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Rare complement factor I variants associated with reduced macular thickness and age-related macular degeneration in the UK Biobank.

ABSTRACT: 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.

SUBMITTER: Tzoumas N

PROVIDER: S-EPMC9402241 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Rare complement factor I variants associated with reduced macular thickness and age-related macular degeneration in the UK Biobank.

Tzoumas Nikolaos N Kavanagh David D Cordell Heather J HJ Lotery Andrew J AJ Patel Praveen J PJ Steel David H DH

Human molecular genetics 20220801 16

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 ...[more]

PMID: 35285476

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Project description:PurposeTo evaluate associations between rare dysfunctional complement factor I (CFI) genetic variant status and progression to advanced age-related macular degeneration (AAMD), geographic atrophy (GA), and neovascular disease (NV).DesignProspective, longitudinal study.ParticipantsPatients aged 55 to 80 years at baseline identifying as White with non-AAMD in 1 or both eyes at baseline were included. Follow-up grades were assigned as early, intermediate, or AAMD (GA or NV). CFI variants were categorized using genotyping and sequencing platforms.MethodsAnalyses were performed using the Seddon Longitudinal Cohort Study (N = 2116 subjects, 3901 eyes, and mean follow-up of 8.3 years) and the Age-Related Eye Disease Study (N = 2837 subjects, 5200 eyes, and mean follow-up of 9.2 years). CFI rare variants associated with low serum factor I (FI) protein levels and decreased FI function (type 1), other AMD genetic variants, and demographic, behavioral, and ocular factors were evaluated. Generalized estimating equations methods were used to assess the association between CFI rare variants and progression, independent of other genetic variants and covariates.Main outcome measuresProgression to AAMD, GA, or NV.ResultsIn the prospective cohort of 4953 subjects (9101 eyes with non-AAMD at baseline), 1% were type 1 rare CFI carriers. Over 12 years, progression to AAMD was 44% for carriers and 20% for noncarriers (P < 0.001), 30% of carriers versus 10% of noncarriers progressed to GA (P < 0.001), and 18% of carriers compared with 11% of noncarriers progressed to NV (P = 0.049). CFI carriers were more likely to have a family history of AMD (P for trend = 0.035) and a higher baseline AMD grade (P < 0.001). After adjusting for all covariates, CFI carrier status was associated with progression to GA (odds ratio [OR] = 1.91; 95% confidence interval [CI] = 1.03, 3.52) but not NV (OR = 0.96). Higher body mass index was associated with progression among CFI carriers (body mass index ≥ 25 vs. < 25; OR = 5.8; 95% CI 1.5, 22.3) but not for noncarriers (OR = 1.1; 95% CI = 0.9, 1.3), with P_interaction = 0.011.ConclusionsResults suggest that carriers of rare dysfunctional type 1 CFI variants are at higher risk for progression to AAMD with GA.Financial disclosuresProprietary or commercial disclosure may be found after the references.

Dataset Information

Rare complement factor I variants associated with reduced macular thickness and age-related macular degeneration in the UK Biobank.

Publications

Rare complement factor I variants associated with reduced macular thickness and age-related macular degeneration in the UK Biobank.

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