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7. A perspective on muscle phenotyping in musculoskeletal research

Author

Foessl, Ines, Ackert-Bicknell, Cheryl L., Kague, Erika, Laskou, Faidra, Jakob, Franz, Karasik, David, Obermayer-Pietsch, Barbara, Alonso, Nerea, Bjørnerem, Åshild, Brandi, Maria Luisa, Busse, Björn, Calado, Ângelo, Cebi, Alper Han, Christou, Maria, Curran, Kathleen M., Hald, Jannie Dahl, Semeraro, Maria Donatella, Douni, Eleni, Duncan, Emma L., Duran, Ivan, Formosa, Melissa M., Gabet, Yankel, Ghatan, Samuel, Gkitakou, Artemis, Hassler, Eva Maria, Högler, Wolfgang, Heino, Terhi J., Hendrickx, Gretl, Khashayar, Patricia, Kiel, Douglas P., Koromani, Fjorda, Langdahl, Bente, Lopes, Philippe, Mäkitie, Outi, Maurizi, Antonio, Medina-Gomez, Carolina, Ntzani, Evangelia, Ohlsson, Claes, Prijatelj, Vid, Rabionet, Raquel, Reppe, Sjur, Rivadeneira, Fernando, Roshchupkin, Gennady, Sharma, Neha, Søe, Kent, Styrkarsdottir, Unnur, Szulc, Pavel, Teti, Anna, Tobias, Jon, Valjevac, Amina, van de Peppel, Jeroen, van der Eerden, Bram, van Rietbergen, Bert, Zekic, Tatjana, and Zillikens, M. Carola

Published
2024
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10. The International X-Linked Hypophosphatemia (XLH) Registry: first interim analysis of baseline demographic, genetic and clinical data

Author

Ariceta, Gema, Beck-Nielsen, Signe Sparre, Boot, Annemieke M., Brandi, Maria Luisa, Briot, Karine, de Lucas Collantes, Carmen, Emma, Francesco, Giannini, Sandro, Haffner, Dieter, Keen, Richard, Levtchenko, Elena, Mӓkitie, Outi, Mughal, M. Zulf, Nilsson, Ola, Schnabel, Dirk, Tripto-Shkolnik, Liana, Liu, Jonathan, Williams, Angela, Wood, Sue, and Zillikens, M. Carola

Published
2023
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15. Rationale and design of the B-PROOF study, a randomized controlled trial on the effect of supplemental intake of vitamin B12 and folic acid on fracture incidence

Author

van Wijngaarden Janneke P, Dhonukshe-Rutten Rosalie AM, van Schoor Natasja M, van der Velde Nathalie, Swart Karin MA, Enneman Anke W, van Dijk Suzanne C, Brouwer-Brolsma Elske M, Zillikens M Carola, van Meurs Joyce BJ, Brug Johannes, Uitterlinden André G, Lips Paul, and de Groot Lisette CPGM

Subjects
Geriatrics, RC952-954.6
Abstract

Abstract Background Osteoporosis is a major health problem, and the economic burden is expected to rise due to an increase in life expectancy throughout the world. Current observational evidence suggests that an elevated homocysteine concentration and poor vitamin B12 and folate status are associated with an increased fracture risk. As vitamin B12 and folate intake and status play a large role in homocysteine metabolism, it is hypothesized that supplementation with these B-vitamins will reduce fracture incidence in elderly people with an elevated homocysteine concentration. Methods/Design The B-PROOF (B-Vitamins for the PRevention Of Osteoporotic Fractures) study is a randomized double-blind placebo-controlled trial. The intervention comprises a period of two years, and includes 2919 subjects, aged 65 years and older, independently living or institutionalized, with an elevated homocysteine concentration (≥ 12 μmol/L). One group receives daily a tablet with 500 μg vitamin B12 and 400 μg folic acid and the other group receives a placebo tablet. In both tablets 15 μg (600 IU) vitamin D is included. The primary outcome of the study is osteoporotic fractures. Measurements are performed at baseline and after two years and cover bone health i.e. bone mineral density and bone turnover markers, physical performance and physical activity including falls, nutritional intake and status, cognitive function, depression, genetics and quality of life. This large multi-center project is carried out by a consortium from the Erasmus MC (Rotterdam, the Netherlands), VUmc (Amsterdam, the Netherlands) and Wageningen University, (Wageningen, the Netherlands), the latter acting as coordinator. Discussion To our best knowledge, the B-PROOF study is the first intervention study in which the effect of vitamin B12 and folic acid supplementation on osteoporotic fractures is studied in a general elderly population. We expect the first longitudinal results of the B-PROOF intervention in the second semester of 2013. The results of this intervention will provide evidence on the efficacy of vitamin B12 and folate supplementation in the prevention of osteoporotic fractures. Trial Registration The B-PROOF study is registered with the Netherlands Trial (NTR NTR1333) and with ClinicalTrials.gov (NCT00696514).

