Identification and functional validation of an enhancer variant in the 9p21.3 locus associated with glaucoma risk and elevated expression of p16INK4a

被引:0
|
作者
Zhu, Yizhou [1 ]
Tazearslan, Cagdas [2 ]
Rosenfeld, Michael G. [3 ,4 ]
Fiser, Andras [5 ,6 ]
Suh, Yousin [1 ,7 ]
机构
[1] Columbia Univ, Dept Obstet & Gynecol, New York, NY 10027 USA
[2] Albert Einstein Coll Med, Dept Genet, Bronx, NY USA
[3] Univ Calif, Sch Med, Dept Med, La Jolla, CA USA
[4] Univ Calif, Howard Hughes Med Inst, La Jolla, CA USA
[5] Albert Einstein Coll Med, Dept Syst & Computat Biol, New York, NY USA
[6] Albert Einstein Coll Med, Dept Biochem, New York, NY USA
[7] Columbia Univ, Dept Genet & Dev, New York, NY USA
基金
美国国家卫生研究院;
关键词
9p21; cellular senescence; genome-wide association study; glaucoma; molecular genetics; p16INK4A; YY1; OPEN-ANGLE GLAUCOMA; CELLULAR SENESCENCE; TUMOR-SUPPRESSOR; PREVALENCE; TRANSCRIPTION;
D O I
10.1111/acel.13908
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Glaucoma is a leading cause of irreversible blindness, with advanced age being the single most significant risk factor. However, the mechanisms underlying the relationship between aging and glaucoma remain unclear. Genome-wide association studies (GWAS) have successfully identified genetic variants strongly associated with increased glaucoma risk. Understanding how these variants function in pathogenesis is crucial for translating genetic associations into molecular mechanisms and, ultimately, clinical applications. The chromosome 9p21.3 locus is among the most replicated glaucoma risk loci discovered by GWAS. Nonetheless, the absence of protein-coding genes in the locus makes interpreting the disease association challenging, leaving the causal variant and molecular mechanism elusive. In this study, we report the identification of a functional glaucoma risk variant, rs6475604. By employing computational and experimental methods, we demonstrated that rs6475604 resides in a repressive regulatory element. Risk allele of rs6475604 disrupts the binding of YY1, a transcription factor known to repress the expression of a neighboring gene in 9p21.3, p16INK4A, which plays a crucial role in cellular senescence and aging. These findings suggest that the glaucoma disease variant contributes to accelerated senescence, providing a molecular link between glaucoma risk and an essential cellular mechanism for human aging.
引用
收藏
页数:6
相关论文
共 50 条
  • [41] P16INK4a expression and progression risk of low-grade intraepithelial neoplasia of the cervix uteri
    Giovanni Negri
    Fabio Vittadello
    Fabio Romano
    Armin Kasal
    Francesco Rivasi
    Salvatore Girlando
    Christine Mian
    Eduard Egarter-Vigl
    Virchows Archiv, 2004, 445 : 616 - 620
  • [42] High-risk human papillomavirus infection and p16INK4a protein expression in laryngeal lesions
    Laco, Jan
    Slaninka, Igor
    Jirasek, Michal
    Celakovsky, Petr
    Vosmikova, Hana
    Ryska, Ales
    PATHOLOGY RESEARCH AND PRACTICE, 2008, 204 (08) : 545 - 552
  • [43] A novel p16INK4A mutation associated with esophageal squamous cell carcinoma in a high risk population
    Qureshi, Meenu Asaas
    Jan, Nishawar
    Dar, Nazir Ahmed
    Hussain, Mahboobul
    Andrabi, Khurshid Iqbal
    BIOMARKERS, 2012, 17 (06) : 552 - 556
  • [45] MULTI-ANCESTRY GENOME-WIDE ASSOCIATION STUDY OF 4,069 CHILDREN WITH GLIOMA IDENTIFIES 9P21.3 RISK LOCUS
    Foss-Skiftesvik, J.
    Li, S.
    Rosenbaum, A.
    Hagen, C. M.
    Stoltze, U. K.
    Ljungqvist, S.
    Hjalmars, U.
    Schmiegelow, K.
    Morimoto, L.
    De Smith, A. J.
    Mathiasen, R.
    Metayer, C.
    Hougaard, D. M.
    Melin, B.
    Walsh, K. M.
    Bybjerg-Grauholm, J.
    Dahlin, A. M.
    Wiemels, J. L.
    NEURO-ONCOLOGY, 2023, 25
  • [46] Elevated p16ink4a Expression in Human Labial Salivary Glands as a Potential Correlate of Cognitive Aging in Late Midlife
    Sorensen, Christiane Elisabeth
    Tritsaris, Katerina
    Reibel, Jesper
    Lauritzen, Martin
    Mortensen, Erik Lykke
    Osler, Merete
    Pedersen, Anne Marie Lynge
    PLOS ONE, 2016, 11 (03):
  • [47] Loss of p16INK4a expression is associated with vascular endothelial growth factor expression in squamous cell carcinoma of the esophagus
    Takeuchi, H
    Ozawa, S
    Shih, CH
    Ando, N
    Kitagawa, Y
    Ueda, M
    Kitajima, M
    INTERNATIONAL JOURNAL OF CANCER, 2004, 109 (04) : 483 - 490
  • [48] P16INK4A expression might be associated with a favorable prognosis for cervical adenocarcinoma via dysregulation of the RB pathway
    Ishikawa, Masako
    Nakayama, Kentaro
    Nakamura, Kohei
    Yamashita, Hitomi
    Ishibashi, Tomoka
    Minamoto, Toshiko
    Sawada, Kiyoka
    Yoshimura, Yuki
    Iida, Kouji
    Razia, Sultana
    Ishikawa, Noriyoshi
    Nakayama, Satoru
    Otsuki, Yoshiro
    Kyo, Satoru
    SCIENTIFIC REPORTS, 2021, 11 (01)
  • [49] Loss of p16INK4A expression is associated with allelic imbalance/loss of heterozygosity of chromosome 9p21 in microdissected malignant peripheral nerve sheath tumors
    Sabah, M
    Cummins, R
    Leader, M
    Kay, E
    APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY, 2006, 14 (01) : 97 - 102
  • [50] Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney
    Melk, A
    Schmidt, BMW
    Takeuchi, O
    Sawitzki, B
    Rayner, DC
    Halloran, PF
    KIDNEY INTERNATIONAL, 2004, 65 (02) : 510 - 520