A common variant in MIR182 is associated with primary open-angle glaucoma in the NEIGHBORHOOD consortium

Yutao Liu, Jessica Cooke Bailey, Inas Helwa, W. Michael Dismuke, Jingwen Cai, Michelle Drewry, Murray H. Brilliant, Donald L. Budenz, William G. Christen, Daniel I. Chasman, John H. Fingert, Douglas Gaasterland, Terry Gaasterland, Mae O. Gordon, Robert P. Igo, Jae H. Kang, Michael A. Kass, Peter Kraft, Richard K. Lee, Paul Lichter & 25 others Sayoko E. Moroi, Anthony Realini, Julia E. Richards, Robert Ritch, Joel S. Schuman, William K. Scott, Kuldev Singh, Arthur J. Sit, Yeunjoo E. Song, Douglas Vollrath, Robert Weinreb, Felipe Medeiros, Gadi Wollstein, Donald J. Zack, Kang Zhang, Margaret A. Pericak-Vance, Pedro Gonzalez, W. Daniel Stamer, John Kuchtey, Rachel W. Kuchtey, R. Rand Allingham, Michael A. Hauser, Louis R. Pasquale, Jonathan L. Haines, Janey L. Wiggs

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

PURPOSE. Noncoding microRNAs (miRNAs) have been implicated in the pathogenesis of glaucoma. We aimed to identify common variants in miRNA coding genes (MIR) associated with primary open-angle glaucoma (POAG). METHODS. Using the NEIGHBORHOOD data set (3853 cases/33,480 controls with European ancestry), we first assessed the relation between 85 variants in 76 MIR genes and overall POAG. Subtype-specific analyses were performed in high-tension glaucoma (HTG) and normal-tension glaucoma subsets. Second, we examined the expression of miR-182, which was associated with POAG, in postmortem human ocular tissues (ciliary body, cornea, retina, and trabecular meshwork [TM]), using miRNA sequencing (miRNA-Seq) and droplet digital PCR (ddPCR). Third, miR-182 expression was also examined in human aqueous humor (AH) by using miRNA-Seq. Fourth, exosomes secreted from primary human TM cells were examined for miR-182 expression by using miRNA-Seq. Fifth, using ddPCR we compared miR-182 expression in AH between five HTG cases and five controls. RESULTS. Only rs76481776 in MIR182 gene was associated with POAG after adjustment for multiple comparisons (odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.11-1.42, P = 0.0002). Subtype analysis indicated that the association was primarily in the HTG subset (OR = 1.26, 95% CI: 1.08-1.47, P = 0.004). The risk allele T has been associated with elevated miR-182 expression in vitro. Data from ddPCR and miRNA-Seq confirmed miR-182 expression in all examined ocular tissues and TM-derived exosomes. Interestingly, miR-182 expression in AH was 2-fold higher in HTG patients than nonglaucoma controls (P = 0.03) without controlling for medication treatment. CONCLUSIONS. Our integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression.

Original languageEnglish (US)
Pages (from-to)4528-4535
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume57
Issue number10
DOIs
StatePublished - Aug 1 2016

Fingerprint

MicroRNAs
Trabecular Meshwork
Glaucoma
Aqueous Humor
Exosomes
Polymerase Chain Reaction
Odds Ratio
Confidence Intervals
Low Tension Glaucoma
Genes
Ciliary Body
Cornea
Retina
Primary Open Angle Glaucoma
Alleles