Published
2011
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17. Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium

Author

Merino, Jordi, Dashti, Hassan S, Li, Sherly X, Sarnowski, Chloé, Justice, Anne E, Graff, Misa, Papoutsakis, Constantina, Smith, Caren E, Dedoussis, George V, Lemaitre, Rozenn N, Wojczynski, Mary K, Männistö, Satu, Ngwa, Julius S, Kho, Minjung, Ahluwalia, Tarunveer S, Pervjakova, Natalia, Houston, Denise K, Bouchard, Claude, Huang, Tao, Orho-Melander, Marju, Frazier-Wood, Alexis C, Mook-Kanamori, Dennis O, Pérusse, Louis, Pennell, Craig E, de Vries, Paul S, Voortman, Trudy, Li, Olivia, Kanoni, Stavroula, Rose, Lynda M, Lehtimäki, Terho, Zhao, Jing Hua, Feitosa, Mary F, Luan, Jian’an, McKeown, Nicola M, Smith, Jennifer A, Hansen, Torben, Eklund, Niina, Nalls, Mike A, Rankinen, Tuomo, Huang, Jinyan, Hernandez, Dena G, Schulz, Christina-Alexandra, Manichaikul, Ani, Li-Gao, Ruifang, Vohl, Marie-Claude, Wang, Carol A, van Rooij, Frank JA, Shin, Jean, Kalafati, Ioanna P, Day, Felix, Ridker, Paul M, Kähönen, Mika, Siscovick, David S, Langenberg, Claudia, Zhao, Wei, Astrup, Arne, Knekt, Paul, Garcia, Melissa, Rao, DC, Qi, Qibin, Ferrucci, Luigi, Ericson, Ulrika, Blangero, John, Hofman, Albert, Pausova, Zdenka, Mikkilä, Vera, Wareham, Nick J, Kardia, Sharon LR, Pedersen, Oluf, Jula, Antti, Curran, Joanne E, Zillikens, M Carola, Viikari, Jorma S, Forouhi, Nita G, Ordovás, José M, Lieske, John C, Rissanen, Harri, Uitterlinden, André G, Raitakari, Olli T, Kiefte-de Jong, Jessica C, Dupuis, Josée, Rotter, Jerome I, North, Kari E, Scott, Robert A, Province, Michael A, Perola, Markus, Cupples, L Adrienne, Turner, Stephen T, Sørensen, Thorkild IA, Salomaa, Veikko, Liu, Yongmei, Sung, Yun J, Qi, Lu, Bandinelli, Stefania, Rich, Stephen S, de Mutsert, Renée, Tremblay, Angelo, Oddy, Wendy H, Franco, Oscar H, and Paus, Tomas

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Obesity, Human Genome, Genetics, Prevention, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Cardiovascular, Metabolic and endocrine, Aged, Aging, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Cohort Studies, Energy Intake, Female, Fibroblast Growth Factors, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Genotype, Heart Diseases, Humans, Male, Membrane Proteins, Middle Aged, Nutrients, Polymorphism, Single Nucleotide, Receptors, Retinoic Acid, White People, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P

Published
2019

18. Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan

Author

Vandenput, L., Johansson, H., McCloskey, E. V., Liu, E., Åkesson, K. E., Anderson, F. A., Azagra, R., Bager, C. L., Beaudart, C., Bischoff-Ferrari, H. A., Biver, E., Bruyère, O., Cauley, J. A., Center, J. R., Chapurlat, R., Christiansen, C., Cooper, C., Crandall, C. J., Cummings, S. R., da Silva, J. A. P., Dawson-Hughes, B., Diez-Perez, A., Dufour, A. B., Eisman, J. A., Elders, P. J. M., Ferrari, S., Fujita, Y., Fujiwara, S., Glüer, C.-C., Goldshtein, I., Goltzman, D., Gudnason, V., Hall, J., Hans, D., Hoff, M., Hollick, R. J., Huisman, M., Iki, M., Ish-Shalom, S., Jones, G., Karlsson, M. K., Khosla, S., Kiel, D. P., Koh, W.-P., Koromani, F., Kotowicz, M. A., Kröger, H., Kwok, T., Lamy, O., Langhammer, A., Larijani, B., Lippuner, K., Mellström, D., Merlijn, T., Nordström, A., Nordström, P., O’Neill, T. W., Obermayer-Pietsch, B., Ohlsson, C., Orwoll, E. S., Pasco, J. A., Rivadeneira, F., Schei, B., Schott, A.-M., Shiroma, E. J., Siggeirsdottir, K., Simonsick, E. M., Sornay-Rendu, E., Sund, R., Swart, K. M. A., Szulc, P., Tamaki, J., Torgerson, D. J., van Schoor, N. M., van Staa, T. P., Vila, J., Wareham, N. J., Wright, N. C., Yoshimura, N., Zillikens, M. C., Zwart, M., Harvey, N. C., Lorentzon, M., Leslie, W. D., and Kanis, J. A.

