罕见的功能失调性基因变异与进展为晚期年龄相关性黄斑变性
Rare Dysfunctional Genetic Variants and Progression to Advanced Age-Related Macular Degeneration.
作者信息
Seddon Johanna M, Rosner Bernard, De Dikha, Huan Tianxiao, Java Anuja, Atkinson John
机构信息
Department of Ophthalmology and Visual Sciences, University of Massachusetts Chan Medical School, Worcester, Massachusetts.
Channing Division of Network Medicine, Harvard Medical School, Boston, Massachusetts.
出版信息
Ophthalmol Sci. 2022 Dec 30;3(2):100265. doi: 10.1016/j.xops.2022.100265. eCollection 2023 Jun.
PURPOSE
To evaluate associations between rare dysfunctional () 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). 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). 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 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 carriers. Over 12 years, progression to AAMD was 44% for carriers and 20% for noncarriers ( < 0.001), 30% of carriers versus 10% of noncarriers progressed to GA ( < 0.001), and 18% of carriers compared with 11% of noncarriers progressed to NV ( = 0.049). carriers were more likely to have a family history of AMD ( for trend = 0.035) and a higher baseline AMD grade ( < 0.001). After adjusting for all covariates, 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 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 variants are at higher risk for progression to AAMD with GA.
FINANCIAL DISCLOSURES
Proprietary or commercial disclosure may be found after the references.
目的
评估罕见功能失调性（）基因变异状态与进展为晚期年龄相关性黄斑变性（AAMD）、地图样萎缩（GA）和新生血管性疾病（NV）之间的关联。
设计
前瞻性纵向研究。
参与者
纳入基线时年龄在55至80岁、自我认定为白人、一只或两只眼睛基线时无AAMD的患者。随访分级分为早期、中期或AAMD（GA或NV）。使用基因分型和测序平台对变异进行分类。
方法
使用塞登纵向队列研究（N = 2116名受试者，3901只眼睛，平均随访8.3年）和年龄相关性眼病研究（N = 2837名受试者，5200只眼睛，平均随访9.2年）进行分析。评估与低血清因子I（FI）蛋白水平和FI功能降低相关的罕见变异（1型）、其他AMD基因变异以及人口统计学、行为和眼部因素。使用广义估计方程方法评估罕见变异与进展之间的关联，独立于其他基因变异和协变量。
主要观察指标
进展为AAMD、GA或NV。
结果
在4953名受试者的前瞻性队列中（9101只眼睛基线时无AAMD），1%为1型罕见携带者。在12年中，携带者进展为AAMD的比例为44%，非携带者为20%（P < 0.001），30%的携带者进展为GA，而10%的非携带者进展为GA（P < 0.001），18%的携带者进展为NV，而11%的非携带者进展为NV（P = 0.049）。携带者更有可能有AMD家族史（趋势P = 0.035）和更高的基线AMD分级（P < 0.001）。在调整所有协变量后，携带者状态与进展为GA相关（优势比[OR] = 1.91；95%置信区间[CI] = [1.03, 3.52]），但与NV无关（OR = 0.96）。较高的体重指数与携带者的进展相关（体重指数≥25与<25相比；OR = 5.8；95% CI [1.5, 22.3]），但与非携带者无关（OR = 1.1；95% CI = [0.9, 1.3]），交互作用P = 0.011。
结论
结果表明，罕见功能失调性1型变异的携带者进展为伴有GA的AAMD的风险更高。
财务披露
专有或商业披露信息可在参考文献之后找到。
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