Dataset Information

Modelling the genetic risk in age-related macular degeneration.

ABSTRACT: Late-stage age-related macular degeneration (AMD) is a common sight-threatening disease of the central retina affecting approximately 1 in 30 Caucasians. Besides age and smoking, genetic variants from several gene loci have reproducibly been associated with this condition and likely explain a large proportion of disease. Here, we developed a genetic risk score (GRS) for AMD based on 13 risk variants from eight gene loci. The model exhibited good discriminative accuracy, area-under-curve (AUC) of the receiver-operating characteristic of 0.820, which was confirmed in a cross-validation approach. Noteworthy, younger AMD patients aged below 75 had a significantly higher mean GRS (1.87, 95% CI: 1.69-2.05) than patients aged 75 and above (1.45, 95% CI: 1.36-1.54). Based on five equally sized GRS intervals, we present a risk classification with a relative AMD risk of 64.0 (95% CI: 14.11-1131.96) for individuals in the highest category (GRS 3.44-5.18, 0.5% of the general population) compared to subjects with the most common genetic background (GRS -0.05-1.70, 40.2% of general population). The highest GRS category identifies AMD patients with a sensitivity of 7.9% and a specificity of 99.9% when compared to the four lower categories. Modeling a general population around 85 years of age, 87.4% of individuals in the highest GRS category would be expected to develop AMD by that age. In contrast, only 2.2% of individuals in the two lowest GRS categories which represent almost 50% of the general population are expected to manifest AMD. Our findings underscore the large proportion of AMD cases explained by genetics particularly for younger AMD patients. The five-category risk classification could be useful for therapeutic stratification or for diagnostic testing purposes once preventive treatment is available.

SUBMITTER: Grassmann F

PROVIDER: S-EPMC3364197 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Modelling the genetic risk in age-related macular degeneration.

Grassmann Felix F Fritsche Lars G LG Keilhauer Claudia N CN Heid Iris M IM Weber Bernhard H F BH

PloS one 20120530 5

Late-stage age-related macular degeneration (AMD) is a common sight-threatening disease of the central retina affecting approximately 1 in 30 Caucasians. Besides age and smoking, genetic variants from several gene loci have reproducibly been associated with this condition and likely explain a large proportion of disease. Here, we developed a genetic risk score (GRS) for AMD based on 13 risk variants from eight gene loci. The model exhibited good discriminative accuracy, area-under-curve (AUC) of ...[more]

PMID: 22666427

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Project description:Deficient 25-hydroxyvitamin D (25[OH]D) concentrations have been associated with increased odds of age-related macular degeneration (AMD).To examine whether this association is modified by genetic risk for AMD and whether there is an association between AMD and single-nucleotide polymorphisms of genes involved in vitamin D transport, metabolism, and genomic function.Postmenopausal women (N?=?913) who were participants of the Carotenoids in Age-Related Eye Disease Study (CAREDS) (aged 54 to <75 years) with available serum 25(OH)D concentrations (assessed October 1, 1993, to December 31, 1998), genetic data, and measures of AMD (n?=?142) assessed at CAREDS baseline from May 14, 2001, through January 31, 2004, were studied.Prevalent early or late AMD was determined from graded, stereoscopic fundus photographs. Logistic regression was used to estimate odds ratios (ORs) and 95% CIs for AMD by the joint effects of 25(OH)D (<12, ?12 to <20, ?20 to <30, and ?30 ng/mL) and risk genotype (noncarrier, 1 risk allele, or 2 risk alleles). The referent group was noncarriers with adequate vitamin D status (?30 ng/mL). Joint effect ORs were adjusted for age, smoking, iris pigmentation, self-reported cardiovascular disease, self-reported diabetes status, and hormone use. Additive and multiplicative interactions were assessed using the synergy index (SI) and an interaction term, respectively. To examine the association between AMD and variants in vitamin D-related genes, age-adjusted ORs and 95% CIs were estimated using logistic regression.Among the 913 women, 550 had adequate levels of vitamin D (?20 ng/mL), 275 had inadequate levels (?12 to <20 mg/mL), and 88 had deficient levels (<12 ng/mL). A 6.7-fold increased odds of AMD (95% CI,?1.6-28.2) was observed among women with deficient vitamin D status (25[OH]D <12 ng/mL) and 2 risk alleles for CFH Y402H (SI for additive interaction,?1.4; 95% CI,?1.1-1.7; P for multiplicative interaction?=?.25). Significant additive (SI,?1.4; 95% CI,?1.1-1.7) and multiplicative interactions (P?=?.02) were observed for deficient women with 2 high-risk CFI (rs10033900) alleles (OR,?6.3; 95% CI,?1.6-24.2). The odds of AMD did not differ by genotype of candidate vitamin D genes.In this study, the odds of AMD were highest in those with deficient vitamin D status and 2 risk alleles for the CFH and CFI genotypes, suggesting a synergistic effect between vitamin D status and complement cascade protein function. Limited sample size led to wide CIs. Findings may be due to chance or explained by residual confounding.

Project description:Age-related macular degeneration (AMD) is a common condition among the elderly population that leads to the progressive central vision loss and serious compromise of quality of life for its sufferers. It is also one of the few disorders for whom the investigation of its genetics has yielded rich insights into its diversity and causality and holds the promise of enabling clinicians to provide better risk assessments for individuals as well as to develop and selectively deploy new therapeutics to either prevent or slow the development of disease and lessen the threat of vision loss. The genetics of AMD began initially with the appreciation of familial aggregation and increase risk and expanded with the initial association of APOE variants with the disease. The first major breakthroughs came with family-based linkage studies of affected (and discordant) sibs, which identified a number of genetic loci and led to the targeted search of the 1q31 and 10q26 loci for associated variants. Three of the initial four reports for the CFH variant, Y402H, were based on regional candidate searches, as were the two initial reports of the ARMS2/HTRA1 locus variants. Case-control association studies initially also played a role in discovering the major genetic variants for AMD, and the success of those early studies have been used to fuel enthusiasm for the methodology for a number of diseases. Until 2010, all of the subsequent genetic variants associated with AMD came from candidate gene testing based on the complement factor pathway. In 2010, several large-scale genome-wide association studies (GWAS) identified genes that had not been previously identified. Much of this historical information is available in a number of recent reviews (Chen et al., 2010b; Deangelis et al., 2011; Fafowora and Gorin, 2012b; Francis and Klein, 2011; Kokotas et al., 2011). Large meta analysis of AMD GWAS has added new loci and variants to this collection (Chen et al., 2010a; Kopplin et al., 2010; Yu et al., 2011). This paper will focus on the ongoing controversies that are confronting AMD genetics at this time, rather than attempting to summarize this field, which has exploded in the past 5 years.

Dataset Information

Modelling the genetic risk in age-related macular degeneration.

Publications

Modelling the genetic risk in age-related macular degeneration.

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