications were hypothesized to serve as catalysts of AMD pathology (11, 15, 17). In support of this hypothesis, mice immunized with CEP-adducted mouse albumin develop a dry AMD-like phenotype that includes sub-RPE deposits resembling drusen and RPE lesions mimicking geographic atrophy (18).Although identified AMD susceptibility genes account for over half of AMD cases (19), many individuals carrying AMD risk genotypes may never develop the disease. Likewise only a fraction of those diagnosed with early AMD progress to advanced stage disease with severe visual loss (2). Toward the discovery of better methods to predict susceptibility to advanced AMD, we quantified CEP adducts and autoantibodies in over 1400 plasma donors and also genotyped many of these donors for AMD risk polymorphisms in complement factor H (CFH) (4–7), complement C3 (9, 10), age-related maculopathy susceptibility 2 (ARMS2; also known as LOC387715) (19–22), and high temperature requirement factor A1 (HTRA1) (23, 24). The results demonstrate that combined CEP proteomic and genomic biomarker measurements are more effective in assessing AMD risk than either method alone. 相似文献
10.
Chee Wai Wong Jiemin Liao Gemmy C. Cheung Chiea Chuen Khor Eranga N. Vithana Jie Jin Wang Paul Mitchell Tin Aung Tien Y. Wong Ching-Yu Cheng 《PloS one》2015,10(3)
Aims
To determine the differential effects of genetic polymorphism in CFH and ARMS2 on risk of age-related macular degeneration (AMD) between phakic vs. pseudophakic/aphakic eyes.Methods
9,529 eyes of 4,918 participants from the Singapore Malay Eye Study and Singapore Indian Eye Study were analyzed. Participants had detailed eye examinations, including slit-lamp examinations and dilated fundus photography. AMD grading was performed according to the Wisconsin age-related maculopathy grading system. Lens status was defined. Single nucleotide polymorphisms (SNPs) rs10801555 (Y402H) within CFH and rs3750847 in ARMS2 were assessed. The main outcome measure was early AMD or any AMD.Results
No significant associations between the CFH Y402H genotypes and early AMD were found in phakic individuals. In contrast, among pseudophakic/aphakic individuals, the CFH Y402H risk genotypes were significantly associated with higher odds of early AMD, with an OR of 1.57 (95% CI: 1.07–2.29) for GA genotype and 2.40 (95% CI: 1.25–4.61) for AA genotype, compared to those with GG genotype. There was significant interaction between pseudophakic/aphakic status and CFH Y402H variant on risk of early AMD (p = 0.037), adjusting for age, gender, and the first 5 genetic principal components. No significant interaction was found between lens status and ARMS2 rs3750847.Conclusions
CFH genetic polymorphism and pseudophakic/aphakic status may have a potential synergistic effect on early AMD, suggesting roles for the complement system and related pathways in the pathogenesis of AMD in eyes after cataract surgery. 相似文献11.
