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140 results on '"Klein, M.L."'

1. Adaptive insertion of a hydrophobic anchor into a poly(ethylene glycol) host for programmable surface functionalization

Author

Zhang, S., Li, W., Luan, J., Srivastava, A., Carnevale, V., Klein, M.L., Sun, J., Wang, D., Teora, S.P., Rijpkema, S.J., Meeldijk, J.D., Wilson, D.A., Zhang, S., Li, W., Luan, J., Srivastava, A., Carnevale, V., Klein, M.L., Sun, J., Wang, D., Teora, S.P., Rijpkema, S.J., Meeldijk, J.D., and Wilson, D.A.

Abstract

Contains fulltext : 290188.pdf (Publisher’s version ) (Open Access)

Published
2023

5. No CFH or ARMS2 Interaction with Omega-3 Fatty Acids, Low versus High Zinc, or beta-Carotene versus Lutein and Zeaxanthin on Progression of Age-Related Macular Degeneration in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report No. 18

Author

Asten, F. van, Chiu, C.Y., Agron, E., Clemons, T.E., Ratnapriya, R., Swaroop, A., Klein, M.L., Fan, R., and Chew, E.Y.

Subjects
genetic structures, sense organs, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], eye diseases
Abstract

Item does not contain fulltext PURPOSE: To assess whether genotypes at 2 major loci associated with age-related macular degeneration (AMD), complement factor H (CFH), or age-related maculopathy susceptibility 2 (ARMS2), modify the response to oral nutrients for the treatment of AMD in the Age-Related Eye Disease Study 2 (AREDS2). DESIGN: Post hoc analysis of a randomized trial. PARTICIPANTS: White AREDS2 participants. METHODS: AREDS2 participants (n = 4203) with bilateral large drusen or late AMD in 1 eye were assigned randomly to lutein and zeaxanthin, omega-3 fatty acids, both, or placebo, and most also received the AREDS supplements. A secondary randomization assessed modified AREDS supplements in 4 treatment arms: lower zinc dosage, omission of beta-carotene, both, or no modification. To evaluate the progression to late AMD, fundus photographs were obtained at baseline and annual study visits, and history of treatment for late AMD was obtained at study visits and 6-month interim telephone calls. Participants were genotyped for the single-nucleotide polymorphisms rs1061170 in CFH and rs10490924 in ARMS2. Bivariate frailty models using both eyes were conducted, including a gene-supplement interaction term and adjusting for age, gender, level of education, and smoking status. The main treatment effects, as well as the direct comparison between lutein plus zeaxanthin and beta-carotene, were assessed for genotype interaction. MAIN OUTCOME MEASURES: The interaction between genotype and the response to AREDS2 supplements regarding progression to late AMD, any geographic atrophy (GA), and neovascular AMD. RESULTS: Complete data were available for 2775 eyes without baseline late AMD (1684 participants). The participants (mean age +/- standard deviation, 72.1+/-7.7 years; 58.5% female) were followed up for a median of 5 years. The ARMS2 risk allele was associated significantly with progression to late AMD and neovascular AMD (P = 2.40 x 10(-5) and P = 0.002, respectively), but not any GA (P = 0.097). The CFH risk allele was not associated with AMD progression. Genotype did not modify significantly the response to any of the AREDS2 supplements. CONCLUSIONS: CFH and ARMS2 risk alleles do not modify the response to the AREDS2 nutrient supplements with respect to the progression to late AMD (GA and neovascular AMD).

Published
2019

6. Genetic and phenotypic heterogeneity in pattern dystrophy

Author

Francis, P.J., Schultz, D.W., Gregory, A.M., Schain, M.B., Barra, R., Majewski, J., Ott, J., Acott, T., Weleber, R.G., and Klein, M.L.

