Macular thickness varies with age-related macular degeneration genetic risk variants in the UK Biobank cohort.
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ABSTRACT:
SUBMITTER: Kaye RA
PROVIDER: S-EPMC8636487 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To evaluate potential diagnostic and therapeutic biomarkers for age-related macular degeneration (AMD), we identified 8433 UK Biobank participants with rare complement Factor I gene (CFI) variants, 579 with optical coherence tomography-derived macular thickness data. We stratified these variants by predicted gene expression and measured their association with retinal pigment epithelium-Bruch's membrane (RPE-BM) complex and retinal thicknesses at nine macular subfields, as well as AMD risk, using multivariable regression models adjusted for the common complement Factor H gene (CFH) p.Y402H and age-related maculopathy susceptibility protein 2 gene (ARMS2) p.A69S risk genotypes. CFI variants associated with low Factor I levels predicted a thinner mean RPE-BM (95% confidence interval [CI] -1.66 to -0.37 μm, P = 0.002) and retina (95% CI -5.88 to -0.13 μm, P = 0.04) and a higher AMD risk (odds ratio [OR] = 2.26, 95% CI 1.56 to 3.27, P < 0.001). CFI variants associated with normal Factor I levels did not impact mean RPE-BM/retinal thickness (P = 0.28; P = 0.99) or AMD risk (P = 0.97). CFH p.Y402H was associated with a thinner RPE-BM (95% CI -0.31 to -0.18 μm, P < 0.001 heterozygous; 95% CI -0.62 to -0.42 μm, P < 0.001 homozygous) and retina (95% CI -0.73 to -0.12 μm, P = 0.007 heterozygous; 95% CI -1.08 to -0.21 μm, P = 0.004 homozygous). ARMS2 p.A69S did not influence RPE-BM (P = 0.80 heterozygous; P = 0.12 homozygous) or retinal thickness (P = 0.75 heterozygous; P = 0.07 homozygous). p.Y402H and p.A69S exhibited a significant allele-dose response with AMD risk. Thus, CFI rare variants associated with low Factor I levels are robust predictors of reduced macular thickness and AMD. The observed association between macular thickness and CFH p.Y402H, but not ARMS2 p.A69S, highlights the importance of complement dysregulation in early pathogenesis.
| S-EPMC9402241 | biostudies-literature
Project description:PurposeThe prevalence of age-related macular degeneration (AMD) increases dramatically with age. This large collaborative study investigates the effects of 51 late-AMD-associated genetic variants in different ages, focusing on individuals above the age of 90 years.MethodsThe study included 27,996 individuals of the International AMD Genomics Consortium; 14,539 showed late AMD (51.9%) and 13,457 were controls (48.1%). Four age groups were compiled: 60 to 69 years, n = 6514, AMD = 2210 (33.9%); 70 to 79 years, n = 12228, AMD = 6217 (51.7%); 80 to 89 years, n = 8285, AMD = 5326 (64.3%); and ≥90 years, n = 969, AMD = 686 (70.8%). The effect sizes of 51 AMD-associated genetic variants were calculated for all age groups and were compared among the age groups.ResultsSix variants were associated with late AMD in individuals ≥ 90 years of age (P ≤ 0.0006). For rs10922109 and rs570618 (both in CFH), the minor allele (MA) was protective, and minor allele frequency (MAF) increased with age in cases and controls. For rs116503776 in C2/CFB/SKIV2L, the MA was protective, and MAF increased in cases. For rs3750846 in ARMS2/HTRA1, the MA increased risk, and MAF was lower in cases with increasing age. For rs6565597 in NPLOC4/TSPAN10, the MA increased risk. For rs5754227 in SYN3/TIMP3, the MA was protective, and there was no consistent variation in MAF with age. Variants in CFH and ARMS2 showed lower effect sizes at greater age. Interaction analysis showed strong age-related effects for rs570618 (P = 2.24 × 10-7) and rs3750846 (P = 0.001). Total genetic risk was lower in individuals ≥ 90 years old (area under the curve [AUC], 0.795) than in those 70 to 79 years old (AUC, 0.831; P = 0.03).ConclusionsEffect sizes and MAF of genetic risk factors for late AMD differed among the age groups. These results could guide future work on AMD risk assessment in older individuals.