Keywords

  • Exosome
  • Genetic association
  • NEIGHBORHOOD
  • POAG
  • miR-182

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

A common variant in MIR182 is associated with primary open-angle glaucoma in the NEIGHBORHOOD consortium. / Liu, Yutao; Bailey, Jessica Cooke; Helwa, Inas; Dismuke, W. Michael; Cai, Jingwen; Drewry, Michelle; Brilliant, Murray H.; Budenz, Donald L.; Christen, William G.; Chasman, Daniel I.; Fingert, John H.; Gaasterland, Douglas; Gaasterland, Terry; Gordon, Mae O.; Igo, Robert P.; Kang, Jae H.; Kass, Michael A.; Kraft, Peter; Lee, Richard K.; Lichter, Paul; Moroi, Sayoko E.; Realini, Anthony; Richards, Julia E.; Ritch, Robert; Schuman, Joel S.; Scott, William K.; Singh, Kuldev; Sit, Arthur J.; Song, Yeunjoo E.; Vollrath, Douglas; Weinreb, Robert; Medeiros, Felipe; Wollstein, Gadi; Zack, Donald J.; Zhang, Kang; Pericak-Vance, Margaret A.; Gonzalez, Pedro; Stamer, W. Daniel; Kuchtey, John; Kuchtey, Rachel W.; Allingham, R. Rand; Hauser, Michael A.; Pasquale, Louis R.; Haines, Jonathan L.; Wiggs, Janey L.

In: Investigative Ophthalmology and Visual Science, Vol. 57, No. 10, 01.08.2016, p. 4528-4535.

Research output: Contribution to journalArticle

Liu, Y, Bailey, JC, Helwa, I, Dismuke, WM, Cai, J, Drewry, M, Brilliant, MH, Budenz, DL, Christen, WG, Chasman, DI, Fingert, JH, Gaasterland, D, Gaasterland, T, Gordon, MO, Igo, RP, Kang, JH, Kass, MA, Kraft, P, Lee, RK, Lichter, P, Moroi, SE, Realini, A, Richards, JE, Ritch, R, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Song, YE, Vollrath, D, Weinreb, R, Medeiros, F, Wollstein, G, Zack, DJ, Zhang, K, Pericak-Vance, MA, Gonzalez, P, Stamer, WD, Kuchtey, J, Kuchtey, RW, Allingham, RR, Hauser, MA, Pasquale, LR, Haines, JL & Wiggs, JL 2016, 'A common variant in MIR182 is associated with primary open-angle glaucoma in the NEIGHBORHOOD consortium', Investigative Ophthalmology and Visual Science, vol. 57, no. 10, pp. 4528-4535. https://doi.org/10.1167/IOVS.16-19688
Liu, Yutao ; Bailey, Jessica Cooke ; Helwa, Inas ; Dismuke, W. Michael ; Cai, Jingwen ; Drewry, Michelle ; Brilliant, Murray H. ; Budenz, Donald L. ; Christen, William G. ; Chasman, Daniel I. ; Fingert, John H. ; Gaasterland, Douglas ; Gaasterland, Terry ; Gordon, Mae O. ; Igo, Robert P. ; Kang, Jae H. ; Kass, Michael A. ; Kraft, Peter ; Lee, Richard K. ; Lichter, Paul ; Moroi, Sayoko E. ; Realini, Anthony ; Richards, Julia E. ; Ritch, Robert ; Schuman, Joel S. ; Scott, William K. ; Singh, Kuldev ; Sit, Arthur J. ; Song, Yeunjoo E. ; Vollrath, Douglas ; Weinreb, Robert ; Medeiros, Felipe ; Wollstein, Gadi ; Zack, Donald J. ; Zhang, Kang ; Pericak-Vance, Margaret A. ; Gonzalez, Pedro ; Stamer, W. Daniel ; Kuchtey, John ; Kuchtey, Rachel W. ; Allingham, R. Rand ; Hauser, Michael A. ; Pasquale, Louis R. ; Haines, Jonathan L. ; Wiggs, Janey L. / A common variant in MIR182 is associated with primary open-angle glaucoma in the NEIGHBORHOOD consortium. In: Investigative Ophthalmology and Visual Science. 2016 ; Vol. 57, No. 10. pp. 4528-4535.
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abstract = "PURPOSE. Noncoding microRNAs (miRNAs) have been implicated in the pathogenesis of glaucoma. We aimed to identify common variants in miRNA coding genes (MIR) associated with primary open-angle glaucoma (POAG). METHODS. Using the NEIGHBORHOOD data set (3853 cases/33,480 controls with European ancestry), we first assessed the relation between 85 variants in 76 MIR genes and overall POAG. Subtype-specific analyses were performed in high-tension glaucoma (HTG) and normal-tension glaucoma subsets. Second, we examined the expression of miR-182, which was associated with POAG, in postmortem human ocular tissues (ciliary body, cornea, retina, and trabecular meshwork [TM]), using miRNA sequencing (miRNA-Seq) and droplet digital PCR (ddPCR). Third, miR-182 expression was also examined in human aqueous humor (AH) by using miRNA-Seq. Fourth, exosomes secreted from primary human TM cells were examined for miR-182 expression by using miRNA-Seq. Fifth, using ddPCR we compared miR-182 expression in AH between five HTG cases and five controls. RESULTS. Only rs76481776 in MIR182 gene was associated with POAG after adjustment for multiple comparisons (odds ratio [OR] = 1.23, 95{\%} confidence interval [CI]: 1.11-1.42, P = 0.0002). Subtype analysis indicated that the association was primarily in the HTG subset (OR = 1.26, 95{\%} CI: 1.08-1.47, P = 0.004). The risk allele T has been associated with elevated miR-182 expression in vitro. Data from ddPCR and miRNA-Seq confirmed miR-182 expression in all examined ocular tissues and TM-derived exosomes. Interestingly, miR-182 expression in AH was 2-fold higher in HTG patients than nonglaucoma controls (P = 0.03) without controlling for medication treatment. CONCLUSIONS. Our integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression.",
keywords = "Exosome, Genetic association, NEIGHBORHOOD, POAG, miR-182",
author = "Yutao Liu and Bailey, {Jessica Cooke} and Inas Helwa and Dismuke, {W. Michael} and Jingwen Cai and Michelle Drewry and Brilliant, {Murray H.} and Budenz, {Donald L.} and Christen, {William G.} and Chasman, {Daniel I.} and Fingert, {John H.} and Douglas Gaasterland and Terry Gaasterland and Gordon, {Mae O.} and Igo, {Robert P.} and Kang, {Jae H.} and Kass, {Michael A.} and Peter Kraft and Lee, {Richard K.} and Paul Lichter and Moroi, {Sayoko E.} and Anthony Realini and Richards, {Julia E.} and Robert Ritch and Schuman, {Joel S.} and Scott, {William K.} and Kuldev Singh and Sit, {Arthur J.} and Song, {Yeunjoo E.} and Douglas Vollrath and Robert Weinreb and Felipe Medeiros and Gadi Wollstein and Zack, {Donald J.} and Kang Zhang and Pericak-Vance, {Margaret A.} and Pedro Gonzalez and Stamer, {W. Daniel} and John Kuchtey and Kuchtey, {Rachel W.} and Allingham, {R. Rand} and Hauser, {Michael A.} and Pasquale, {Louis R.} and Haines, {Jonathan L.} and Wiggs, {Janey L.}",
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TY - JOUR

