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Association of Rare Predicted Loss-of-Function Variants in Cellular Pathways with Sub-Phenotypes in Age-Related Macular Degeneration
Ophthalmology ( IF 13.7 ) Pub Date : 2017-12-08 , DOI: 10.1016/j.ophtha.2017.10.027
Alexandra Pietraszkiewicz , Freekje van Asten , Alan Kwong , Rinki Ratnapriya , Goncalo Abecasis , Anand Swaroop , Emily Y. Chew

Purpose

To investigate the association of rare predicted loss-of-function (pLoF) variants within age-related macular degeneration (AMD) risk loci and AMD sub-phenotypes.

Design

Case-control study.

Participants

Participants of AREDS, AREDS2, and Michigan Genomics Initiative.

Methods

Whole genome sequencing data were analyzed for rare pLoF variants (frequency <0.1%) in the regions of previously identified 52 independent risk variants known to be associated with AMD. Frequency of the rare pLoF variants in cases with intermediate or advanced AMD was compared with controls. Variants were assigned to the complement, extracellular matrix (ECM), lipid, cell survival, immune system, metabolism, or unknown/other pathway. Associations of rare pLoF variant pathways with AMD sub-phenotypes were analyzed using logistic and linear regression, and Cox proportional hazards models.

Main Outcome Measures

Differences in rare pLoF variant pathway burden and association of rare pLoF variant pathways with sub-phenotypes within the population with AMD were evaluated.

Results

Rare pLoF variants were found in 298 of 1689 cases (17.6%) and 237 of 1518 controls (15.6%) (odds ratio [OR], 1.11; 95% confidence interval [CI], 0.91–1.36; P = 0.310). An enrichment of rare pLoF variants in the complement pathway in cases versus controls (OR, 2.94; 95% CI, 1.49–5.79; P = 0.002) was observed. Within cases, associations between all rare pLoF variants and choroidal neovascularization (CNV) (OR, 1.34; 95% CI, 1.04–1.73; P = 0.023), calcified drusen (OR, 1.33; 95% CI, 1.04–1.72; P = 0.025), higher scores on the AREDS Extended AMD Severity Scale (Standardized Coefficient Beta (β)=0.346 [0.086–0.605], P = 0.009), and progression to advanced disease (hazard ratio, 1.25; 95% CI, 1.01–1.55; P = 0.042) were observed. At the pathway level, there were associations between the complement pathway and geographic atrophy (GA) (OR, 2.17; 95% CI, 1.12–4.24; P = 0.023), the complement pathway and calcified drusen (OR, 3.75; 95% CI, 1.79–7.86; P < 0.001), and the ECM pathway and more severe levels in the AREDS Extended AMD Severity Scale (β = 0.62; 95% CI, 0.04–1.20; P = 0.035).

Conclusions

Rare pLoF variants are associated with disease progression. Variants in the complement pathway modify the clinical course of AMD and increase the risk of developing specific sub-phenotypes.



中文翻译:

与年龄相关的黄斑变性中亚表型的细胞途径中罕见的预测功能丧失变异之间的联系

目的

调查年龄相关性黄斑变性(AMD)风险基因座和AMD亚表型内罕见的预测功能丧失(pLoF)变异的关联。

设计

病例对照研究。

参加者

AREDS,AREDS2和密歇根州基因组计划的参与者。

方法

对全基因组测序数据分析了先前确定的52个与AMD相关的独立风险变体区域中的罕见pLoF变体(频率<0.1%)。将中度或晚期AMD病例中罕见的pLoF变体的频率与对照进行了比较。将变体分配至补体,细胞外基质(ECM),脂质,细胞存活,免疫系统,新陈代谢或未知/其他途径。使用logistic和线性回归以及Cox比例风险模型分析了罕见的pLoF变异途径与AMD亚表型的关联。

主要观察指标

评价了AMD人群中罕见pLoF变异途径负担的差异以及罕见pLoF变异途径与亚表型的关联。

结果

在1689例病例中有298例(17.6%)和1518例对照中有237例(15.6%)中发现了罕见的pLoF变异(赔率[OR]为1.11; 95%置信区间[CI]为0.91-1.36;P  = 0.310)。与对照组相比,病例中补体途径中罕见的pLoF变体富集(OR,2.94; 95%CI,1.49-5.79;P  = 0.002)。在病例中,所有罕见的pLoF变异与脉络膜新生血管(CNV)之间的关联(OR,1.34; 95%CI,1.04–1.73;P  = 0.023),钙化玻璃疣(OR,1.33; 95%CI,1.04-1.72;P  = 0.025),AREDS扩展AMD严重程度评分(标准系数Beta(β)= 0.346 [0.086–0.605],P  = 0.009)得分更高,并发展为晚期疾病(危险比,1.25; 95%CI,1.01-1.55) ;P  = 0.042)。在途径水平上,补体途径与地理萎缩(GA)之间存在关联(OR,2.17; 95%CI,1.12-4.24;P  = 0.023),补体途径与钙化玻璃疣(OR,3.75; 95%CI)相关,1.79–7.86;P <0.001),以及AREDS扩展AMD严重程度量表中的ECM通路和更严重的水平(β= 0.62; 95%CI,0.04–1.20;P  = 0.035)。

结论

罕见的pLoF变异与疾病进展有关。补体途径的变异改变了AMD的临床过程,并增加了发展特定亚表型的风险。

更新日期:2017-12-08
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