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Mutations in MERTK are not associated with age-related macular degeneration.

ABSTRACT: PURPOSE:To assess whether mutations in Mer tyrosine kinase (MERTK) are associated with age-related macular degeneration (AMD). METHODS:An association study using whole-genome sequencing was performed to determine whether rare variants in MERTK are associated with AMD. The data set included 4787 propensity score-matched case-control samples: 2394 AMD cases and 2393 controls. Whole-genome sequencing was performed and variants in MERTK were identified. Combined annotation-dependent depletion (CADD) scores and allele frequencies were calculated for each variant identified in MERTK. Student's t-test was used to assess the mean number of MERTK variants per subject between case and control cohorts (Bonferroni adjusted ? = 0.0125). The number of subjects carrying at least one high CADD score loss-of-function or nonsynonymous mutation in each cohort was compared using Fisher's exact test (p < 0.05). RESULTS:No significant difference was found in the mean number of MERTK variants in AMD versus control subjects (p = 0.0502). Additionally, there was no significant difference between cohorts in the number of subjects with at least one high CADD score loss-of-function or nonsynonymous variant (p = 0.15 at CADD > 10 and p = 0.91 at CADD > 20). CONCLUSIONS:The present study provides a meaningfully negative result demonstrating that rare variants in MERTK are not associated with AMD. The study also demonstrates the role of large sample size genetic studies utilizing whole-genome sequencing as a powerful tool that can resolve clinically relevant questions regarding the genetic basis of ophthalmic disease.

SUBMITTER: Al-Khersan H

PROVIDER: S-EPMC6092259 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Mutations in MERTK are not associated with age-related macular degeneration.

Al-Khersan Hasenin H Kwong Alan A Grassi Michael A MA

International ophthalmology 20180103 1

<h4>Purpose</h4>To assess whether mutations in Mer tyrosine kinase (MERTK) are associated with age-related macular degeneration (AMD).<h4>Methods</h4>An association study using whole-genome sequencing was performed to determine whether rare variants in MERTK are associated with AMD. The data set included 4787 propensity score-matched case-control samples: 2394 AMD cases and 2393 controls. Whole-genome sequencing was performed and variants in MERTK were identified. Combined annotation-dependent d ...[more]

PMID: 29299721

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Project description:ImportanceSingle-nucleotide polymorphisms (SNPs) associated with the CFH, ARMS2, C3, LIPC, CFB, and C2 genes are associated with age-related macular degeneration (AMD); however, the association of these SNPs with angiographic features of neovascular AMD has been inconsistent in previous studies, and to date, no studies have addressed their association with features on optical coherence tomography.ObjectiveTo evaluate the influence of genotype of SNPs previously associated with AMD on the phenotype of neovascular lesions.Design, setting, and participantsParticipants for this cross-sectional study were recruited from the 1185 patients enrolled in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT), a randomized clinical trial. Eligibility criteria for CATT specified that eyes have choroidal neovascularization and visual acuity between 20/25 and 20/320. A subgroup of 835 patients provided blood samples from July 2010 through September 2011 and were genotyped for the SNPs rs1061170 (CFH), rs10490924 (ARMS2),rs2230199 (C3), rs10468017 (LIPC), rs4151667 (CFB), rs547154 (C2) using TaqMan SNP genotyping assays. Data analysis was initiated in November 2013 and completed in January 2016.Main outcomes and measuresPretreatment ocular characteristics on fluorescein angiography (lesion type, area of neovascularization and total lesion, retinal angiomatous proliferation) and on time-domain optical coherence tomography (presence of intraretinal, subretinal, and subretinal pigment epithelium fluid; thickness at the foveal center of the retina, subretinal fluid, and subretinal tissue complex), visual acuity, and age.ResultsA total of 835 (73%) of 1150 CATT patients were genotyped. Mean age decreased with the number of risk alleles for CFH (P < .001), ARMS2 (P < .001), and C3 (P = .005). The following results were found as the number of risk alleles increased from 0 to 1 to 2. For CFH, mean total thickness decreased from 476 to 476 to 434 µm (P = .01; adjusted for age, sex, and smoking status). For ARMS2, the mean area of the total lesion increased from 2.0 to 2.8 to 2.4 mm2 (P = .03), the proportion with retinal angiomatous proliferation lesions increased from 8% to 10% to 12% (P = .05), and the proportion with intraretinal fluid increased from 72% to 71% to 82% (P = .008). For C3, the proportion with intraretinal fluid decreased from 78% to 69% to 64% (P = .001), and the mean retinal thickness decreased from 225 to 207 to 197 µm (P = .02).Conclusions and relevanceCFH, ARMS2, and C3 were associated with specific features of neovascularization at the time patients were enrolled in CATT. Previously identified associations of ARMS2 and CFH with type of choroidal neovascularization on fluorescein angiography were not confirmed. New associations with OCT features identified in CATT need confirmation to establish whether a true association exists.Trial registrationclinicaltrials.gov Identifier: NCT00593450.

Dataset Information

Mutations in MERTK are not associated with age-related macular degeneration.

Publications

Mutations in MERTK are not associated with age-related macular degeneration.

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