遺傳變異與非洲血統人群原發性開角型青光眼的關係
作者：
小柯機器人發布時間：2019/11/7 16:22:33
非洲人後裔青光眼遺傳學（GGLAD）聯盟宣布他們分析了遺傳變異與非洲血統人群原發性開角型青光眼的關係。2019年11月5日出版的《美國醫學會雜誌》發表了這項成果。
據悉，非洲裔人群中原發性開角型青光眼的患病率和臨床嚴重程度高於歐洲或亞洲裔人群。但非洲裔人群致盲性疾病基因組的研究仍不充分。
這項全基因組關聯研究（GWAS）包括2個階段。2003年至2018年，研究組從加納、奈及利亞、南非、美國、坦尚尼亞、英國、喀麥隆、沙特、巴西、剛果、摩洛哥、秘魯和馬裡招募原發性開角型青光眼且無高眼壓的非洲裔患者。對照組人群既無眼壓升高，又無青光眼的跡象。
共有2320名原發性開角型青光眼患者和2121例對照組參與者納入第一階段的研究。Meta分析顯示人澱粉狀蛋白β（A4）前體蛋白結合家族B2（APBB2；4號染色體，rs59892895T>C）的變異與原發性開角型青光眼顯著相關。
通過對第二階段中6937名受影響個體和14917名未受影響個體進行分析，驗證了這種關聯性。把所有數據都納入薈萃分析，發現rs59892895T*C風險等位基因的每個拷貝都顯著增加了原發性開角型青光眼的風險。rs59892895T*C風險等位基因在非洲裔人群中存在頻率較高。相反，在歐洲或亞洲血裔人群中，rs59892895T*C風險等位基因的頻率低於0.1%。
總之，在這項GWAS中，APBB2位點的變異體與原發性開角型青光眼顯著相關，且與血統有關。
附：英文原文
Title: Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry
Author: Michael A. Hauser, R. Rand Allingham, Tin Aung, Carly J. Van Der Heide, Kent D. Taylor, Jerome I. Rotter, Shih-Hsiu J. Wang, Pieter W. M. Bonnemaijer, Susan E. Williams, Sadiq M. Abdullahi, Khaled K. Abu-Amero, Michael G. Anderson, Stephen Akafo, Mahmoud B. Alhassan, Ifeoma Asimadu, Radha Ayyagari, Saydou Bakayoko, Prisca Biangoup Nyamsi, Donald W. Bowden, William C. Bromley, Donald L. Budenz, Trevor R. Carmichael, Pratap Challa, Yii-Der Ida Chen, Chimdi M. Chuka-Okosa, Jessica N. Cooke Bailey, Vital Paulino Costa, Dianne A. Cruz, Harvey DuBiner, John F. Ervin, Robert M. Feldman, Miles Flamme-Wiese, Douglas E. Gaasterland, Sarah J. Garnai, Christopher A. Girkin, Nouhoum Guirou, Xiuqing Guo, Jonathan L. Haines, Christopher J. Hammond, Leon Herndon, Thomas J. Hoffmann, Christine M. Hulette, Abba Hydara, Robert P. Igo, Eric Jorgenson, Joyce Kabwe, Ngoy Janvier Kilangalanga, Nkiru Kizor-Akaraiwe, Rachel W. Kuchtey, Hasnaa Lamari, Zheng Li, Jeffrey M. Liebmann, Yutao Liu, Ruth J.F. Loos, Monica B. Melo, Sayoko E. Moroi, Joseph M. Msosa, Robert F. Mullins, Girish Nadkarni, Abdoulaye Napo, Maggie C. Y. Ng, Hugo Freire Nunes, Ebenezer Obeng-Nyarkoh, Anthony Okeke
Issue&Volume: 2019/11/05
Abstract:
Importance Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.
Objectives To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.
Design, Settings, and Participants A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14?917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.
Exposures Genetic variants associated with primary open-angle glaucoma.
Main Outcomes and Measures Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10−8 in the discovery stage and in the meta-analysis of combined discovery and validation data.
Results A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10−8). The association was validated in an analysis of an additional 6937 affected individuals and 14?917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10−13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.
Conclusions and Relevance In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.
DOI: 10.1001/jama.2019.16161
Source: https://jamanetwork.com/journals/jama/article-abstract/2753899