| S-EPMC7745630 | biostudies-literature
Project description:The macula, located near the center of the retina in the human eye, is responsible for providing critical functions, such as central, sharp vision. Structural changes in the macula are associated with many ocular diseases, including age-related macular degeneration (AMD) and glaucoma. Although macular thickness is a highly heritable trait, there are no prior reported genome-wide association studies (GWASs) of it. Here we describe the first GWAS of macular thickness, which was measured by spectral-domain optical coherence tomography using 68 423 participants from the UK Biobank cohort. We identified 139 genetic loci associated with macular thickness at genome-wide significance (P < 5 × 10-8). The most significant loci were LINC00461 (P = 5.1 × 10-120), TSPAN10 (P = 1.2 × 10-118), RDH5 (P = 9.2 × 10-105) and SLC6A20 (P = 1.4 × 10-71). Results from gene expression demonstrated that these genes are highly expressed in the retina. Other hits included many previously reported AMD genes, such as NPLOC4 (P = 1.7 × 10-103), RAD51B (P = 9.1 × 10-14) and SLC16A8 (P = 1.7 × 10-8), further providing functional significance of the identified loci. Through cross-phenotype analysis, these genetic loci also exhibited pleiotropic effects with myopia, neurodegenerative diseases (e.g. Parkinson's disease, schizophrenia and Alzheimer's disease), cancer (e.g. breast, ovarian and lung cancers) and metabolic traits (e.g. body mass index, waist circumference and type 2 diabetes). Our findings provide the first insight into the genetic architecture of macular thickness and may further elucidate the pathogenesis of related ocular diseases, such as AMD.
| S-EPMC6423416 | biostudies-literature
Project description:To compare axial length (AL) and subfoveal choroidal thickness (SFCT) between individuals with age-related macular degeneration (AMD) and controls with no lesions.This was a case-control study. In total, 853 eyes of 484 patients (>65 years), including 397 eyes at various AMD stages and 456 eyes with no fundus lesions (controls) were recruited. Using color fundus photography, eyes were grouped according to AMD degree. AL was automatically measured using IOL Master and SFCT was manually measured by two independent observers. The associations among age, AL, SFCT, and each AMD grade were analyzed.Out of 853 eyes, 456 had no lesions, 217 contained drusen only, 134 had early AMD, and 46 had late AMD. The eyes with late AMD were older (p = 0.007) and had longer AL (p ? 0.001) and thinner SFCT (p < 0.001) compared with groups of no fundus lesions, drusen only, and early AMD. SFCT in eyes with late AMD decreased by 19.20 ?m (p = 0.049), 24.78 ?m (p = 0.029), and 15.56 ?m (p = 0.162) compared with groups of no fundus lesions, drusen only, and early AMD, respectively. SFCT decreased by 14.18 ?m/mm increase in AL (p < 0.001). The odds ratio (OR) for late AMD by longer AL (?25 mm) and thinner SFCT (<240 ?m) was 4.54 (?2 = 9.36; p = 0.002) and 4.86 (?2 = 17.62; p < 0.001), respectively, and was 9.57 (?2 = 18.07; p < 0.001) when both AL ? 25 ?m and SFCT < 240 ?m.Eyes with late AMD have distinct reduced SFCT and elongated AL. Eyes with thinner SFCT and longer AL showed high ORs for late AMD and even higher ORs when both factors were simultaneously present. These findings illustrate the crucial pathophysiological role of these two important ocular fac tors and arouse our attention to patients with both characteristics, especially in Asian countries where the prevalence of myopia are disturbingly high.
| S-EPMC5602135 | biostudies-other
Project description:CLINICAL QUESTION:Is there any new knowledge about the pathogenesis and treatment of age-related macular degeneration (AMD)? RESULTS:We now understand better the biochemical and pathological pathways involved in the genesis of AMD. Treatment of exudative AMD is based on intravitreal injection of new antivascular endothelial growth factor drugs for which there does not yet exist a unique recognized strategy of administration. No therapies are actually available for atrophic AMD, despite some experimental new pharmacological approaches. IMPLEMENTATION:strategy of administration, safety of intravitreal injection.
| S-EPMC3102591 | biostudies-literature
Project description:Background and Objectives: Patients with cataract and age-related macular degeneration (AMD) may safely undergo cataract phacoemulsification to enhance visual acuity. Although it has not been proven that cataract surgery can cause AMD progression, different phacoemulsification effects are observed not only on retinal but also on choroidal tissues. The purpose of this study was to evaluate the effect of phacoemulsification on the choroidal thickness (CT) in eyes with and without AMD. Materials and Methods: In 32 eyes of 32 patients with senile cataract (No-AMD group) and in 32 eyes of 32 patients with cataract and dry AMD (AMD group), who had phacoemulsification without intraoperative complications and intraocular lens implantation, foveal retinal thickness (FRT) and CT were evaluated three times: at 1-2 post meridiem preoperatively, then 1 month and 3 months postoperatively, using 1050 nm swept source-optical coherence tomography (Topcon, Tokyo, Japan). Results: In both groups, a significant increase in FRT was observed after one month and a decrease after three months without reaching the baseline. One month after surgery, a sectorial CT increase was apparent in all sectors in both groups. A negative association between CT and age was disclosed in the No-AMD group almost for all regions at all time points. Furthermore, CT was significantly negatively associated with axial length (AL) in all sectors at all time points in the AMD group. Conclusion: Uneventful phacoemulsification may induce changes in the posterior eye segment. An increase in CT and FRT was observed in both groups one month after the surgery. However, three months after surgery, CT changes were different in both groups, while FRT decreased in both groups. CT changes negatively associated with age in the No-AMD group and with AL in the AMD eyes. These postoperative changes in the choroid and retina may not only lead to the late-onset pseudophakic cystoid macular edema but also to progression of AMD.
