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1. Hypothesis-independent pathway analysis implicates GABA and Acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma

Author

Bailey, JNC, Yaspan, BL, Pasquale, LR, Hauser, MA, Kang, JH, Loomis, SJ, Brilliant, M, Budenz, DL, Christen, WG, Fingert, J, Gaasterland, D, Gaasterland, T, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, McCarty, CA, Moroi, SE, Richards, JE, Realini, T, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Wollstein, G, Zack, DJ, Zhang, K, Pericak-Vance, MA, Allingham, RR, Weinreb, RN, Haines, JL, and Wiggs, JL

Subjects
Genetics & Heredity, Genetics, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine
Abstract

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. Using genome-wide association single-nucleotide polymorphism data from the Glaucoma Genes and Environment study and National Eye Institute Glaucoma Human Genetics Collaboration comprising 3,108 cases and 3,430 controls, we assessed biologic pathways as annotated in the KEGG database for association with risk of POAG. After correction for genic overlap among pathways, we found 4 pathways, butanoate metabolism (hsa00650), hematopoietic cell lineage (hsa04640), lysine degradation (hsa00310) and basal transcription factors (hsa03022) related to POAG with permuted p

Published
2014

2. Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma

Author

Kang, JH, Loomis, SJ, Yaspan, BL, Bailey, JC, Weinreb, RN, Lee, RK, Lichter, PR, Budenz, DL, Liu, Y, Realini, T, Gaasterland, D, Gaasterland, T, Friedman, DS, McCarty, CA, Moroi, SE, Olson, L, Schuman, JS, Singh, K, Vollrath, D, Wollstein, G, Zack, DJ, Brilliant, M, Sit, AJ, Christen, WG, Fingert, J, Forman, JP, Buys, ES, Kraft, P, Zhang, K, Allingham, RR, Pericak-Vance, MA, Richards, JE, Hauser, MA, Haines, JL, Wiggs, JL, and Pasquale, LR

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Aging, Neurosciences, Genetics, Eye Disease and Disorders of Vision, Neurodegenerative, Clinical Research, Cardiovascular, AMP-Activated Protein Kinases, Aged, Case-Control Studies, Caveolin 1, Dynamin II, Dynamins, Endothelium, Vascular, Female, GTP-Binding Proteins, Genetic Predisposition to Disease, Genotype, Glaucoma, Open-Angle, Humans, Inositol 1, 4, 5-Trisphosphate Receptors, Intraocular Pressure, Male, Middle Aged, Muscle, Smooth, Vascular, Nitric Oxide Synthase Type III, Polymorphism, Single Nucleotide, Receptor, Endothelin B, Receptors, Endothelin, Signal Transduction, Clinical Sciences, Immunology, Opthalmology and Optometry, Ophthalmology & Optometry, Ophthalmology and optometry
Abstract

AimsVascular perfusion may be impaired in primary open-angle glaucoma (POAG); thus, we evaluated a panel of markers in vascular tone-regulating genes in relation to POAG.MethodsWe used Illumina 660W-Quad array genotype data and pooled P-values from 3108 POAG cases and 3430 controls from the combined National Eye Institute Glaucoma Human Genetics Collaboration consortium and Glaucoma Genes and Environment studies. Using information from previous literature and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we compiled single-nucleotide polymorphisms (SNPs) in 186 vascular tone-regulating genes. We used the 'Pathway Analysis by Randomization Incorporating Structure' analysis software, which performed 1000 permutations to compare the overall pathway and selected genes with comparable randomly generated pathways and genes in their association with POAG.ResultsThe vascular tone pathway was not associated with POAG overall or POAG subtypes, defined by the type of visual field loss (early paracentral loss (n=224 cases) or only peripheral loss (n=993 cases)) (permuted P≥0.20). In gene-based analyses, eight were associated with POAG overall at permuted P