Subjects
Gene mutations -- Analysis, Retinal degeneration -- Genetic aspects, Health
Published
2005

7. Progression of Geographic Atrophy in Age-related Macular Degeneration: AREDS2 Report Number 16

Author

Keenan, T.D., Agron, E., Domalpally, A., Clemons, T.E., Asten, F. van, Wong, W.T., Danis, R.G., Sadda, S., Rosenfeld, P.J., Klein, M.L., Ratnapriya, R., Swaroop, A., Ferris, F.L., 3rd, and Chew, E.Y.

Subjects
genetic structures, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], eye diseases
Abstract

Item does not contain fulltext PURPOSE: To analyze the prevalence, incidence, and clinical characteristics of eyes with geographic atrophy (GA) in age-related macular degeneration (AMD), including clinical and genetic factors affecting enlargement. DESIGN: Prospective cohort study within a controlled clinical trial. PARTICIPANTS: Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50-85 years. METHODS: Baseline and annual stereoscopic color fundus photographs were evaluated for GA presence and area. Analyses included GA prevalence and incidence rates, Kaplan-Meier rates, mixed-model regression, and multivariable analysis of the square root of GA, area adjusted for covariates, including clinical/imaging characteristics and genotype. MAIN OUTCOME MEASURES: (1) Presence or development of GA; (2) change in the square root of GA area over time. RESULTS: At baseline, 517 eyes (6.2%) of 411 participants (9.8%) had pre-existing GA (without neovascular AMD), with the following characteristics: 33% central, 67% noncentral; and the following configurations: 36% small, 26% solid/unifocal, 24% multifocal, 9% horseshoe/ring, and 6% indeterminate. Of the remaining 6530 eyes at risk, 1099 eyes (17.3%) of 883 participants developed incident GA without prior neovascular disease during mean follow-up of 4.4 years. The Kaplan-Meier rate of incident GA was 19% of eyes at 5 years. In eyes with incident GA, 4-year risk of subsequent neovascular AMD was 29%. In eyes with incident noncentral GA, 4-year risk of central involvement was 57%. GA enlargement rate (following square root transformation) was similar in eyes with pre-existing GA (0.29 mm/year; 95% confidence interval 0.27-0.30) and incident GA (0.28 mm/year; 0.27-0.30). In the combined group, GA enlargement was significantly faster with noncentrality, multifocality, intermediate baseline size, and bilateral GA (P < 0.0001 for interaction in each case) but not with AREDS2 treatment assignment (P = 0.33) or smoking status (P = 0.05). Enlargement was significantly faster with ARMS2 risk (P < 0.0001), C3 non-risk (P = 0.0002), and APOE non-risk (P = 0.001) genotypes. CONCLUSIONS: Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.

Published
2018
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10. Reply

Author

Asten, F. van, Chiu, C.Y., Agrón, E., Clemons, T.E., Ratnapriya, R., Swaroop, A., Klein, M.L., Fan, R., Chew, E.Y., Asten, F. van, Chiu, C.Y., Agrón, E., Clemons, T.E., Ratnapriya, R., Swaroop, A., Klein, M.L., Fan, R., and Chew, E.Y.

Abstract

Contains fulltext : 220964.pdf (Publisher’s version ) (Closed access)

Published
2020

12. Screening Libraries of Amphiphilic Janus Dendrimers Based on Natural Phenolic Acids to Discover Monodisperse Unilamellar Dendrimersomes

Author

Buzzacchera, Irene, Xiao, Q., Han, Hong, Rahimi, Khosrow, Li, Shangda, Kostina, Nina Yu., Toebes, B.J., Wilson, Daniela A., Klein, M.L., Percec, Virgil, Buzzacchera, Irene, Xiao, Q., Han, Hong, Rahimi, Khosrow, Li, Shangda, Kostina, Nina Yu., Toebes, B.J., Wilson, Daniela A., Klein, M.L., and Percec, Virgil

Abstract

Contains fulltext : 201525.pdf (publisher's version ) (Open Access)

