Do age-related macular degeneration genes show association with keratoconus?

Background: Keratoconus (KC) is a common corneal condition with an unknown gender predominance. Although numerous studies have investigated the genetic component of KC, no specific genes have yet been attributed to the condition. We recently reported posterior segment changes occurring in the eyes of KC patients.

Association of Genetic Variants With Response to Anti-Vascular Endothelial Growth Factor Therapy in Age-Related Macular Degeneration.

Importance: Visual acuity (VA) outcomes differ considerably among patients with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs. Identification of pharmacogenetic associations may help clinicians understand the mechanisms underlying this variability as well as pave the way for personalized treatment in nAMD.

Objective: To identify genetic factors associated with variability in the response to anti-VEGF therapy for patients with nAMD.

Recurrent structural variation, clustered sites of selection, and disease risk for the complement factor H () gene family.

Structural variation and single-nucleotide variation of the complement factor H () gene family underlie several complex genetic diseases, including age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome (AHUS). To understand its diversity and evolution, we performed high-quality sequencing of this ∼360-kbp locus in six primate lineages, including multiple human haplotypes. Comparative sequence analyses reveal two distinct periods of gene duplication leading to the emergence of four -related () gene paralogs ( and ∼25-35 Mya and and ∼7-13 Mya).

GWAS study using DNA pooling strategy identifies association of variant rs4910623 in OR52B4 gene with anti-VEGF treatment response in age-related macular degeneration.

Pooled DNA based GWAS to determine genetic association of SNPs with visual acuity (VA) outcome in anti-vascular endothelial growth factor (anti-VEGF) treated neovascular age-related macular degeneration (nAMD) patients. We performed pooled DNA based GWAS on 285 anti-VEGF treated nAMD patients using high density Illumina 4.3 M array.

Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD).

Background: Age-related macular degeneration (AMD) is the leading cause of vision loss in Western societies with a strong genetic component. Candidate gene studies as well as genome-wide association studies strongly implicated genetic variations in complement genes to be involved in disease risk. So far, no association of AMD with complement component 4 (C4) was reported probably due to the complex nature of the C4 locus on chromosome 6.

Association Study of Mannose-Binding Lectin Levels and Genetic Variants in Lectin Pathway Proteins with Susceptibility to Age-Related Macular Degeneration: A Case-Control Study.

Background: In age-related macular degeneration (AMD) the complement system is thought to be activated by chronic oxidative damage with genetic variants identified in the alternative pathway as susceptibility factors. However, the involvement of the lectin pathway of complement, a key mediator of oxidative damage, is controversial. This study investigated whether mannose-binding lectin (MBL) levels and genetic variants in lectin pathway proteins, are associated with the predisposition to and severity of AMD.

Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia.

Myopia can cause severe visual impairment. Here, we report a two-stage genome-wide association study for three myopia-related traits in 9,804 Japanese individuals, which was extended with trans-ethnic replication in 2,674 Chinese and 2,690 Caucasian individuals. We identify WNT7B as a novel susceptibility gene for axial length (rs10453441, Pmeta=3.

Age-related macular degeneration phenotypes associated with mutually exclusive homozygous risk variants in CFH and HTRA1 genes.

Purpose: To determine age-related macular degeneration (AMD) phenotypes associated with mutually exclusive homozygotic risk variants in rs1061170 (CFH) and rs11200638 (HTRA1).

Methods: Nested case-control study of 2,982 eyes (2,129 control, 809 drusen ≥125 μm, 44 advanced AMD) homozygous for CFH [TT or CC] and HTRA1 [GG or AA] were analyzed using logistic regression and generalized estimating equations specifically regards to homozygous risk variants in one but homozygous no-risk in the other gene.

Results: In early AMD, [CFH HTRA1] and [CFH HTRA1] were associated with central drusen (odds ratio [95% confidence interval] = 4.

Polymorphisms in the APOE gene and the location of retinal fluid in eyes with neovascular age-related macular degeneration.

Background: Previous reports suggest that the outcome of age-related macular degeneration treatment is dependent on variants in the apolipoprotein E (APOE) gene. We wish to establish if variants in this gene are associated with anatomical location of fluid within the macula on optical coherence tomography imaging before and after three anti-vascular endothelial growth factor treatments.

Methods: Patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration were prospectively enrolled and monitored over a 12-month period.

Association of the hepatocyte growth factor gene with keratoconus in an Australian population.