Published
2014

3. Glycemic control in critically ill surgical patients: risks and benefits

Author

Mukherjee K, Albaugh VL, Richards JE, Rumbaugh KA, and May AK

Subjects
Surgery, RD1-811
Abstract

Kaushik Mukherjee,1 Vance L Albaugh,2 Justin E Richards,3 Kelli A Rumbaugh,4 Addison K May1 1Division of Trauma and Surgical Critical Care, 2Division of General Surgery, 3Department of Anesthesiology, 4Department of Pharmaceutical Services, Vanderbilt University Medical Center, Nashville, TN, USA Abstract: Glucose metabolism in humans is exceedingly complex. At baseline, it is controlled by elaborate signaling mechanisms, and these mechanisms are profoundly altered by the surge of catecholamines and cytokines associated with acute postsurgical and post-traumatic stress. These alterations in signaling mechanisms result in hyperglycemia; although this hyperglycemia can start very rapidly after the traumatic or surgical insult, it can persist during the entire period of critical illness and even afterward. Numerous randomized clinical trials have been conducted to determine if hyperglycemia is associated with increased mortality in surgical patients. These studies have had different conclusions that are difficult to interpret in light of differences in study methodology, but there is certainly ample evidence that inadequately controlled hyperglycemia causes harm due to increased infectious morbidity, and possibly increased mortality. As we have become more proficient in controlling hyperglycemia, the concept of insulin resistance, determined as the amount of insulin required to achieve hyperglycemia, has come to the fore. Insulin resistance is not a static concept, and may change before significant events such as infection. Patients with elevated and persistent insulin resistance have been demonstrated to suffer increased infectious morbidity and mortality, albeit in nonrandomized studies. Along with insulin resistance, the concept of glycemic variability, the amount of variation in serum blood glucose over time, has also become relevant; increased variability has been associated with hypoglycemia and mortality. Both of these risks can result from aggressive insulin therapy, and glycemic control protocols must be appropriately planned and implemented to avoid hypoglycemia and excessive externally induced variability. Computer-assisted protocols may be of significant benefit in optimizing glycemic control. The most recent recommendations available are to keep serum blood glucose levels below 150 mg/dL and to avoid hypoglycemia. Keywords: insulin resistance, hypoglycemia, insulin signaling, hyperglycemia, critical illness, glycemic variability

Published
2015

10. Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author

Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Grp, BMES-G, Consortium, N, and Control, WTC

Subjects
Lumican, genetic structures, Fibrillin-1, General Physics and Astronomy, Gene Expression, Q1, Corneal Diseases, Marfan Syndrome, Cornea, ADAMTS Proteins, Myopia, Link (knot theory), lcsh:Science, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Corneal Dystrophies, Hereditary, Multidisciplinary, Eye Diseases, Hereditary, symbols, NEIGHBORHOOD consortium, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Proteoglycans, Decorin, Glaucoma, Open-Angle, Science, Quantitative Trait Loci, Computational biology, Biology, Keratoconus, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, White People, Article, symbols.namesake, Transforming Growth Factor beta2, Quantitative Trait, Heritable, Asian People, Genome-Wide Association Analysis, Humans, Author Correction, Eye Disease and Disorders of Vision, Loeys-Dietz Syndrome, Genome, Human, Wellcome Trust Case Control Consortium 2, Blue Mountains Eye Study - GWAS group, General Chemistry, Mendelian Randomization Analysis, R1, eye diseases, Mendelian inheritance, Ehlers-Danlos Syndrome, lcsh:Q, sense organs, Genome-Wide Association Study
Abstract

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = −0.62, P = 5.30 × 10−5) but not between CCT and primary open-angle glaucoma (r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation., Reduced central corneal thickness (CCT) is observed in common eye diseases as well as in rare Mendelian disorders. Here, in a cross-ancestry GWAS, the authors identify 19 novel genetic loci associated with CCT, a subset of which is involved in rare corneal or connective tissue disorders.