Published
2019

13. Vitamin D, osteocalcin, and risk for adiposity as comorbidities in middle school children

Author

Boucher-Berry, C., Speiser, P.W., Carey, D.E., Shelov, S.P., Accacha, S., Fennoy, I., Rapaport, R., Espinal, Y., Rosenbaum, M., Altshuler, L., Bhangoo, A., Close, S., Conroy, R., DeSantis, D., Gupta, R., Hassoun, A.A., Iazetti, L., Jacques, F.J., Jean, A.M., Klein, M.L., Levine, R.L., Lowell, B., Michel, L, Pavlovich, K., Rosenfeld, W, Shamoon, E., and Ten, S.

Subjects
Male, Vitamin, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Osteocalcin, Comorbidity, Type 2 diabetes, Article, vitamin D deficiency, Body Mass Index, Bone remodeling, chemistry.chemical_compound, Insulin resistance, Risk Factors, Internal medicine, medicine, Vitamin D and neurology, Humans, Glucose homeostasis, Orthopedics and Sports Medicine, Vitamin D, Child, Adiposity, Demography, Inflammation, Schools, Anthropometry, biology, business.industry, medicine.disease, Glucose, Endocrinology, chemistry, biology.protein, Regression Analysis, Female, business, Biomarkers
Abstract

Nonclassic actions of vitamin D include potential regulation of immune function and glucose homeostasis. The bone-metabolism loop has recently been expanded to include osteocalcin, which appears to play a more direct role in pancreatic beta cell function and energy metabolism. We hypothesized that both vitamin D and osteocalcin would correlate negatively with indices of adiposity-related comorbidity risk in periadolescents, varying by ethnic group. We analyzed anthropometric, metabolic, and inflammatory markers from a multiethnic population of 106 school children 11 to 14 years of age studied as part of the Reduce Obesity and Diabetes (ROAD) consortium. As expected, 25-hydroxyvitamin D (25-OH vitamin D) was inversely correlated with intact parathyroid hormone (iPTH); total osteocalcin (OCN) and uncarboxylated osteocalcin (uOCN) were directly correlated with each other. OCN and uOCN concentrations correlated inversely with age. Vitamin D deficiency was most prevalent among East Asians (EA) and African Americans (AA). The highest lipid risk scores and homeostatic model for assessment of insulin resistance (HOMA-IR) values were seen in the South Asian (SA) group. Overall, adiposity measures were inversely correlated with OCN and iPTH, whereas such relationships were not observed for vitamin D. Acute insulin response to glucose challenge correlated negatively with uOCN in all subjects; however, lipid risk score correlated negatively with uOCN only in whites. The relationships between markers of calcium metabolism and body composition, glucose homeostasis, lipids, and inflammation all showed racial and ethnic differences. No consistent relationship was found between vitamin D and adiposity or vitamin D and glucose metabolism; instead vitamin D levels varied by race and ethnicity in this school-based group. These findings are consistent with the hypothesis that markers of calcium and bone metabolism may reflect risk for adiposity-related comorbidities in children.

Published
2012
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14. Membrane Protein Structure, Function, and Dynamics: a Perspective from Experiments and Theory

Author

Cournia, Z. Allen, T.W. Andricioaei, I. Antonny, B. Baum, D. Brannigan, G. Buchete, N.-V. Deckman, J.T. Delemotte, L. del Val, C. Friedman, R. Gkeka, P. Hege, H.-C. Hénin, J. Kasimova, M.A. Kolocouris, A. Klein, M.L. Khalid, S. Lemieux, M.J. Lindow, N. Roy, M. Selent, J. Tarek, M. Tofoleanu, F. Vanni, S. Urban, S. Wales, D.J. Smith, J.C. Bondar, A.-N.

