非洲人后裔青光眼遗传学（GGLAD）联盟宣布他们分析了遗传变异与非洲血统人群原发性开角型青光眼的关系。2019年11月5日出版的《美国医学会杂志》发表了这项成果。

据悉，非洲裔人群中原发性开角型青光眼的患病率和临床严重程度高于欧洲或亚洲裔人群。但非洲裔人群致盲性疾病基因组的研究仍不充分。

这项全基因组关联研究（GWAS）包括2个阶段。2003年至2018年，研究组从加纳、尼日利亚、南非、美国、坦桑尼亚、英国、喀麦隆、沙特、巴西、刚果、摩洛哥、秘鲁和马里招募原发性开角型青光眼且无高眼压的非洲裔患者。对照组人群既无眼压升高，又无青光眼的迹象。

共有2320名原发性开角型青光眼患者和2121例对照组参与者纳入第一阶段的研究。Meta分析显示人淀粉状蛋白β（A4）前体蛋白结合家族B2（APBB2；4号染色体，rs59892895T>C）的变异与原发性开角型青光眼显著相关。

通过对第二阶段中6937名受影响个体和14917名未受影响个体进行分析，验证了这种关联性。把所有数据都纳入荟萃分析，发现rs59892895T*C风险等位基因的每个拷贝都显著增加了原发性开角型青光眼的风险。rs59892895T*C风险等位基因在非洲裔人群中存在频率较高。相反，在欧洲或亚洲血裔人群中，rs59892895T*C风险等位基因的频率低于0.1%。

总之，在这项GWAS中，APBB2位点的变异体与原发性开角型青光眼显著相关，且与血统有关。

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