Published
2019

12. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases (vol 9, 1864, 2018)

Author

Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, and Whittaker, P

Abstract

Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019

14. Using hyperpolarised NMR and DFT to rationalise the unexpected hydrogenation of quinazoline to 3,4-dihydroquinazoline

Author

Richards, JE, Hooper, AJJ, Bayfield, OW, Cockett, MCR, Dear, GJ, Holmes, AJ, John, RO, Mewis, R, Pridmore, N, Roberts, AD, Whitwood, AC, Duckett, SB, Richards, JE, Hooper, AJJ, Bayfield, OW, Cockett, MCR, Dear, GJ, Holmes, AJ, John, RO, Mewis, R, Pridmore, N, Roberts, AD, Whitwood, AC, and Duckett, SB

Abstract

PHIP and SABRE hyperpolarized NMR methods are used to follow the unexpected metal-catalysed hydrogenation of quinazoline (Qu) to 3,4-dihydroquinazoline as the sole product. A solution of [IrCl(IMes)(COD)] in dichloromethane reacts with H2 and Qu to form [IrCl(H)2(IMes)(Qu)2] (2). The addition of methanol then results in its conversion to [Ir(H)2(IMes)(Qu)3]Cl (3) which catalyses the hydrogenation reaction. Density functional theory calculations are used to rationalise a proposed outer sphere mechanism in which (3) converts to [IrCl(H)2(H2)(IMes)(Qu)2]Cl (4) and neutral [Ir(H)3(IMes)(Qu)2] (6), both of which are involved in the formation of 3,4-dihydroquinazoline via the stepwise transfer of H+ and H−, with H2 identified as the reductant. Successive ligand exchange in 3 results in the production of thermodynamically stable [Ir(H)2(IMes)(3,4-dihydroquinazoline)3]Cl (5).

Published
2018

15. Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: analysis in Two Large Datasets

Author

Bailey, JNC, Gharahkhani, P, Kang, JH, Butkiewicz, M, Sullivan, DA, Weinreb, RN, Aschard, H, Allingham, RR, Ashley-Koch, A, Lee, RK, Moroi, SE, Brilliant, MH, Wollstein, G, Schuman, JS, Fingert, JH, Budenz, DL, Realini, T, Gaasterland, T, Scott, WK, Singh, K, Sit, AJ, Igo, RP, Song, YE, Hark, L, Ritch, R, Rhee, DJ, Vollrath, D, Zack, DJ, Medeiros, F, Vajaranant, TS, Chasman, DI, Christen, WG, Pericak-Vance, MA, Liu, Y, Kraft, P, Richards, JE, Rosner, BA, Hauser, MA, Craig, JE, Burdon, KP, Hewitt, AW, Mackey, DA, Haines, JL, MacGregor, S, Wiggs, JL, Pasquale, LR, Bailey, JNC, Gharahkhani, P, Kang, JH, Butkiewicz, M, Sullivan, DA, Weinreb, RN, Aschard, H, Allingham, RR, Ashley-Koch, A, Lee, RK, Moroi, SE, Brilliant, MH, Wollstein, G, Schuman, JS, Fingert, JH, Budenz, DL, Realini, T, Gaasterland, T, Scott, WK, Singh, K, Sit, AJ, Igo, RP, Song, YE, Hark, L, Ritch, R, Rhee, DJ, Vollrath, D, Zack, DJ, Medeiros, F, Vajaranant, TS, Chasman, DI, Christen, WG, Pericak-Vance, MA, Liu, Y, Kraft, P, Richards, JE, Rosner, BA, Hauser, MA, Craig, JE, Burdon, KP, Hewitt, AW, Mackey, DA, Haines, JL, MacGregor, S, Wiggs, JL, and Pasquale, LR

Abstract

PURPOSE: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. METHODS: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). RESULTS: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. CONCLUSIONS: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