Liu L Zhong R Wei S Yin JY Xiang H Zou L Chen W Chen JG Zheng XW Huang LJ Zhu BB Chen Q Duan SY Rui R Yang BF Sun JW Xie DS Xu YH Miao XP Nie SF 《PloS one》2011,6(11):e27301
Background
Metabolic syndrome traits play an important role in the development of colorectal cancer. Adipokines, key metabolic syndrome cellular mediators, when abnormal, may induce carcinogenesis.Methodology/Principal Findings
To investigate whether polymorphisms of important adipokines, adiponectin (ADIPOQ) and its receptors, either alone or in combination with environmental factors, are implicated in colorectal cancer, a two-stage case-control study was conducted. In the first stage, we evaluated 24 tag single nucleotide polymorphisms (tag SNPs) across ADIPOQ ligand and two ADIPOQ receptors (ADIPOR1 and ADIPOR2) among 470 cases and 458 controls. One SNP with promising association was then analyzed in stage 2 among 314 cases and 355 controls. In our study, ADIPOQ rs1063538 was consistently associated with increased colorectal cancer risk, with an odds ratio (OR) of 1.94 (95%CI: 1.48–2.54) for CC genotype compared with TT genotype. In two-factor gene-environment interaction analyses, rs1063538 presented significant interactions with smoking status, family history of cancer and alcohol use, with ORs of 4.52 (95%CI: 2.78–7.34), 3.18 (95%CI: 1.73–5.82) and 1.97 (95%CI: 1.27–3.04) for smokers, individuals with family history of cancer or drinkers with CC genotype compared with non-smokers, individuals without family history of cancer or non-drinkers with TT genotype, respectively. Multifactor gene-environment interactions analysis revealed significant interactions between ADIPOQ rs1063538, ADIPOR1 rs1539355, smoking status and BMI. Individuals carrying one, two and at least three risk factors presented 1.18–fold (95%CI:0.89–fold to 1.58–fold), 1.87–fold (95%CI: 1.38–fold to2.54–fold) and 4.39–fold (95%CI: 2.75–fold to 7.01–fold) increased colorectal cancer risk compared with those who without risk factor, respectively (P trend <0.0001).Conclusions/Significance
Our results suggest that variants in ADIPOQ may contribute to increased colorectal cancer risk in Chinese and this contribution may be modified by environmental factors, such as smoking status, family history of cancer and BMI. 相似文献12.
Robyn H. Guymer Paul N. Baird Mary Varsamidis Lucy Busija Peter N. Dimitrov Khin Zaw Aung Galina A. Makeyeva Andrea J. Richardson Lyndell Lim Liubov D. Robman 《PloS one》2013,8(12)
Background
HMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined.Methodology/Principal Findings
Objectives: To evaluate the effect of simvastatin on AMD progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH) genes. Design: A proof of concept double-masked randomized controlled study. Participants: 114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA≥20/60 in at least one eye, and a normal lipid profile. Intervention: Simvastatin 40 mg/day or placebo, allocated 1∶1. Main outcome measures: Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70% in the placebo and 54% in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18–0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27–3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo [adjusted OR 0.23 (0.07–0.75), p = 0.015]. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene [OR 0.08 (0.02–0.45), p = 0.004]. No evidence of harm from simvastatin intervention was detected.Conclusion/Significance
Simvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC (Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted.Trial Registration
Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065 相似文献13.
Sivakumaran TA Igo RP Kidd JM Itsara A Kopplin LJ Chen W Hagstrom SA Peachey NS Francis PJ Klein ML Chew EY Ramprasad VL Tay WT Mitchell P Seielstad M Stambolian DE Edwards AO Lee KE Leontiev DV Jun G Wang Y Tian L Qiu F Henning AK LaFramboise T Sen P Aarthi M George R Raman R Das MK Vijaya L Kumaramanickavel G Wong TY Swaroop A Abecasis GR Klein R Klein BE Nickerson DA Eichler EE Iyengar SK 《PloS one》2011,6(10):e25598
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 ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number. 相似文献
14.
Brunner EJ Kivimäki M Witte DR Lawlor DA Davey Smith G Cooper JA Miller M Lowe GD Rumley A Casas JP Shah T Humphries SE Hingorani AD Marmot MG Timpson NJ Kumari M 《PLoS medicine》2008,5(8):e155
Background
Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables.Methods and Findings
We genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29–1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p = 0.52–0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p = 0.007–0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p = 0.25–0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations.Conclusions
Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP. 相似文献15.
