ABSTRACT
Age-related macular degeneration (AMD) is a leading cause of visual impairment in aging populations in industrialized countries. Here we investigated whether the genotype of vascular endothelial growth factor A (VEGFA) gene is associated with response to anti-VEGF therapy. 223 eyes with neovascular AMD were treated with intravitreal anti-VEGF therapy. Responders were defined as patients who had an improvement in best corrected visual acuity (BCVA) of at least 5 letters or one line on the EDTRS visual acuity chart along with resolution of intraretinal or subretinal fluid over 12 months. Patients who did not meet the definition of responders were classified as poor-responders. The vision of responders (n = 148) improved while the vision of poor-responders (n = 75) worsened (P<0.001). Responders on average had a decrease in central foveal thickness (CFT), while poor-responders had an increase in CFT (P <0.001). Compared with the responder group, the poor-responder group had a higher frequency of the risk (T) allele (Allelic P = 0.019) and TT genotype (P = 0.002 under a recessive model) for the VEGFA-rs943080 polymorphism. VEGFA expression was 1.8-fold higher in cells with the VEGFA rs943080 TT genotype than in cells with the VEGFA rs943080 CC genotype (P = 0.012). Age, gender, smoking, diabetes mellitus, and hypertension did not play a significant role in treatment response, but BMI was found to be significantly different between responders and poorresponders (P = 0.033). In conclusion, we demonstrated a potential pharmacogenetic relationship between the VEGFA gene and treatment response to anti-VEGF therapy.The studies are registered at ClinicalTrials.gov under the identifiers NCT00474695 (http://clinicaltrials. gov/ct2/show/NCT00474695) and NCT01464723 (http://clinicaltrials.gov/ct2/show/NCT01464723).
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Polymorphism, Single Nucleotide/genetics , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/genetics , Wet Macular Degeneration/drug therapy , Wet Macular Degeneration/genetics , Aged, 80 and over , Antibodies, Monoclonal, Humanized/pharmacology , Bevacizumab , Demography , Female , Gene Expression Regulation/drug effects , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Lymphocytes/drug effects , Lymphocytes/metabolism , Male , RanibizumabABSTRACT
PURPOSE: To determine whether there is an association between hepatic lipase (LIPC) and age-related macular degeneration (AMD) in two independent Caucasian cohorts. METHODS: A discovery cohort of 1626 patients with advanced AMD and 859 normal controls and a replication cohort of 2159 cases and 1150 controls were genotyped for two single-nucleotide polymorphisms (SNPs) in the promoter region of LIPC. The associations between the SNPs and AMD were examined by χ(2) tests. RESULTS: In the discovery cohort, rs493258 and rs10468017 were both associated with advanced AMD (P=9.63E-3 and P=0.048, respectively). The association was corroborated in the replication cohort (P=4.48E-03 for rs493258 and P=0.015 for rs10468017). Combined analysis resulted in even more significant associations (P=1.21E-04 for rs493258 and P=1.67E-03 for rs10468017). CONCLUSION: The LIPC promoter variants rs493258 and rs10468017 were associated with advanced AMD in two independent Caucasian populations, confirming that LIPC polymorphisms may be a genetic risk factor for AMD in the Caucasian population.
Subject(s)
Lipase/genetics , Macular Degeneration/genetics , Polymorphism, Single Nucleotide , Aged , Aged, 80 and over , Alleles , Cohort Studies , Female , Gene Frequency , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Promoter Regions, Genetic/geneticsABSTRACT
AIM: To investigate clinical presentation and genotypes in patients with simultaneous geographic atrophy (GA) and choroidal neovascularization (CNV) and to compare with patients with GA or CNV only. PATIENTS AND METHODS: Twenty patients with combined CNV-GA and 154 CNV only and 154 GA only were chosen based on clinical exam and imaging. Six single-nucleotide polymorphisms (SNPs)-rs2274700 and rs1061170 (complement factor H), rs10490924 and rs11200638 (HTRA1/LOC387715), rs2230199 (C3), rs9332739 (C2)-were genotyped using the SNaPshot method. Chi-squared tests were used for genetic analysis. RESULTS: In patients with CNV-GA, GA progressed slowly and often preceded CNV. CNV presented as subretinal haemorrhage or fluid, with a sudden drop in visual acuity (VA). Comparing combined CNV-GA to GA and CNV only, patients with both had a higher frequency of at-risk alleles at both SNPs within the HTRA1 gene-rs10490924 (52.5%), rs11200638 (52.6%). Statistical significance was not achieved. CNV-GA patients had no protective alleles at SNP rs9332739 (C2), compared with GA (27%) and CNV only (10%). CONCLUSION: There is a paucity of reports describing simultaneous CNV-GA. Clinical and genetic results may support the fact that GA and CNV fit on an age-related macular degeneration (AMD)-disease continuum and may clarify the disease processes in AMD.