T1 - A common variant in MIR182 is associated with primary open-angle glaucoma in the NEIGHBORHOOD consortium

AU - Liu, Yutao

AU - Bailey, Jessica Cooke

AU - Helwa, Inas

AU - Dismuke, W. Michael

AU - Cai, Jingwen

AU - Drewry, Michelle

AU - Brilliant, Murray H.

AU - Budenz, Donald L.

AU - Christen, William G.

AU - Chasman, Daniel I.

AU - Fingert, John H.

AU - Gaasterland, Douglas

AU - Gaasterland, Terry

AU - Gordon, Mae O.

AU - Igo, Robert P.

AU - Kang, Jae H.

AU - Kass, Michael A.

AU - Kraft, Peter

AU - Lee, Richard K.

AU - Lichter, Paul

AU - Moroi, Sayoko E.

AU - Realini, Anthony

AU - Richards, Julia E.

AU - Ritch, Robert

AU - Schuman, Joel S.

AU - Scott, William K.

AU - Singh, Kuldev

AU - Sit, Arthur J.

AU - Song, Yeunjoo E.

AU - Vollrath, Douglas

AU - Weinreb, Robert

AU - Medeiros, Felipe

AU - Wollstein, Gadi

AU - Zack, Donald J.

AU - Zhang, Kang

AU - Pericak-Vance, Margaret A.