Abstract

Membrane proteins mediate processes that are fundamental for the flourishing of biological cells. Membrane-embedded transporters move ions and larger solutes across membranes; receptors mediate communication between the cell and its environment and membrane-embedded enzymes catalyze chemical reactions. Understanding these mechanisms of action requires knowledge of how the proteins couple to their fluid, hydrated lipid membrane environment. We present here current studies in computational and experimental membrane protein biophysics, and show how they address outstanding challenges in understanding the complex environmental effects on the structure, function, and dynamics of membrane proteins. © 2015, Springer Science+Business Media New York.

Published
2015

15. Bioactive cell-like hybrids coassembled from (glyco)dendrimersomes with bacterial membranes

Author

Xiao, Q., Yadavalli, S.S., Zhang, S.D., Sherman, S.E., Fiorin, E., da Silva, L., Wilson, D.A., Hammer, D.A., Andre, S., Gabius, H.J., Klein, M.L., Goulian, M., Percec, V., Xiao, Q., Yadavalli, S.S., Zhang, S.D., Sherman, S.E., Fiorin, E., da Silva, L., Wilson, D.A., Hammer, D.A., Andre, S., Gabius, H.J., Klein, M.L., Goulian, M., and Percec, V.

Abstract

Item does not contain fulltext

Published
2016

16. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

Author

Fritsche, L.G. (Lars), Igl, W. (Wilmar), Cooke Bailey, J.N. (Jessica N.), Grassmann, F. (Felix), Sengupta, S. (Sebanti), Bragg-Gresham, J.L. (Jennifer L.), Burdon, K.P. (Kathryn P.), Hebbring, S.J. (Scott J.), Wen, C. (Cindy), Gorski, M. (Mathias), Kim, I.K. (Ivana), Cho, D. (David), Zack, D. (Donald), Souied, E.H. (Eric), Scholl, H.P.N. (Hendrik), Bala, E. (Elisa), ELee, K. (Kristine), Hunter, D. (David), Sardell, R.J. (Rebecca J.), Mitchell, P. (Paul), Merriam, J.E. (Joanna), Cipriani, F. (Francesco), Hoffman, J.D. (Joshua D.), Schick, T. (Tina), Lechanteur, Y.T.E. (Yara T. E.), Guymer, R.H. (Robyn), Johnson, M.P. (Matthew), Jiang, Y., Stanton, C.M. (Chloe), Buitendijk, G.H.S. (Gabrielle), Zhan, X. (Xiaowei), Kwong, A.M. (Alan M.), Boleda, A. (Alexis), Brooks, M. (Matthew), Gieser, L. (Linn), Ratna Priya, R. (Rinki), Branham, K.E. (Kari), Foerster, J.R. (Johanna R.), Heckenlively, J.R. (John), Othman, M.I. (Mohammad), Vote, B.J. (Brendan J.), Liang, H.H. (Helena Hai), Souzeau, E. (Emmanuelle), McAllister, I.L. (Ian L.), Isaacs, T. (Timothy), Hall, J. (Janette), Lake, S. (Stewart), Mackey, D.A. (David), Constable, I.J. (Ian J.), Craig, J.E. (Jamie E.), Kitchner, T.E. (Terrie E.), Yang, Z. (Zhenglin), Su, Z. (Zhiguang), Luo, H. (Hongrong), Chen, D. (Daniel), Ouyang, H. (Hong), Flagg, K. (Ken), Lin, D. (Danni), Mao, G. (Guanping), Ferreyra, H.A. (Henry), Stark, K. (Klaus), Strachwitz, C. (Claudia) von, Wolf, A. (Armin), Brandl, C. (Caroline), Rudolph, G. (Guenther), Olden, M. (Matthias), Morrison, M.A. (Margaux), Morgan, D.J. (Denise), Schu, M. (Matthew), Ahn, J. (Jeeyun), Silvestri, G. (Giuliana), Tsironi, E.E. (Evangelia), Park, K.H. (Kyu Hyung), Farrer, L.A. (Lindsay), Orlin, A. (Anton), Brucker, A. (Alexander), Curcio, C.A. (Christine A.), Mohand-Sa'd, S. (Saddek), Sahel, J.