Francis PJ George S Schultz DW Rosner B Hamon S Ott J Weleber RG Klein ML Seddon JM 《Human heredity》2007,63(3-4):212-218
BACKGROUND AND AIMS: Age-related macular degeneration (AMD) is the leading cause of blindness in the Western World. It is now evident that both genetic and environmental factors contribute to disease susceptibility. We tested the hypotheses that (a) a common coding SNP in the LOC387715 gene is associated with advanced AMD (geographic atrophy or choroidal neovascularization), and (b) that modifiable environmental exposures alter AMD susceptibility associated with this SNP. METHODS: A case-control association analysis was performed on participants (530 advanced AMD cases and 280 controls) ascertained as part of the multi-center Age-Related Eye Disease Study. AMD status was determined by the reading center from fundus photographs using the AREDS AMD grading categorization. Environmental risk factor exposure data was collected from participants whose DNA was also genotyped for the LOC387715 gene SNP rs10490924. Multivariate logistic regression analyses were performed. RESULTS AND CONCLUSIONS: The number of risk alleles at the LOC387715 SNP was associated with advanced AMD, with odds ratios (OR) = 3.0 (95% confidence interval (CI) 2.1-4.3) for the GT heterozygous genotype and OR = 12.1 (5.6-26.5) for the homozygous TT risk genotype, after controlling for demographic and behavioral risk factors. The LOC387715 SNP was associated with both forms of advanced AMD. Current cigarette smoking and body mass index were independently related to AMD, controlling for genotype. However, there was no statistical interaction between LOC387715 genotype and smoking with regard to advanced AMD development. 相似文献
16.
Purpose
To 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.Methods
We 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.Results
Polymorphism 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.Conclusions
rs1061170 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. 相似文献17.
Zhang XM Zhong R Liu L Wang Y Yuan JX Wang P Sun C Zhang Z Song WG Miao XP 《PloS one》2011,6(7):e21894
Background
Over-expression and increased activity of cyclooxygenase (COX)-2 induced by smoking has been implicated in the development of cancer. This study aimed to explore the interaction between smoking and functional polymorphisms of COX-2 in modulation of gastric cardia adenocarcinoma (GCA) risk.Methods and Findings
Three COX-2 polymorphisms, including –1195G>A (rs689466), –765G>C (rs20417), and 587Gly>Arg (rs3218625), were genotyped in 357 GCA patients and 985 controls. In the multivariate logistic regression analysis, we found that the –1195AA, –765GC, and 587Arg/Arg genotypes were associated with increased risk of GCA (OR = 1.50, 95% CI = 1.05–2.13; OR = 2.06, 95% CI = 1.29–3.29 and OR = 1.67, 95% CI = 1.04–2.66, respectively). Haplotype association analysis showed that compared with G−1195-G−765- GGly587Arg, the A−1195-C−765-AGly587Arg conferred an increased risk of GCA (OR = 2.49, 95% CI = 1.54–4.01). Moreover, significant multiplicative interactions were observed between smoking and these three polymorphisms of –1195G>A, –765G>C, and 587Gly>Arg, even after correction by false discovery rate (FDR) method for multiple comparisons (FDR-P interaction = 0.006, 5.239×10−4 and 0.017, respectively). Similarly, haplotypes incorporating these three polymorphisms also showed significant interaction with smoking in the development of GCA (P for multiplicative interaction = 2.65×10−6).Conclusion
These findings indicated that the functional polymorphisms of COX-2, in interaction with smoking, may play a substantial role in the development of GCA. 相似文献18.
Lin KP Chen SY Lai LC Huang YL Chen JH Chen TF Sun Y Wen LL Yip PK Chu YM Chen WJ Chen YC 《PloS one》2011,6(6):e20573
Background
Accumulated evidences have shown that vascular risk factors, e.g., hypertension, diabetes mellitus and hyperlipidemia, may be related to the risk of dementia. This study investigated the association between genetic polymorphisms of a vascular susceptibility gene, Ninjurin2 (NINJ2), and the risk of dementia, which has not been explored previously.Methods
A total of 275 Alzheimer''s disease (AD) patients and 119 vascular dementia (VaD) patients aged 50 or older were recruited from three teaching hospitals from 2007 to 2010. Healthy controls (n = 423) with the same age of cases were recruited from the health checkup and volunteers worked at the hospital during the same time period. Five common (frequency >5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) in NINJ2 were genotyped to test for the association between sequence variants of NINJ2 and dementia risk, and how vascular risk factors modify this association.Results
Homozygosity of two NINJ2 SNPs was significantly associated with a decreased risk of AD [rs11833579: adjusted odds ratio (AOR) = 0.43; 95% confidence interval (CI) = 0.23–0.80; rs12425791: AOR = 0.33, 95% CI = 0.12–0.96]. Five common haplotypes (cumulative frequency = 97%) were identified. The global test for the association between NINJ2 haplotypes and AD was significant (p = 0.03). Haplotype CAGGA was significantly associated with a decreased risk of AD (AOR = 0.32, 95% CI = 0.11–0.94). No associations were observed for VaD.Conclusion
Inherited polymorphisms of the vascular susceptibility gene NINJ2 were associated with AD risk. 相似文献19.