| S-EPMC7279142 | biostudies-literature
Project description:The clinical course of age-related macular degeneration (AMD) is related to choroidal conditions, and can be determined by the evaluation of the central choroidal thickness (CCT). The aim of this study was to determine the association between the axial length (AL) and choroidal thickness in AMD by measuring these parameters in patients with and without AMD. Seventy eyes of 70 patients (34 men and 36 women; age, 64-88 years; mean age, 77.0 ± 6.5 years) who underwent cataract surgery from February 2015 to March 2020 at the Department of Ophthalmology, Keio University School of Medicine were retrospectively analyzed. The AMD group (29 patients, 29 eyes) included eyes with early AMD, whereas the control group (41 patients, 41 eyes) included those without ocular diseases other than cataract. Optical coherence tomography images were used to measure the CCT and the choroidal vessel diameter (CVD). The IOL Master was used to measure the AL. The results revealed that mean CCT was greater in the AMD group (238.3 ± 108.3 μm) compared with the age-matched control group (187.2 ± 66.8 μm) (p = 0.03). The CCT was negatively correlated with AL in the overall sample (r = -0.42, p = 0.001), the AMD group (r = -0.42, p = 0.02), and the control group (r = -0.42, p = 0.006). Note that all eyes with CCT > 350 μm were included in the AMD group. CCT and CVD were positively correlated in the overall sample (r = 0.76, p < 0.001) as well as in the individual groups (AMD: r = 0.82, p < 0.001; control: r = 0.76, p = 0.004). Given that CCT is an important parameter for predicting the prognosis of subfoveal diseases, routine evaluation of AL may be valuable for a better understanding of the pathogenesis of AMD.
| S-EPMC7546466 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE28002: Gene expression of the whole mouse eye GSE28032: Epigenetic Regulation of IL17RC in Age-related Macular Degeneration (MeDIP-chip) Refer to individual Series
2011-03-22 | E-GEOD-28033 | biostudies-arrayexpress
Project description:Age-related macular degeneration (AMD) leads to irreversible visual loss, therefore, early intervention is desirable, but due to its multifactorial nature, diagnosis of early disease might be challenging. Identification of early markers for disease development and progression is key for disease diagnosis. Suitable biomarkers can potentially provide opportunities for clinical intervention at a stage of the disease when irreversible changes are yet to take place. One of the most metabolically active tissues in the human body is the retina, making the use of hypothesis-free techniques, like metabolomics, to measure molecular changes in AMD appealing. Indeed, there is increasing evidence that metabolic dysfunction has an important role in the development and progression of AMD. Therefore, metabolomics appears to be an appropriate platform to investigate disease-associated biomarkers. In this review, we explored what is known about metabolic changes in the retina, in conjunction with the emerging literature in AMD metabolomics research. Methods for metabolic biomarker identification in the eye have also been discussed, including the use of tears, vitreous, and aqueous humor, as well as imaging methods, like fluorescence lifetime imaging, that could be translated into a clinical diagnostic tool with molecular level resolution.
| S-EPMC6358913 | biostudies-other
Project description:Age-related macular degeneration (AMD), the most common form of irreversible blindness in the industrially developed world, can present years before a patient begins to lose vision. For most of these patients, AMD never progresses past its early stages to the advanced forms that are principally responsible for the vast majority of vision loss. Advanced AMD can manifest as either an advanced avascular form known as geographic atrophy (GA) marked by regional retinal pigment epithelium (RPE) cell death or as an advanced form known as neovascular AMD marked by the intrusion of fragile new blood vessels into the normally avascular retina. Physicians have several therapeutic interventions available to combat neovascular AMD, but GA has no approved effective therapies as of yet. In this chapter, we will discuss the current strategies for limiting dry AMD in patients. We will also discuss previous attempts at pharmacological intervention that were tested in a clinical setting and consider reasons why these putative therapeutics did not perform successfully in large-scale trials. Despite the number of unsuccessful past trials, new pharmacological interventions may succeed. These future therapies may aid millions of AMD patients worldwide.
| S-EPMC5472449 | biostudies-other