Published
2018

18. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Author

Bailey, JNC, Loomis, SJ, Kang, JH, Allingham, RR, Gharahkhani, P, Khor, CC, Burdon, KP, Aschard, H, Chasman, DI, Igo, RP, Hysi, PG, Glastonbury, CA, Ashley-Koch, A, Brilliant, M, Brown, AA, Budenz, DL, Buil, A, Cheng, CY, Choi, H, Christen, WG, Curhan, G, De Vivo, I, Fingert, JH, Foster, PJ, Fuchs, C, Gaasterland, D, Gaasterland, T, Hewitt, AW, Hu, F, Hunter, DJ, Khawaja, AP, Lee, RK, Li, Z, Lichter, PR, Mackey, DA, McGuffin, P, Mitchell, P, Moroi, SE, Perera, SA, Pepper, KW, Qi, Q, Realini, T, Richards, JE, Ridker, PM, Rimm, E, Ritch, R, Ritchie, M, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Song, YE, Tamimi, RM, Topouzis, F, Viswanathan, AC, Verma, SS, Vollrath, D, Wang, JJ, Weisschuh, N, Wissinger, B, Wollstein, G, Wong, TY, Yaspan, BL, Zack, DJ, Zhang, K, Weinreb, RN, Pericak-Vance, MA, Small, K, Hammond, CJ, Aung, T, Liu, Y, Vithana, EN, MacGregor, S, Craig, JE, Kraft, P, Howell, G, Hauser, MA, and Pasquale, LR

Subjects
ANZRAG Consortium
Abstract

© 2016 Nature America, Inc. Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10 -11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10 -10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10 -10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

Published
2016

20. A common variant near TGFBR3 is associated with primary open angle glaucoma

Author

Li, Z, Allingham, RR, Nakano, M, Jia, L, Chen, Y, Ikeda, Y, Mani, B, Chen, L-J, Kee, C, Garway-Heath, DF, Sripriya, S, Fuse, N, Abu-Amero, KK, Huang, C, Namburi, P, Burdon, K, Perera, SA, Gharahkhani, P, Lin, Y, Ueno, M, Ozaki, M, Mizoguchi, T, Krishnadas, SR, Osman, EA, Lee, MC, Chan, ASY, Tajudin, L-SA, Do, T, Goncalves, A, Reynier, P, Zhang, H, Bourne, R, Goh, D, Broadway, D, Husain, R, Negi, AK, Su, DH, Ho, C-L, Blanco, AA, Leung, CKS, Wong, TT, Yakub, A, Liu, Y, Nongpiur, ME, Han, JC, Hon, DN, Shantha, B, Zhao, B, Sang, J, Zhang, N, Sato, R, Yoshii, K, Panda-Jonas, S, Koch, AEA, Herndon, LW, Moroi, SE, Challa, P, Foo, JN, Bei, J-X, Zeng, Y-X, Simmons, CP, Tran, NBC, Sharmila, PF, Chew, M, Lim, B, Tam, POS, Chua, E, Ng, XY, Yong, VHK, Chong, YF, Meah, WY, Vijayan, S, Seongsoo, S, Xu, W, Teo, YY, Bailey, JNC, Kang, JH, Haines, JL, Cheng, CY, Saw, S-M, Tai, E-S, Richards, JE, Ritch, R, Gaasterland, DE, Pasquale, LR, Liu, J, Jonas, JB, Milea, D, George, R, Al-Obeidan, SA, Mori, K, Macgregor, S, Hewitt, AW, Girkin, CA, Zhang, M, Sundaresan, P, Vijaya, L, Mackey, DA, Wong, TY, Craig, JE, Sun, X, Kinoshita, S, Wiggs, JL, Khor, C-C, Yang, Z, Pang, CP, Wang, N, Hauser, MA, Tashiro, K, Aung, T, Vithana, EN, Li, Z, Allingham, RR, Nakano, M, Jia, L, Chen, Y, Ikeda, Y, Mani, B, Chen, L-J, Kee, C, Garway-Heath, DF, Sripriya, S, Fuse, N, Abu-Amero, KK, Huang, C, Namburi, P, Burdon, K, Perera, SA, Gharahkhani, P, Lin, Y, Ueno, M, Ozaki, M, Mizoguchi, T, Krishnadas, SR, Osman, EA, Lee, MC, Chan, ASY, Tajudin, L-SA, Do, T, Goncalves, A, Reynier, P, Zhang, H, Bourne, R, Goh, D, Broadway, D, Husain, R, Negi, AK, Su, DH, Ho, C-L, Blanco, AA, Leung, CKS, Wong, TT, Yakub, A, Liu, Y, Nongpiur, ME, Han, JC, Hon, DN, Shantha, B, Zhao, B, Sang, J, Zhang, N, Sato, R, Yoshii, K, Panda-Jonas, S, Koch, AEA, Herndon, LW, Moroi, SE, Challa, P, Foo, JN, Bei, J-X, Zeng, Y-X, Simmons, CP, Tran, NBC, Sharmila, PF, Chew, M, Lim, B, Tam, POS, Chua, E, Ng, XY, Yong, VHK, Chong, YF, Meah, WY, Vijayan, S, Seongsoo, S, Xu, W, Teo, YY, Bailey, JNC, Kang, JH, Haines, JL, Cheng, CY, Saw, S-M, Tai, E-S, Richards, JE, Ritch, R, Gaasterland, DE, Pasquale, LR, Liu, J, Jonas, JB, Milea, D, George, R, Al-Obeidan, SA, Mori, K, Macgregor, S, Hewitt, AW, Girkin, CA, Zhang, M, Sundaresan, P, Vijaya, L, Mackey, DA, Wong, TY, Craig, JE, Sun, X, Kinoshita, S, Wiggs, JL, Khor, C-C, Yang, Z, Pang, CP, Wang, N, Hauser, MA, Tashiro, K, Aung, T, and Vithana, EN