AU - Gonzalez, Pedro

AU - Stamer, W. Daniel

AU - Kuchtey, John

AU - Kuchtey, Rachel W.

AU - Allingham, R. Rand

AU - Hauser, Michael A.

AU - Pasquale, Louis R.

AU - Haines, Jonathan L.

AU - Wiggs, Janey L.

PY - 2016/8/1

Y1 - 2016/8/1

N2 - PURPOSE. Noncoding microRNAs (miRNAs) have been implicated in the pathogenesis of glaucoma. We aimed to identify common variants in miRNA coding genes (MIR) associated with primary open-angle glaucoma (POAG). METHODS. Using the NEIGHBORHOOD data set (3853 cases/33,480 controls with European ancestry), we first assessed the relation between 85 variants in 76 MIR genes and overall POAG. Subtype-specific analyses were performed in high-tension glaucoma (HTG) and normal-tension glaucoma subsets. Second, we examined the expression of miR-182, which was associated with POAG, in postmortem human ocular tissues (ciliary body, cornea, retina, and trabecular meshwork [TM]), using miRNA sequencing (miRNA-Seq) and droplet digital PCR (ddPCR). Third, miR-182 expression was also examined in human aqueous humor (AH) by using miRNA-Seq. Fourth, exosomes secreted from primary human TM cells were examined for miR-182 expression by using miRNA-Seq. Fifth, using ddPCR we compared miR-182 expression in AH between five HTG cases and five controls. RESULTS. Only rs76481776 in MIR182 gene was associated with POAG after adjustment for multiple comparisons (odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.11-1.42, P = 0.0002). Subtype analysis indicated that the association was primarily in the HTG subset (OR = 1.26, 95% CI: 1.08-1.47, P = 0.004). The risk allele T has been associated with elevated miR-182 expression in vitro. Data from ddPCR and miRNA-Seq confirmed miR-182 expression in all examined ocular tissues and TM-derived exosomes. Interestingly, miR-182 expression in AH was 2-fold higher in HTG patients than nonglaucoma controls (P = 0.03) without controlling for medication treatment. CONCLUSIONS. Our integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression.

AB - PURPOSE. Noncoding microRNAs (miRNAs) have been implicated in the pathogenesis of glaucoma. We aimed to identify common variants in miRNA coding genes (MIR) associated with primary open-angle glaucoma (POAG). METHODS. Using the NEIGHBORHOOD data set (3853 cases/33,480 controls with European ancestry), we first assessed the relation between 85 variants in 76 MIR genes and overall POAG. Subtype-specific analyses were performed in high-tension glaucoma (HTG) and normal-tension glaucoma subsets. Second, we examined the expression of miR-182, which was associated with POAG, in postmortem human ocular tissues (ciliary body, cornea, retina, and trabecular meshwork [TM]), using miRNA sequencing (miRNA-Seq) and droplet digital PCR (ddPCR). Third, miR-182 expression was also examined in human aqueous humor (AH) by using miRNA-Seq. Fourth, exosomes secreted from primary human TM cells were examined for miR-182 expression by using miRNA-Seq. Fifth, using ddPCR we compared miR-182 expression in AH between five HTG cases and five controls. RESULTS. Only rs76481776 in MIR182 gene was associated with POAG after adjustment for multiple comparisons (odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.11-1.42, P = 0.0002). Subtype analysis indicated that the association was primarily in the HTG subset (OR = 1.26, 95% CI: 1.08-1.47, P = 0.004). The risk allele T has been associated with elevated miR-182 expression in vitro. Data from ddPCR and miRNA-Seq confirmed miR-182 expression in all examined ocular tissues and TM-derived exosomes. Interestingly, miR-182 expression in AH was 2-fold higher in HTG patients than nonglaucoma controls (P = 0.03) without controlling for medication treatment. CONCLUSIONS. Our integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression.

KW - Exosome

KW - Genetic association

KW - NEIGHBORHOOD

KW - POAG

KW - miR-182

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U2 - 10.1167/IOVS.16-19688

DO - 10.1167/IOVS.16-19688

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JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

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