-A. (José-Alain), Audo, I. (Isabelle), Benchaboune, M. (Mustapha), Cree, A.J. (Angela), Rennie, C.A. (Christina A.), Goverdhan, S.V. (Srinivas V.), Grunin, M. (Michelle), Hagbi-Levi, S. (Shira), Campochiaro, B. (Betsy), Katsanis, N. (Nicholas), Holz, F.G. (Frank), Blond, F. (Frédéric), Blanché, H. (Hél'ne), Deleuze, J.-F. (Jean-Fran'ois), Igo Jr., R.P. (Robert), Truitt, B.J. (Barbara), Peachey, N.S. (Neal ), Meuer, S.M. (Stacy), Myers, C.E. (Chelsea), Moore, E.L. (Emily L.), Klein, R. (Ronald), Hauser, M.A. (Michael), Postel, E.A. (Eric), Courtenay, M.D. (Monique D.), Schwartz, S.M. (Stephen), Kovach, J.L. (Jaclyn), Scott, W.K. (William), Liew, G. (Gerald), Tan, A.G. (Ava G.), Gopinath, B. (Bamini), Smith, T. (Tim), Khan, J.C. (Jane), Shahid, M. (Mohammad), Moore, A.T. (Anthony), McGrath, J.A. (J Allie), Laux, R. (Reneé), Brantley, M.A. (Milam), Agarwal, A. (Anita), Ersoy, L. (Lebriz), Caramoy, A. (Albert), Langmann, T. (Thomas), Saksens, N.T.M. (Nicole T.), Jong, E.K. (Eiko Kde), Hoyng, C.B. (Carel), Cain, M.S. (Melinda), Richardson, A.J. (Andrea), Martin, T.M. (Tammy M.), Blangero, J. (John), Weeks, D.E. (Daniel), Dhillon, B. (Bal), Duijn, C.M. (Cornelia) van, Doheny, K.F. (Kimberly), Romm, J. (Jane), Klaver, C.C.W. (Caroline), Hayward, C. (Caroline), Gorin, M.B. (Michael B.), Klein, M.L. (Michael), Baird, P.N. (Paul), Hollander, A.I. (Anneke), Fauser, S. (Sascha), WYates, J.R. (John R.), Allikmets, R. (Rando), Wang, J.J. (Jie Jin), Schaumberg, D.A. (Debra), Klein, B.E.K. (Barbara), Hagstrom, S.A. (Stephanie), Chowers, Y. (Yehuda), Lotery, A.J. (Andrew), Léveillard, T. (Thierry), Zhang, K. (Kang), Brilliant, M.H. (Murray H.), Hewit, A.W. (Alex), Swaroop, A. (Anand), Chew, E.Y. (Emily Y.), Pericak-Vance, M.A. (Margaret), DeAngelis, M.M. (Margaret), Stambolian, D. (Dwight), Haines, J.L. (Jonathan), Iyengar, S.K. (Sudha), Weber, B.H.F. (Bernhard), Abecasis, G.R. (Gonçalo), Heid, I.M. (Iris), Li, M. (Mingyao), Fritsche, L.G. (Lars), Igl, W. (Wilmar), Cooke Bailey, J.N. (Jessica N.), Grassmann, F. (Felix), Sengupta, S. (Sebanti), Bragg-Gresham, J.L. (Jennifer L.), Burdon, K.P. (Kathryn P.), Hebbring, S.J. (Scott J.), Wen, C. (Cindy), Gorski, M. (Mathias), Kim, I.K. (Ivana), Cho, D. (David), Zack, D. (Donald), Souied, E.H. (Eric), Scholl, H.P.N. (Hendrik), Bala, E. (Elisa), ELee, K. (Kristine), Hunter, D. (David), Sardell, R.J. (Rebecca J.), Mitchell, P. (Paul), Merriam, J.E. (Joanna), Cipriani, F. (Francesco), Hoffman, J.D. (Joshua D.), Schick, T. (Tina), Lechanteur, Y.T.E. (Yara T. E.), Guymer, R.H. (Robyn), Johnson, M.P. (Matthew), Jiang, Y., Stanton, C.M. (Chloe), Buitendijk, G.H.S. (Gabrielle), Zhan, X. (Xiaowei), Kwong, A.M. (Alan M.), Boleda, A. (Alexis), Brooks, M. (Matthew), Gieser, L. (Linn), Ratna