Abstract

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.

Published
2015

21. Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

Author

Hysi, PG, Cheng, C-Y, Springelkamp, H, Macgregor, S, Bailey, JNC, Wojciechowski, R, Vitart, V, Nag, A, Hewitt, AW, Hohn, R, Venturini, C, Mirshahi, A, Ramdas, WD, Thorleifsson, G, Vithana, E, Khor, C-C, Stefansson, AB, Liao, J, Haines, JL, Amin, N, Wang, YX, Wild, PS, Ozel, AB, Li, JZ, Fleck, BW, Zeller, T, Staffieri, SE, Teo, Y-Y, Cuellar-Partida, G, Luo, X, Allingham, RR, Richards, JE, Senft, A, Karssen, LC, Zheng, Y, Bellenguez, C, Xu, L, Iglesias, AI, Wilson, JF, Kang, JH, van Leeuwen, EM, Jonsson, V, Thorsteinsdottir, U, Despriet, DDG, Ennis, S, Moroi, SE, Martin, NG, Jansonius, NM, Yazar, S, Tai, E-S, Amouyel, P, Kirwan, J, van Koolwijk, LME, Hauser, MA, Jonasson, F, Leo, P, Loomis, SJ, Fogarty, R, Rivadeneira, F, Kearns, L, Lackner, KJ, de Jong, PTVM, Simpson, CL, Pennell, CE, Oostra, BA, Uitterlinden, AG, Saw, S-M, Lotery, AJ, Bailey-Wilson, JE, Hofman, A, Vingerling, JR, Maubaret, C, Pfeiffer, N, Wolfs, RCW, Lemij, HG, Young, TL, Pasquale, LR, Delcourt, C, Spector, TD, Klaver, CCW, Small, KS, Burdon, KP, Stefansson, K, Wong, T-Y, Viswanathan, A, Mackey, DA, Craig, JE, Wiggs, JL, van Duijn, CM, Hammond, CJ, Aung, T, Hysi, PG, Cheng, C-Y, Springelkamp, H, Macgregor, S, Bailey, JNC, Wojciechowski, R, Vitart, V, Nag, A, Hewitt, AW, Hohn, R, Venturini, C, Mirshahi, A, Ramdas, WD, Thorleifsson, G, Vithana, E, Khor, C-C, Stefansson, AB, Liao, J, Haines, JL, Amin, N, Wang, YX, Wild, PS, Ozel, AB, Li, JZ, Fleck, BW, Zeller, T, Staffieri, SE, Teo, Y-Y, Cuellar-Partida, G, Luo, X, Allingham, RR, Richards, JE, Senft, A, Karssen, LC, Zheng, Y, Bellenguez, C, Xu, L, Iglesias, AI, Wilson, JF, Kang, JH, van Leeuwen, EM, Jonsson, V, Thorsteinsdottir, U, Despriet, DDG, Ennis, S, Moroi, SE, Martin, NG, Jansonius, NM, Yazar, S, Tai, E-S, Amouyel, P, Kirwan, J, van Koolwijk, LME, Hauser, MA, Jonasson, F, Leo, P, Loomis, SJ, Fogarty, R, Rivadeneira, F, Kearns, L, Lackner, KJ, de Jong, PTVM, Simpson, CL, Pennell, CE, Oostra, BA, Uitterlinden, AG, Saw, S-M, Lotery, AJ, Bailey-Wilson, JE, Hofman, A, Vingerling, JR, Maubaret, C, Pfeiffer, N, Wolfs, RCW, Lemij, HG, Young, TL, Pasquale, LR, Delcourt, C, Spector, TD, Klaver, CCW, Small, KS, Burdon, KP, Stefansson, K, Wong, T-Y, Viswanathan, A, Mackey, DA, Craig, JE, Wiggs, JL, van Duijn, CM, Hammond, CJ, and Aung, T

