Family History of Age-Related Macular Degeneration and Genetics Predict Progression to Advanced Age-Related Macular Degeneration Adjusting for Macular Status, Demographic, and Lifestyle Factors.

PURPOSE: To determine if a family history of age-related macular degeneration (AMD) and genetic variants identify eyes at higher risk for progression to advanced AMD (AAMD), after controlling for baseline demographics, behavioral factors, and macular status. DESIGN: Prospective, longitudinal cohort study. METHODS: Eyes were classified using the Age-Related Eye Disease Study severity scale. Non-genetic and genetic predictors for progression to AAMD, geographic atrophy, and neovascular disease were evaluated. Cox proportional hazards models using the eye as the unit of analysis were used to calculate hazard ratios (HRs), accounting for correlated data. Discrimination between progressing and non-progressing eyes was assessed using C-statistics and net reclassification improvement (NRI). RESULTS: Among 4910 eyes, 863 progressed to AAMD over 12 years. Baseline AMD severity scale and status of the fellow eye were important predictors; genes provided additional discrimination. A family history of AMD also independently predicted progression after accounting for genetic and other covariates: 1 family member versus none (HR 1.21 [95% confidence interval {CI} 1.02-1.43]; P = 0.03); ≥2 family members versus none (HR 1.55 [95% CI 1.26-1.90]; P < 0.001). A composite risk score calculated using ß estimates of both non-genetic and significant genetic factors predicted progression to AAMD (HR 5.57; 90th vs 10th percentile; area under the receiver operating characteristic curve [AUC] = 0.92), providing superior fit compared with other models, including one with only ocular variables (NRI = 0.34; P < 0.001; AUC = 0.87, ΔAUC 0.05 ± 0.005; P < 0.001). CONCLUSION: Genetic variants and family history provided additional discrimination for predicting progression to AAMD, after accounting for baseline macular status and other covariates.

Rare Dysfunctional Complement Factor I Genetic Variants and Progression to Advanced Age-Related Macular Degeneration.

Purpose: To 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). Design: Prospective, longitudinal study. Participants: Patients 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. Methods: Analyses 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 Measures: Progression to AAMD, GA, or NV. Results: In 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. Conclusions: Results suggest that carriers of rare dysfunctional type 1 CFI variants are at higher risk for progression to AAMD with GA. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Attitudes towards participating in research involving digital pill systems to measure oral HIV pre-exposure chemoprophylaxis: a cross-sectional study among men who have sex with men with substance use in the USA.

OBJECTIVES: This quantitative survey sought to understand, among men who have sex with men (MSM) with potentially problematic substance use, the attitudes towards participation in research involving digital pill systems (DPS) for HIV pre-exposure prophylaxis (PrEP) adherence measurement, and the barriers and facilitators to research participation. DESIGN: One-time, cross-sectional, online sampling-based survey. SETTING: US social networking app predominantly focused on MSM. PARTICIPANTS: MSM without HIV who reported current use of oral PrEP, potentially problematic substance use and sexual activity in the past 3 months. A total of 157 participants were eligible, passed validity checks and enrolled. OUTCOME MEASURES: Perceptions of DPS usefulness, accuracy and usability (System Usability Scale (SUS)); willingness and motivations to participate in DPS research; preferences for access to and feedback on DPS adherence data; data sharing considerations; and medical mistrust (Group-Based Medical Mistrust Scale (GBMMS)). RESULTS: Most of the sample (N=157) was white (n=119, 75.8%), gay (n=124, 79.0%) and cisgender (n=150, 95.5%). The median age was 33 years (IQR: 14). The mean GBMMS score was 13.5 (SD=5.2), and the median SUS score was 70 (IQR: 27.5). In the past 3 months, 36.3% (n=57) reported frequent use of substances before or during sex, and 62.4% (n=98) engaged in condomless sex. While most were adherent to PrEP, approximately 34.4% (n=54) expressed significant worry about daily adherence. Participants wished to monitor their PrEP adherence daily (n=66, 42.0%) and 52% (n=82) were very willing to participate in DPS-based research. The majority were minimally concerned about sharing DPS-detected adherence data with research teams (n=126, 80.3%), and were extremely willing to share these data with healthcare providers (n=109, 69.4%). CONCLUSIONS: In this sample, MSM without HIV who use substances reported willingness to use DPS to measure PrEP adherence in a research context, and identified benefits to accessing real-time, DPS-detected adherence data.

Diversity in Digital Pill Systems: Differences in Perceptions and Attitudes Towards Use of a Digital Pill System for HIV Pre-Exposure Prophylaxis Among Men Who Have Sex with Men with Diverse Racial and Ethnic Identities.

Nonadherence, particularly among men who have sex with men (MSM) with substance use disorders, increases the risk of HIV acquisition. Measuring adherence to HIV pre-exposure chemoprophylaxis (PrEP), and responding to suboptimal adherence or changes in adherence behavior remains a challenging public health problem. Despite the importance of accurate adherence measurement, there is no gold standard for detecting medication ingestion events in HIV research. Current adherence measures indirectly infer ingestion events or measure medication concentrations over time, yet such approaches fail to provide direct confirmation of ingestions and contextual information surrounding adherence and nonadherence. A digital pill system (DPS) - a novel tool that leverages ingestible radiofrequency sensors to measure actual ingestion events - may advance adherence measurement in HIV research. We examined and compared the willingness of MSM across racial and ethnic identities to operate a DPS in the context of PrEP adherence measurement and suggest potential future applications of this technology.

Risk and protection of different rare protein-coding variants of complement component C4A in age-related macular degeneration.

Introduction: Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly. One-third of the genetic contribution to this disease remains unexplained. Methods: We analyzed targeted sequencing data from two independent cohorts (4,245 cases, 1,668 controls) which included genomic regions of known AMD loci in 49 genes. Results: At a false discovery rate of <0.01, we identified 11 low-frequency AMD variants (minor allele frequency <0.05). Two of those variants were present in the complement C4A gene, including the replacement of the residues that contribute to the Rodgers-1/Chido-1 blood group antigens: [VDLL1207-1210ADLR (V1207A)] with discovery odds ratio (OR) = 1.7 (p = 3.2 × 10-5) which was replicated in the UK Biobank dataset (3,294 cases, 200,086 controls, OR = 1.52, p = 0.037). A novel variant associated with reduced risk for AMD in our discovery cohort was P1120T, one of the four C4A-isotypic residues. Gene-based tests yielded aggregate effects of nonsynonymous variants in 10 genes including C4A, which were associated with increased risk of AMD. In human eye tissues, immunostaining demonstrated C4A protein accumulation in and around endothelial cells of retinal and choroidal vasculature, and total C4 in soft drusen. Conclusion: Our results indicate that C4A protein in the complement activation pathways may play a role in the pathogenesis of AMD.