Priya, R. (Rinki), Branham, K.E. (Kari), Foerster, J.R. (Johanna R.), Heckenlively, J.R. (John), Othman, M.I. (Mohammad), Vote, B.J. (Brendan J.), Liang, H.H. (Helena Hai), Souzeau, E. (Emmanuelle), McAllister, I.L. (Ian L.), Isaacs, T. (Timothy), Hall, J. (Janette), Lake, S. (Stewart), Mackey, D.A. (David), Constable, I.J. (Ian J.), Craig, J.E. (Jamie E.), Kitchner, T.E. (Terrie E.), Yang, Z. (Zhenglin), Su, Z. (Zhiguang), Luo, H. (Hongrong), Chen, D. (Daniel), Ouyang, H. (Hong), Flagg, K. (Ken), Lin, D. (Danni), Mao, G. (Guanping), Ferreyra, H.A. (Henry), Stark, K. (Klaus), Strachwitz, C. (Claudia) von, Wolf, A. (Armin), Brandl, C. (Caroline), Rudolph, G. (Guenther), Olden, M. (Matthias), Morrison, M.A. (Margaux), Morgan, D.J. (Denise), Schu, M. (Matthew), Ahn, J. (Jeeyun), Silvestri, G. (Giuliana), Tsironi, E.E. (Evangelia), Park, K.H. (Kyu Hyung), Farrer, L.A. (Lindsay), Orlin, A. (Anton), Brucker, A. (Alexander), Curcio, C.A. (Christine A.), Mohand-Sa'd, S. (Saddek), Sahel, J.-A. (José-Alain), Audo, I. (Isabelle), Benchaboune, M. (Mustapha), Cree, A.J. (Angela), Rennie, C.A. (Christina A.), Goverdhan, S.V. (Srinivas V.), Grunin, M. (Michelle), Hagbi-Levi, S. (Shira), Campochiaro, B. (Betsy), Katsanis, N. (Nicholas), Holz, F.G. (Frank), Blond, F. (Frédéric), Blanché, H. (Hél'ne), Deleuze, J.-F. (Jean-Fran'ois), Igo Jr., R.P. (Robert), Truitt, B.J. (Barbara), Peachey, N.S. (Neal ), Meuer, S.M. (Stacy), Myers, C.E. (Chelsea), Moore, E.L. (Emily L.), Klein, R. (Ronald), Hauser, M.A. (Michael), Postel, E.A. (Eric), Courtenay, M.D. (Monique D.), Schwartz, S.M. (Stephen), Kovach, J.L. (Jaclyn), Scott, W.K. (William), Liew, G. (Gerald), Tan, A.G. (Ava G.), Gopinath, B. (Bamini), Smith, T. (Tim), Khan, J.C. (Jane), Shahid, M. (Mohammad), Moore, A.T. (Anthony), McGrath, J.A. (J Allie), Laux, R. (Reneé), Brantley, M.A. (Milam), Agarwal, A. (Anita), Ersoy, L. (Lebriz), Caramoy, A. (Albert), Langmann, T. (Thomas), Saksens, N.T.M. (Nicole T.), Jong, E.K. (Eiko Kde), Hoyng, C.B. (Carel), Cain, M.S. (Melinda), Richardson, A.J. (Andrea), Martin, T.M. (Tammy M.), Blangero, J. (John), Weeks, D.E. (Daniel), Dhillon, B. (Bal), Duijn, C.M. (Cornelia) van, Doheny, K.F. (Kimberly), Romm, J. (Jane), Klaver, C.C.W. (Caroline), Hayward, C. (Caroline), Gorin, M.B. (Michael B.), Klein, M.L. (Michael), Baird, P.N. (Paul), Hollander, A.I. (Anneke), Fauser, S. (Sascha), WYates, J.R. (John R.), Allikmets, R. (Rando), Wang, J.J. (Jie Jin), Schaumberg, D.A. (Debra), Klein, B.E.K. (Barbara), Hagstrom, S.A. (Stephanie), Chowers, Y. (Yehuda), Lotery, A.J. (Andrew), Léveillard, T. (Thierry), Zhang, K. (Kang), Brilliant, M.H. (Murray H.), Hewit, A.W. (Alex), Swaroop, A. (Anand), Chew, E.Y. (Emily Y.), Pericak-Vance, M.A. (Margaret), DeAngelis, M.M. (Margaret), Stambolian, D. (Dwight), Haines, J.L. (Jonathan), Iyengar, S.K. (Sudha), Weber, B.H.F. (Bernhard), Abecasis, G.R. (Gonçalo), Heid, I.M. (Iris), and Li, M. (Mingyao)

