Evaluation of variants in the selectin genes in age-related macular degeneration

Background  

Age-related macular degeneration (AMD) is a common disease of the elderly that leads to loss of the central visual field due to atrophic or neovascular events. Evidence from human eyes and animal models suggests an important role for macrophages and endothelial cell activation in the pathogenesis of AMD. We sought to determine whether common ancestral variants in genes encoding the selectin family of proteins are associated with AMD.     

Immunopathological aspects of age-related macular degeneration

Age-related macular degeneration (AMD) represents a leading cause of blindness worldwide. While the clinical and histopathological aspects of AMD are well characterized, its etiology and pathogenesis remain unclear. Recent findings suggest a role for immunologic processes in AMD pathogenesis, including the age-related generation of extracellular deposits inside the Brusch membrane and beneath the retinal pigment epithelium, recruitment of macrophages for clearance of these deposits, complement activation, recruitment of tissue-destructive macrophages, microglial activation and accumulation, and proinflammatory effects of chronic inflammation by Chlamydia pneumoniae. This review discusses the evidence for the role of inflammation in human AMD and in animal models of AMD.     

Choriocapillaris breakdown precedes retinal degeneration in age-related macular degeneration

This work presents a combined light and electron microscopical approach to investigate the initial breakdown of the retinal pigment epithelium (RPE) and choriocapillaris (CC) in age-related macular degeneration (AMD). Perimacular sections of 12 dry and wet AMD eyes (82 ± 15 years) and 7 age-matched controls (75 ± 10 years) without retinal pathology were investigated. Disease progression was classified into 5 stages of retinal degeneration to investigate the concurrent CC breakdown. Special emphasis was laid on transitions where intact CC–RPE–retina complexes went over into highly atrophied areas. AMD sections showed elevated loss of photoreceptors, RPE and CC (p < 0.01), and thickened Bruch's membrane with increased basal laminar and linear deposits compared with controls. Up to 27% of the CC was lost in controls although RPE and retina were still intact. This primary loss of CC further increased with AMD (up to 100%). The data implicate that CC breakdown already occurs during normal aging and precedes degeneration of the RPE and retina with AMD, defining AMD as a vascular disease. Particular attention should be given to the investigation of early AMD stages and transitional stages to the late stage that reveal a possible sequence of degenerative steps with aging and AMD.     

老年性黄斑变性的药物治疗研究新进展

老年性黄斑变性是老年人的主要致盲眼病之一.近年来对老年性黄斑变性相关性脉络膜新生血管的药物治疗研究有了显著进展,在对抗血管内皮生长因子、人工合成的皮质激素、色素上皮源性因子、蛋白激酶C抑制剂、环氧化酶-2抑制剂、尿激酶纤溶酶原激活剂-受体系统抑制剂等药物的临床和实验研究取得了可喜的成果,尤其是抗血管内皮生长因子的各种药物的临床应用已显示明显疗效,为患者带来了复明的希望.     

Multilocus analysis of age-related macular degeneration

Age-related macular degeneration (AMD) is a late onset vision disorder. Recent studies demonstrate that alterations in complement cascade genes are associated with AMD. Of the three identified complement loci, variants in complement factor H (CFH) have the highest impact as does an independent locus at 10q26. Our matched case–control study using the Age-Related Eye Disease Study (AREDS) cohort confirms and extends the associations in these loci. Subjects were genotyped for single nucleotide polymorphisms (SNPs) from CFH, complement component 2 (C2), complement component 3 (C3), complement factor B (CFB), age-related maculopathy susceptibility (ARMS2), HtrA serine peptidase 1 (HTRA1), and apolipoprotein E (APOE). Individual SNPs, and haplotypes showed risk trends consistent with those seen in other population studies for CFH, C3, C2, and CFB. SNP rs10490924 on chromosome 10 in exon 1 of the ARMS2 gene showed a highly significant association with an odds ratio (OR) of 3.2 (95% CI 2.4–4.2) for the risk allele and rs11200638 located in the proximal promoter region of HTRA1 showed a higher significant association with an OR of 3.4 (95% CI 2.5–4.6) with our AMD cases. We found that APOE haplotypes were not significantly associated with disease status. Adjustments for other risk factors did not significantly alter the observed associations. This study validates the complement pathway''s involvement in AMD and suggests that allelic variants in complement genes have a direct role in disease. These results also support previous findings that variants in the region of 10q26 exert an independent risk for AMD.     