Published
2022
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20. Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention

Author

Wang, Zhe, Emmerich, Andrew, Pillon, Nicolas J., Moore, Tim, Hemerich, Daiane, Cornelis, Marilyn C., Mazzaferro, Eugenia, Broos, Siacia, Ahluwalia, Tarunveer S., Bartz, Traci M., Bentley, Amy R., Bielak, Lawrence F., Chong, Mike, Chu, Audrey Y., Berry, Diane, Dorajoo, Rajkumar, Dueker, Nicole D., Kasbohm, Elisa, Feenstra, Bjarke, Feitosa, Mary F., Gieger, Christian, Graff, Mariaelisa, Hall, Leanne M., Haller, Toomas, Hartwig, Fernando P., Hillis, David A., Huikari, Ville, Heard-Costa, Nancy, Holzapfel, Christina, Jackson, Anne U., Johansson, Åsa, Jørgensen, Anja Moltke, Kaakinen, Marika A., Karlsson, Robert, Kerr, Kathleen F., Kim, Boram, Koolhaas, Chantal M., Kutalik, Zoltan, Lagou, Vasiliki, Lind, Penelope A., Lorentzon, Mattias, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Metzendorf, Christoph, Monroe, Kristine R., Pacolet, Alexander, Pérusse, Louis, Pool, Rene, Richmond, Rebecca C., Rivera, Natalia V., Robiou-du-Pont, Sebastien, Schraut, Katharina E., Schulz, Christina-Alexandra, Stringham, Heather M., Tanaka, Toshiko, Teumer, Alexander, Turman, Constance, van der Most, Peter J., Vanmunster, Mathias, van Rooij, Frank J. A., van Vliet-Ostaptchouk, Jana V., Zhang, Xiaoshuai, Zhao, Jing-Hua, Zhao, Wei, Balkhiyarova, Zhanna, Balslev-Harder, Marie N., Baumeister, Sebastian E., Beilby, John, Blangero, John, Boomsma, Dorret I., Brage, Soren, Braund, Peter S., Brody, Jennifer A., Bruinenberg, Marcel, Ekelund, Ulf, Liu, Ching-Ti, Cole, John W., Collins, Francis S., Cupples, L. Adrienne, Esko, Tõnu, Enroth, Stefan, Faul, Jessica D., Fernandez-Rhodes, Lindsay, Fohner, Alison E., Franco, Oscar H., Galesloot, Tessel E., Gordon, Scott D., Grarup, Niels, Hartman, Catharina A., Heiss, Gerardo, Hui, Jennie, Illig, Thomas, Jago, Russell, James, Alan, Joshi, Peter K., Jung, Taeyeong, Kähönen, Mika, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Kolcic, Ivana, Kraft, Peter P., Kuusisto, Johanna, Launer, Lenore J., Li, Aihua, Linneberg, Allan, Luan, Jian’an, Vidal, Pedro Marques, Medland, Sarah E., Milaneschi, Yuri, Moscati, Arden, Musk, Bill, Nelson, Christopher P., Nolte, Ilja M., Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Power, Christine, Raitakari, Olli T., Reedik, Mägi, Reiner, Alex P., Ridker, Paul M., Rudan, Igor, Ryan, Kathy, Sarzynski, Mark A., Scott, Laura J., Scott, Robert A., Sidney, Stephen, Siggeirsdottir, Kristin, Smith, Albert V., Smith, Jennifer A., Sonestedt, Emily, Strøm, Marin, Tai, E. Shyong, Teo, Koon K., Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Uitterlinden, Andre G., Vangipurapu, Jagadish, van Schoor, Natasja, Völker, Uwe, Willemsen, Gonneke, Williams, Kayleen, Wong, Quenna, Xu, Huichun, Young, Kristin L., Yuan, Jian Min, Zillikens, M. Carola, Zonderman, Alan B., Ameur, Adam, Bandinelli, Stefania, Bis, Joshua C., Boehnke, Michael, Bouchard, Claude, Chasman, Daniel I., Smith, George Davey, de Geus, Eco J. C., Deldicque, Louise, Dörr, Marcus, Evans, Michele K., Ferrucci, Luigi, Fornage, Myriam, Fox, Caroline, Garland, Jr, Theodore, Gudnason, Vilmundur, Gyllensten, Ulf, Hansen, Torben, Hayward, Caroline, Horta, Bernardo L., Hyppönen, Elina, Jarvelin, Marjo-Riitta, Johnson, W. Craig, Kardia, Sharon L. R., Kiemeney, Lambertus A., Laakso, Markku, Langenberg, Claudia, Lehtimäki, Terho, Marchand, Loic Le, Magnusson, Patrik K. E., Martin, Nicholas G., Melbye, Mads, Metspalu, Andres, Meyre, David, North, Kari E., Ohlsson, Claes, Oldehinkel, Albertine J., Orho-Melander, Marju, Pare, Guillaume, Park, Taesung, Pedersen, Oluf, Penninx, Brenda W. J. H., Pers, Tune H., Polasek, Ozren, Prokopenko, Inga, Rotimi, Charles N., Samani, Nilesh J., Sim, Xueling, Snieder, Harold, Sørensen, Thorkild I. A., Spector, Tim D., Timpson, Nicholas J., van Dam, Rob M., van der Velde, Nathalie, van Duijn, Cornelia M., Vollenweider, Peter, Völzke, Henry, Voortman, Trudy, Waeber, Gérard, Wareham, Nicholas J., Weir, David R., Wichmann, Heinz-Erich, Wilson, James F., Hevener, Andrea L., Krook, Anna, Zierath, Juleen R., Thomis, Martine A. I., Loos, Ruth J. F., and Hoed, Marcel den