Abstract

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10 -8) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10 -10). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Published
2016
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18. A novel diagnostic test detects a low frequency of the hemicentin Gln5345Arg variant among Northern Irish age related macular degeneration patients

Author

McKay, Gareth, Clarke, Stephen, Hughes, Anne, McConnell, V., Schultz, D.W., Klein, M.L., Silvestri, Giulana, and Simpson, David

Subjects
Ophthalmology, eye diseases
Abstract

Purpose: Age related macular degeneration (AMD) is a common cause of severe vision loss. Identification of genes involved in AMD will facilitate early detection and ultimately help to identify pathways for treatment for this disorder. The A16,263G mutation in the HEMICENTIN-1 gene produces a non-conservative substitution of arginine for glutamine at codon 5345 which has been implicated in familial AMD. The aim of this study is to develop a rapid diagnostic assay for the detection of this mutation and to evaluate its frequency in a sample of AMD patients. Methods: A primer probe set was designed from exon 104 of the HEMICENTIN-1 gene to differentiate between mutant and wild type alleles. A region spanning the mutation was amplified by PCR using a LightCycler (Roche Diagnostic). The mutation was then detected by melt curve analysis of the hybrid formed between the PCR product and a specific fluorescent probe. The frequency of the mutation within the Northern Ireland population was evaluated by assaying 508 affected AMD patients, 25 possibly affected and 163 controls. Results: This assay clearly discriminates between the A16,263G mutant and wild type HEMICENTIN-1 alleles. The wild type sequence has a single base mismatch with the probe which decreases the stability of the hybrid, resulting in a lower TM (TM=51.27 °C) than that observed for the perfectly matched mutant allele (TM=59.9 °C). The mutant allele was detected in only one of the 696 subjects, an affected AMD patient. Conclusions: We describe a rapid assay for the genotyping of the Gln5345Arg mutation using real-time fluorescence PCR to facilitate rapid processing of samples through combined amplification and detection steps. These characteristics are suitable for a clinical setting where high throughput diagnostic procedures are required. The frequency of this mutation within the Northern Ireland population has been estimated at 0.2%, concurring with previous findings that this mutation is a rare variant associated with AMD. A rapid diagnostic assay will facilitate a reliable and convenient evaluation of the frequency of the Gln5345Arg mutation and its association with AMD within other populations.

Published
2004

19. Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies.