Variation in complement component C1 inhibitor in age-related macular degeneration

This study assessed variation in plasma levels of the complement regulatorC1 inhibitor (C1inh) in patients with age related macular degeneration (AMD) and controls. Plasma from391 AMD cases and 370 controls was assayed by rate nephelometry to determine C1inh protein levels. Protein levels were analysed for relationships with age, gender, smoking, AMD disease status and genetic variation in the SERPING1 gene, which encodes C1inh, using a multivariate analysis. t-Tests show a significant difference in C1inh levels in AMD cases compared with controls (p=2.340E-6), smokers compared to non-smokers (p=1.022E-4) and females compared to males (p=1.661E-7). Multivariate analysis shows that after accounting for gender and smoking AMD status remained significant. Age was included in the model but was not significant. Including genetic variation in the model shows that one significant SNP (rs2649663) 5' of the SERPING1 gene is associated with C1inh levels though this SNP is not associated with AMD. This suggests that genetic variation in the promoter region of the SERPING1 gene may influence expression of the gene.     

A search for age-related macular degeneration risk variants in Alzheimer disease genes and pathways

Several lines of inquiry point to overlapping molecular mechanisms between late-onset Alzheimer disease (AD) and age-related macular degeneration (AMD). We evaluated summarized results from large genome-wide association studies for AD and AMD to test the hypothesis that AD susceptibility loci are also associated with AMD. We observed association of both disorders with genes in a region of chromosome 7, including PILRA and ZCWPW1 (peak AMD SNP rs7792525, minor allele frequency [MAF] = 19%, odds ratio [OR] = 1.14, p = 2.34 × 10⁻⁶), and with ABCA7 (peak AMD SNP rs3752228, MAF = 0.054, OR = 1.22, p = 0.00012). Next, we evaluated association of AMD with genes in AD-related pathways identified by canonical pathway analysis of AD-associated genes. Significant associations were observed with multiple previously identified AMD risk loci and 2 novel genes: HGS (peak SNP rs8070488, MAF = 0.23, OR = 0.91, p = 7.52 × 10⁻⁵), which plays a role in the clathrin-mediated endocytosis signaling pathway, and TNF (peak SNP rs2071590, MAF = 0.34, OR = 0.89, p = 1.17 × 10⁻⁵), which is a member of the atherosclerosis signaling and the LXR/RXR activation pathways. Our results suggest that AMD and AD share genetic mechanisms.     

Evaluation of the ABCR and glutathione peroxidase-3 genes in familial and sporadic cases of exudative age-related macular degeneration

Age-related macular degeneration (ARMD) is the most common cause of blindness in older patients and is a major health care epidemic in developed countries. The exact cause of ARMD is not known. It has been recently reported that heterozygous missense ABCR mutations are associated with age-related macular degeneration. In addition, one of the susceptible loci for maculopathy is on chromosome 5 that is very close to the plasma glutathione peroxidase (GPX) gene. Since the retina is highly sensitive to peroxidation and the GPX gene product protects cells from oxidative damage, and the fact that the ABCR gene is considered as a major disease gene in macular degeneration we reasoned that they might serve as candidate genes in a subset of ARMD cases. To test our hypothesis, we have carried out a pilot study by analyzing 8 exudative ARMD patients for allelic variations in the GPX gene and three statistically significant mutations in the ABCR gene (R943Q, G1961E and D2177N). Our analysis failed to identify the above three major alterations in the ABCR gene as well as mutations in the coding sequence of the GPX gene. However, we have been able to identify two polymorphic heterozygous mutations in the promoter region of the GPX gene in one sporadic patient. These mutations have not been seen in any other patients. On the other hand, when 28 individuals from 6 different ethnic backgrounds with no evidence of ARMD were analyzed, four of them showed the same alterations in the GPX promoter region. Although we cannot completely exclude the possibility of alterations in the coding regions of the GPX gene, the promoter mutation identified in the present study statistically may not be associated with this disease. However, it may be associated with other additive factors as might be expected for a complex disorder.     