Purpose: A previous study has indicated suggestive association of the hepatocyte growth factor (HGF) gene with Keratoconus. We wished to assess this association in an independent Caucasian cohort as well as assess its association with corneal curvature.

Participants: Keratoconus patients were recruited from private and public clinics in Melbourne, Australia.

Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration.

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.

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.

Evaluating the association between keratoconus and the corneal thickness genes in an independent Australian population.

Purpose: A recent genome-wide association study (GWAS) identified six loci associated with central corneal thickness that also conferred associated risk of keratoconus (KC). We aimed to assess whether genetic associations existed for these loci with KC or corneal curvature in an independent cohort of European ancestry.

Methods: In total, 157 patients with KC were recruited from public and private clinics in Melbourne, Australia, and 673 individuals without KC were identified through the Genes in Myopia study from Australia.

Identification of a rare coding variant in complement 3 associated with age-related macular degeneration.

Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls.

Association of the del443ins54 at the ARMS2 locus in Indian and Australian cohorts with age-related macular degeneration.

Purpose: The ARMS2/HTRA1 genes at the 10q26 locus have been associated with risk of age-related macular degeneration (AMD), with the most significantly associated variants being A69S (rs10490924), del443ins54 (EU427539) and rs11200638. We wished to explore the association of the del443ins54 in two ethnically different populations from India and Australia.

Methods: The del443ins54 was screened in a large cohort of ~1500 subjects from these two populations by a combination of PCR-based agarose gel electrophoresis and validated by resequencing.

Genetic influences on the outcome of anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration.

Purpose: To determine the association of genetic variants in known age-related macular degeneration (AMD) risk-associated genes with outcome of anti-vascular endothelial growth factor (VEGF) treatment in neovascular AMD.

Design: Prospective cohort study.

Participants: We enrolled 224 consecutive patients with neovascular AMD at the Royal Victorian Eye and Ear Hospital, Australia.

Seven new loci associated with age-related macular degeneration.

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8).

A rare functional haplotype of the P2RX4 and P2RX7 genes leads to loss of innate phagocytosis and confers increased risk of age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness in Western countries and is diagnosed by the clinical appearance of yellow subretinal deposits called drusen. Genetic changes in immune components are clearly implicated in the pathology of this disease. We have previously shown that the purinergic receptor P2X7 can act as a scavenger receptor, mediating phagocytosis of apoptotic cells and insoluble debris.

Variants in the VEGFA gene and treatment outcome after anti-VEGF treatment for neovascular age-related macular degeneration.

Purpose: To determine the association of genetic variants of the VEGFA gene with outcome of anti-vascular endothelial growth factor (VEGF) treatment in neovascular age-related macular degeneration (AMD).

Design: A prospective cohort study.

Participants: We included 201 consecutive patients receiving anti-VEGF injections for neovascular AMD.

Genetic association of refractive error and axial length with 15q14 but not 15q25 in the Blue Mountains Eye Study cohort.

Purpose: Myopia is a common complex condition influenced by genetic and environmental factors. Two recent genome-wide association studies have identified loci on chromosomes 15q25 and 15q14 associated with refractive error in Caucasian populations. Our study aimed to assess the association of these 2 loci with refractive error and ocular biometric measures in an independent ethnically matched Caucasian cohort.

Can genetic associations change with age? CFH and age-related macular degeneration.

Genetic variation in the gene encoding complement factor H (CFH) on chromosome 1q31 has repeatedly been associated with an increased risk of age-related macular degeneration (AMD); however, previous studies have had inadequate numbers of participants across a sufficiently wide age range to determine whether the association varies by age. We conducted a genetic case-control study using data from 2294 cases and 2294 controls selected from the Melbourne Collaborative Cohort Study, matched on age, sex and region of origin. Four consistently replicated CFH single-nucleotide polymorphisms (SNPs) were genotyped: rs1061170 (Y402H), rs2274700, rs393955 and rs800292; their relationship with AMD prevalence was determined across the age range 48-86.

Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes.

Purpose: To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes.

Design: Sibling correlation study and genome-wide association study (GWAS).

Participants: For the sibling correlation study, 209 sibling pairs with advanced AMD were included.

Comprehensive analysis of Copy Number Variation of genes at chromosome 1 and 10 loci associated with late age related macular degeneration.

Copy Number Variants (CNVs) are now recognized as playing a significant role in complex disease etiology. Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the western world. While a number of genes and environmental factors have been associated with both risk and protection in AMD, the role of CNVs has remained largely unexplored.