Abstract

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 × 10(-11) for rs2472493 near ABCA1 and P = 6.39 × 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

Published
2014

25. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma

Author

Wiggs, JL, Yaspan, BL, Hauser, MA, Kang, JH, Allingham, RR, Olson, LM, Abdrabou, W, Fan, BJ, Wang, DY, Brodeur, W, Budenz, DL, Caprioli, J, Crenshaw, A, Crooks, K, DelBono, E, Doheny, KF, Friedman, DS, Gaasterland, D, Gaasterland, T, Laurie, C, Lee, RK, Lichter, PR, Loomis, S, Liu, Y, Medeiros, FA, McCarty, C, Mirel, D, Moroi, SE, Musch, DC, Realini, A, Rozsa, FW, Schuman, JS, Scott, K, Singh, K, Stein, JD, Trager, EH, VanVeldhuisen, P, Vollrath, D, Wollstein, G, Yoneyama, S, Zhang, K, Weinreb, RN, Ernst, J, Kellis, M, Masuda, T, Zack, D, Richards, JE, Pericak-Vance, M, Pasquale, LR, Haines, JL, Wiggs, JL, Yaspan, BL, Hauser, MA, Kang, JH, Allingham, RR, Olson, LM, Abdrabou, W, Fan, BJ, Wang, DY, Brodeur, W, Budenz, DL, Caprioli, J, Crenshaw, A, Crooks, K, DelBono, E, Doheny, KF, Friedman, DS, Gaasterland, D, Gaasterland, T, Laurie, C, Lee, RK, Lichter, PR, Loomis, S, Liu, Y, Medeiros, FA, McCarty, C, Mirel, D, Moroi, SE, Musch, DC, Realini, A, Rozsa, FW, Schuman, JS, Scott, K, Singh, K, Stein, JD, Trager, EH, VanVeldhuisen, P, Vollrath, D, Wollstein, G, Yoneyama, S, Zhang, K, Weinreb, RN, Ernst, J, Kellis, M, Masuda, T, Zack, D, Richards, JE, Pericak-Vance, M, Pasquale, LR, and Haines, JL

Abstract

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10-18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10-11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10-12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10-10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma. © 2012 Wiggs et al.

Published
2012

30. Level 2 genitourinary medicine training and ongoing supervision -- how we can all benefit.

Author

Pattman RS, Richards JE, Pattman, Richard S, and Richards, Jane E

Abstract

An innovative six-month, two sessions a week, funded clinical attachment programme was devised and introduced for practical training and experience to meet the demands and requirements of those wishing practical experience and training in genitourinary medicine. This has been generated by interest from previous theoretical teaching and as a desire to provide Level 2 services in the community. To date four doctors have completed this training with excellent mutual evaluation and a recognition by all involved, including commissioners, of the importance of maintaining a regular formal session while providing Level 2 community sexual health services. To be formally recognized improved evaluation, standardization and certification are required. However, if pursued, this package with continuing specialist links should prove beneficial to all involved and with the current epidemic of sexually transmitted infections will improve and enhance available services. [ABSTRACT FROM AUTHOR]

Published
2004
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47. Cover

Author

Richards, Jeffrey H.

Published
1991

48. Works Cited

Author

Richards, Jeffrey H.

Published
1991

50. Index

Author

Richards, Jeffrey H.

Published
1991

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