CX3CR1 polymorphisms and the risk of age-related macular degeneration

Background: Age-related macular degeneration (AMD), a most common eye disease, can lead to irreversible visual impairment. Age, genetic and environmental factors have been implicated in AMD. Chemokine (C-X3-C motif) receptor 1 (CX3CR1) gene polymorphisms could influence the susceptibility of AMD. Methods: We tested the association between AMD and single nocleotide polymorphisms (SNPs) of CX3CR1 gene (rs3732378 and rs3732379) in 102 cases and 115 controls from China. Genotypes were determined by MassArray genotyping assay method. Association between CX3CR1 gene polymorphisms and AMD were examined by χ² test and logistic regression. Results: Genotype distribution of CX3CR1 gene polymorphisms were in accordance with HWE examination. No obvious differences were observed in the genotypes of rs3732378 polymorphism between case and control groups (P>0.05), but A allele of it could increase the risk of AMD (P=0.025, OR=2.391, 95% CI=1.092-5.237). Both TT genotype and T allele of rs3732379 were significantly associated with the susceptibility of AMD (P=8.663, OR=8.663, 95% CI=1.044-71.874; P=0.021, OR=2.076, 95% CI=1.104-3.903). Age, gender and smoking status were used as common confounders to adjust the association between CX3CR1 gene polymorphism and AMD risk. Then we found that rs3732378 had no obvious association with AMD susceptibility. TT genotype of rs3732379 related to the occurrence of AMD, but the association was not significant (P=0.050, OR=8.274, 95% CI=1.002-69.963). T allele of rs3732379 might increase the susceptibility of AMD (P=0.029, OR=2.033, 95% CI=1.077-3.838). Conclusion: T allele of rs3732379 might have a positive association with the susceptibility of AMD.     

Molecular genetics of age-related macular degeneration.

The numerous conditions that clinicians group under the term 'age-related macular degeneration' (AMD) are collectively the most common cause of severe visual loss in the developed world. Moreover, the number of people affected by these diseases is expected to nearly double in the next 25 years. A growing body of data suggests that a large fraction of AMD is caused by genetic factors. As a result, numerous investigators have sought genes that contribute to this disorder. At least six genes have now been identified that cause heritable macular disease, but none of these seem to cause even a moderate fraction of AMD. Affected pedigree member studies suggest that some regions of the genome do harbor AMD predisposing genes, but none have yet been identified by this approach. Studies of human donor tissue have yielded important new insights into pathways associated with AMD. These studies, when combined with the power of genetic approaches, are likely to ultimately reveal a set of genes responsible for a sizeable fraction of AMD.     

Sparing of age-related macular degeneration in rheumatoid arthritis

Age-related macular degeneration (AMD), for which inflammatory changes have been demonstrated, is the commonest cause of blindness in the elderly. We compared the prevalence of AMD in a prospectively followed cohort of rheumatoid arthritic (RA) patients from Saskatchewan with published data from four racially similar general populations. For individuals 65 years or older, only three cases of AMD were identified in the Saskatchewan cohort of 993 RA patients (0.2% prevalence). This compares with 67 out of 1955 subjects in the Beaver Dam survey (prevalence 3.43%); 101 out of 4071 in the Rotterdam survey (prevalence 2.48%); and 63 out of 1950 in the Blue Mountains survey (prevalence 3.23%). For individuals 75 years or older, only two cases out of 497 were identified in the RA cohort (prevalence 0.40%), compared with 516 cases out of 13,900 in the United Kingdom survey (prevalence 3.72%). Patients with RA appear to be relatively spared from AMD. We hypothesize that this results from long term antiinflammatory treatment. Genetic or environmental factors could also be responsible.     

Complement factor H and hemicentin-1 in age-related macular degeneration and renal phenotypes

In this study, we investigated the associations of complement factor H (CFH) and hemicentin-1 (HMCN1) with age-related macular degeneration (AMD) and renal function. Three scales, measuring the course of AMD and drusen development, were examined in two samples: the Family Age-Related Macular degeneration Study (FARMS), consisting of families ascertained through a single individual with severe AMD, and an unascertained population-based family cohort, the Beaver Dam Eye Study (BDES), which was also used to assess longitudinal changes in AMD and associations with renal function. Associations were performed by a regression accounting for known risk factors as well as familial and sibling effects. Strong evidence of the association of rs1061170 (Y402H) variation with AMD was confirmed (P = 9.15 x 10(-5) in BDES, P = 0.016 in FARMS). This association was observed in multiple AMD scales, suggesting that its role is not phenotype-specific. Polymorphisms in both CFH and HMCN1 appeared to influence the longitudinal rate of change of AMD. The rs1061170 polymorphism was also associated with a reduction in estimated glomerular filtration rate (eGFR) (P = 0.046). Another CFH polymorphism, rs800292, was similarly associated with eGFR [beta = -0.90 (P = 0.022)]. Associations between rs743137 (P = 0.05) and rs680638 (P = 0.022) in HMCN1 with calculated creatinine clearance progression were also observed. Both genes appear to play a role in both AMD and renal pathophysiology. These findings support evidence for common pathways influencing ocular and renal function and suggest that further work is required on their common determinants.