Subject(s)
Choroidal Neovascularization/genetics , Complement C2/genetics , Complement C3/genetics , Geographic Atrophy/genetics , Macular Degeneration/genetics , Polymorphism, Single Nucleotide , Serine Endopeptidases/genetics , Aged , Aged, 80 and over , Choroidal Neovascularization/physiopathology , Complement Factor H/genetics , Disease Progression , Female , Fluorescein Angiography , Gene Frequency , Genotype , Geographic Atrophy/physiopathology , High-Temperature Requirement A Serine Peptidase 1 , Humans , Macular Degeneration/physiopathology , Male , Tomography, Optical Coherence , Visual Acuity/physiologyABSTRACT
BACKGROUND/AIMS: To determine the genetic basis of myotonia congenita (MC) and strabismus in a large Caucasian family. METHODS: Seven patients making up four generations of a family with MC and strabismus were recruited. All patients had at least one standard ophthalmic examination, including best-corrected visual acuity, refraction, and ocular motility measurements. CLCN1 and SCN4A genes were sequenced and analysed for mutations. RESULTS: Five out of the seven family members were diagnosed with MC by clinical history and electromyography. Ophthalmic history and exam revealed eyelid myotonia and strabismus. All patients with MC were diagnosed with strabismus between the ages of 3 and 6 and required surgical restoration of ocular alignment. Sequencing results revealed a c. 1333G>A; p. Val445Met mutation in the SCN4A gene. CONCLUSION: There are few reports describing eyelid myotonia and strabismus in patients diagnosed with MC. We found significant ocular involvement in a family with a mutation in SCN4A. Future studies may confirm that MC with significant ocular involvement can be used to direct genetic analysis.
Subject(s)
Esotropia/genetics , Eyelid Diseases/genetics , Mutation , Myotonia Congenita/genetics , Sodium Channels/genetics , Adult , Aged , Aged, 80 and over , Base Sequence , Child, Preschool , Chloride Channels/genetics , Esotropia/diagnosis , Eye Movements/physiology , Eyelid Diseases/diagnosis , Female , Humans , Male , Molecular Sequence Data , Myotonia Congenita/diagnosis , NAV1.4 Voltage-Gated Sodium Channel , Pedigree , Polymerase Chain Reaction , Visual Acuity/physiologyABSTRACT
PURPOSE: To determine the genetic basis of early onset autosomal recessive Best vitelliform macular dystrophy (arBVMD) in a family with three affected children. DESIGN: Clinical and family-based genetic study. METHODS: Seven subjects making up a family with three children affected by Best vitelliform macular dystrophy were studied. Standard ophthalmic exam with dilated ophthalmoscopy and imaging were performed in each individual. The eleven exons of BEST1 were directly sequenced. RESULTS: All three affected children have the clinical characteristic features of Best vitelliform macular dystrophy: large macular vitelliform lesions, scattered vitelliform lesions along the arcades and in the peripheral retina, and an accumulation of serous retinal fluid. A novel compound heterozygous mutation in the BEST1 gene was found in the three affected individuals (L41P and I201T). The unaffected parents and children only harbor one heterozygous mutation. CONCLUSION: arBVMD can be caused by the compound heterozygous mutation L41P and I201T in the BEST1 gene.