Published
2022
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22. Disentangling the genetics of lean mass.

Author

Karasik, David, Zillikens, M, Hsu, Yi-Hsiang, Aghdassi, Ali, Akesson, Kristina, Amin, Najaf, Barroso, Inês, Bennett, David, Bertram, Lars, Bochud, Murielle, Borecki, Ingrid, Broer, Linda, Buchman, Aron, Byberg, Liisa, Campbell, Harry, Campos-Obando, Natalia, Cauley, Jane, Cawthon, Peggy, Chambers, John, Chen, Zhao, Cho, Nam, Choi, Hyung, Chou, Wen-Chi, Cummings, Steven, de Groot, Lisette, De Jager, Phillip, Demuth, Ilja, Diatchenko, Luda, Econs, Michael, Eiriksdottir, Gudny, Enneman, Anke, Eriksson, Joel, Eriksson, Johan, Estrada, Karol, Evans, Daniel, Feitosa, Mary, Fu, Mao, Gieger, Christian, Grallert, Harald, Gudnason, Vilmundur, Lenore, Launer, Hayward, Caroline, Hofman, Albert, Homuth, Georg, Huffman, Kim, Husted, Lise, Illig, Thomas, Ingelsson, Erik, Ittermann, Till, Jansson, John-Olov, Johnson, Toby, Biffar, Reiner, Jordan, Joanne, Jula, Antti, Karlsson, Magnus, Khaw, Kay-Tee, Kilpeläinen, Tuomas, Klopp, Norman, Kloth, Jacqueline, Koller, Daniel, Kooner, Jaspal, Kraus, William, Kritchevsky, Stephen, Kutalik, Zoltán, Kuulasmaa, Teemu, Kuusisto, Johanna, Laakso, Markku, Lahti, Jari, Langdahl, Bente, Lerch, Markus, Lewis, Joshua, Lill, Christina, Lind, Lars, Lindgren, Cecilia, Liu, Yongmei, Livshits, Gregory, Ljunggren, Östen, Loos, Ruth, Lorentzon, Mattias, Luan, Jianan, Luben, Robert, Malkin, Ida, McGuigan, Fiona, Medina-Gomez, Carolina, Meitinger, Thomas, Melhus, Håkan, Mellström, Dan, Michaëlsson, Karl, Mitchell, Braxton, Morris, Andrew, Mosekilde, Leif, Nethander, Maria, Newman, Anne, OConnell, Jeffery, Oostra, Ben, Orwoll, Eric, Palotie, Aarno, Peacock, Munro, Perola, Markus, and Peters, Annette

Subjects
ADAMTS Proteins, Absorptiometry, Photon, Adipose Tissue, Adolescent, Adult, Aged, Aged, 80 and over, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Body Composition, Body Fluid Compartments, Electric Impedance, Extracellular Matrix Proteins, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Muscle, Skeletal, Phenotype, Polymorphism, Single Nucleotide, RNA-Binding Proteins, Receptor, Melanocortin, Type 4, Versicans, White People, Young Adult
Abstract

BACKGROUND: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. OBJECTIVES: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. METHODS: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). RESULTS: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as sumo wrestler loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed body builder loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in body builder loci were associated with metabolic protection. CONCLUSIONS: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

Published
2019

25. Gene-based association analysis of a large patient cohort provides insights into genetics of atypical femur fractures.