M Menghini B Kloeckener-Gruissem J Fleischhauer MM Kurz-Levin FK Sutter W Berger D Barthelmes 《PloS one》2012,7(7):e42014
Objective
Factors influencing the outcome of anti-VEGF treatment in neovascular AMD are still investigated. We analyzed the impact of a loading phase, the significance of an initial response for the long-term and the effect of the CFH polymorphism (p.His402Tyr) on treatment outcome.Methods
Patients treated with ranibizumab for neovascular AMD were analyzed over a period of 24 months by assessing effects of loading phase, initial response and genotype of CFH rs1061170 (c.1204C>T, p.His402Tyr).Results
204 eyes were included. A change of +5.0 [−1;+11] letters and +1.5 [−5.5;+9.5] was observed with a median of 4 [3]; [7] and 10 [7]; [14] ranibizumab injections during 12 and 24 months, respectively. Loading phase was no significant predictor for treatment as VA outcome in eyes with and without loading phase was similar (p = 0.846 and p = 0.729) at 12 and 24 months. In contrast, initial response was a significant predictor for improving vision of 5 or more letters at 12 (p = 0.001; OR = 6.75) and 24 months (p = 0.01; OR = 4.66). Furthermore, the CT genotype at CFH rs1061170 was identified as a significant predictor for a favorable VA outcome at 12 and 24 months (OR = 6.75, p = 0.001 and OR = 4.66, p = 0.01).Conclusions
Our data suggest that clinical decisions regarding treatment may be guided by observing patients’ initial response as well as their genotype of SNP rs1061170, while the criterion of loading phase may not bear the customary value. 相似文献20.
PurposeStudies that analyzed single nucleotide polymorphisms (SNP) in various genes have shown that genetic factors are strongly associated with age-related macular degeneration (AMD) susceptibility. Copy number variation (CNV) may be an additional type of genetic variation that contributes to AMD pathogenesis. This study investigated CNV in 4 AMD-relevant genes in Korean AMD patients and control subjects.MethodsFour CNV candidate regions located in AMD-relevant genes (VEGFA, ARMS2/HTRA1, CFH and VLDLR), were selected based on the outcomes of our previous study which elucidated common CNVs in the Asian populations. Real-time PCR based TaqMan Copy Number Assays were performed on CNV candidates in 273 AMD patients and 257 control subjects.ResultsThe predicted copy number (PCN, 0, 1, 2 or 3+) of each region was called using the CopyCaller program. All candidate genes except ARMS2/HTRA1 showed CNV in at least one individual, in which losses of VEGFA and VLDLR represent novel findings in the Asian population. When the frequencies of PCN were compared, only the gain in VLDLR showed significant differences between AMD patients and control subjects (p = 0.025). Comparisons of the raw copy values (RCV) revealed that 3 of 4 candidate genes showed significant differences (2.03 vs. 1.92 for VEGFA, p<0.01; 2.01 vs. 1.97 for CFH, p<0.01; 1.97 vs. 2.01, p<0.01 for ARMS2/HTRA1).ConclusionCNVs located in AMD-relevant genes may be associated with AMD susceptibility. Further investigations encompassing larger patient cohorts are needed to elucidate the role of CNV in AMD pathogenesis. 相似文献