Author

McKay, G.J., Patterson, C.C., Chakravarthy, U., Dasari, S., Klaver, C.C., Vingerling, J.R., Ho, L., de Jong, P.T.V.M., Fletcher, A.E., Young, I.S., Seland, J.H., Rahhu, M., Soubrane, G., Tomazzoli, L., Topouzis, F., Vioque, J., Hingorani, A.D., Sofat, R., Dean, M., Sawitzke, J., Seddon, J.M., Peter, I., Webster, A.R., Moore, A.T., Yates, J.R., Cipriani, V., Fritsche, L.G., Weber, B.H., Keilhauer, C.N., Lotery, A.J., Ennis, S., Klein, M.L., Francis, P.J., Stambolian, D., Orlin, A., Gorin, M.B., Weeks, D.E., Kuo, C.L., Swaroop, A., Othman, M., Kanda, A., Chen, W., Abecasis, G.R., Wright, A.F., Hayward, C., Baird, P.N., Guymer, R.H., Attia, J., Thakkinstian, A., Silvestri, G., McKay, G.J., Patterson, C.C., Chakravarthy, U., Dasari, S., Klaver, C.C., Vingerling, J.R., Ho, L., de Jong, P.T.V.M., Fletcher, A.E., Young, I.S., Seland, J.H., Rahhu, M., Soubrane, G., Tomazzoli, L., Topouzis, F., Vioque, J., Hingorani, A.D., Sofat, R., Dean, M., Sawitzke, J., Seddon, J.M., Peter, I., Webster, A.R., Moore, A.T., Yates, J.R., Cipriani, V., Fritsche, L.G., Weber, B.H., Keilhauer, C.N., Lotery, A.J., Ennis, S., Klein, M.L., Francis, P.J., Stambolian, D., Orlin, A., Gorin, M.B., Weeks, D.E., Kuo, C.L., Swaroop, A., Othman, M., Kanda, A., Chen, W., Abecasis, G.R., Wright, A.F., Hayward, C., Baird, P.N., Guymer, R.H., Attia, J., Thakkinstian, A., and Silvestri, G.

Published
2011

20. Variations in apolipoprotein E frequency with age in a pooled analysis of a large group of older people.

Author

McKay, G.J., Silvestri, G., Chakravarthy, U., Dasari, S., Fritsche, L.G., Weber, B.H., Keilhauer, C.N., Klein, M.L., Francis, P.J., Klaver, C.C., Vingerling, J.R., Ho, L., de Jong, P.T.V.M., Dean, M., Sawitzke, J., Baird, P.N., Guymer, R.H., Stambolian, D., Orlin, A., Seddon, J.M., Peter, I., Wright, A.F., Hayward, C., Lotery, A.J., Ennis, S., Gorin, M.B., Weeks, D.E., Kuo, C.L., Hingorani, A.D., Sofat, R., Cipriani, V., Swaroop, A., Othman, M., Kanda, A., Chen, W., Abecasis, G.R., Yates, J.R., Webster, A.R., Moore, A.T., Seland, J.H., Rahu, M., Soubrane, G., Tomazolli, L., Topouzis, F., Vioque, J., Young, I.S., Fletcher, A.E., Patterson, C.C., McKay, G.J., Silvestri, G., Chakravarthy, U., Dasari, S., Fritsche, L.G., Weber, B.H., Keilhauer, C.N., Klein, M.L., Francis, P.J., Klaver, C.C., Vingerling, J.R., Ho, L., de Jong, P.T.V.M., Dean, M., Sawitzke, J., Baird, P.N., Guymer, R.H., Stambolian, D., Orlin, A., Seddon, J.M., Peter, I., Wright, A.F., Hayward, C., Lotery, A.J., Ennis, S., Gorin, M.B., Weeks, D.E., Kuo, C.L., Hingorani, A.D., Sofat, R., Cipriani, V., Swaroop, A., Othman, M., Kanda, A., Chen, W., Abecasis, G.R., Yates, J.R., Webster, A.R., Moore, A.T., Seland, J.H., Rahu, M., Soubrane, G., Tomazolli, L., Topouzis, F., Vioque, J., Young, I.S., Fletcher, A.E., and Patterson, C.C.

Published
2011

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