Author

Zhou, Wei, Ås, Joel, Shore-Lorenti, Catherine, Nguyen, Hanh H, van de Laarschot, Denise M, Sztal-Mazer, Shoshana, Grill, Vivian, Girgis, Christian M, Stricker, Bruno H Ch, van der Eerden, Bram C J, Thakker, Rajesh V, Appelman-Dijkstra, Natasha M, Wadelius, Mia, Clifton-Bligh, Roderick J, Hallberg, Pär, Verkerk, Annemieke J M H, van Rooij, Jeroen G J, Ebeling, Peter R, and Zillikens, M Carola

Abstract

Several small genetic association studies have been conducted for atypical femur fracture (AFF) without replication of results. We assessed previously implicated and novel genes associated with AFFs in a larger set of unrelated AFF cases using whole exome sequencing (WES). We performed gene-based association analysis on 139 European AFF cases and 196 controls matched for bisphosphonate use. We tested all rare, protein-altering variants using both candidate gene and hypothesis-free approaches. In the latter, genes suggestively associated with AFFs (uncorrected p-values <.01) were investigated in a Swedish whole-genome sequencing replication study and assessed in 46 non-European cases. In the candidate gene analysis, PLOD2 showed a suggestive signal. The hypothesis-free approach revealed 10 tentative associations, with XRN2, SORD, and PLOD2 being the most likely candidates for AFF. XRN2 and PLOD2 showed consistent direction of effect estimates in the replication analysis, albeit not statistically significant. Three SNPs associated with SORD expression according to the GTEx portal were in linkage disequilibrium (R2 ≥ 0.2) with an SNP previously reported in a genome-wide association study of AFF. The prevalence of carriers of variants for both PLOD2 and SORD was higher in Asian versus European cases. While we did not identify genes enriched for damaging variants, we found suggestive evidence of a role for XRN2, PLOD2, and SORD, which requires further investigation. Our findings indicate that genetic factors responsible for AFFs are not widely shared among AFF cases. The study provides a stepping-stone for future larger genetic studies of AFF. Lay Summary: We investigated the genetic factors contributing to atypical femur fractures (AFF), which are rare and unusual fractures in the thigh bone. These fractures are related to the use of bisphosphonates (BP), which are prescribed to prevent fractures caused by osteoporosis. Previous studies suggested potential genetic links, but their findings were not confirmed in larger groups. To address this, we analyzed genetic data from 139 European individuals with AFF and 196 individuals without AFF, all of whom used BP, using a genetic technique called whole exome sequencing. Our results suggested three genes—XRN2, SORD, and PLOD2—might be linked to AFF, although the evidence was not conclusive. Importantly, our findings suggest that AFF may be caused by different genes in different individuals. A much larger sample size is now needed to fully understand the genetic architecture of AFF. These findings may guide future research into the genetic causes of AFF. [ABSTRACT FROM AUTHOR]

Published
2024
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26. Functional Insights in PLS3-Mediated Osteogenic Regulation.

Author

Zhong, Wenchao, Neugebauer, Janine, Pathak, Janak L., Li, Xingyang, Pals, Gerard, Zillikens, M. Carola, Eekhoff, Elisabeth M. W., Bravenboer, Nathalie, Zhang, Qingbin, Hammerschmidt, Matthias, Wirth, Brunhilde, and Micha, Dimitra

Subjects
BONE morphogenetic proteins, T helper cells, GENE expression, BONE cells, BONE metabolism
Abstract

Plastin-3 (PLS3) encodes T-plastin, an actin-bundling protein mediating the formation of actin filaments by which numerous cellular processes are regulated. Loss-of-function genetic defects in PLS3 are reported to cause X-linked osteoporosis and childhood-onset fractures. However, the molecular etiology of PLS3 remains elusive. Functional compensation by actin-bundling proteins ACTN1, ACTN4, and FSCN1 was investigated in zebrafish following morpholino-mediated pls3 knockdown. Primary dermal fibroblasts from six patients with a PLS3 variant were also used to examine expression of these proteins during osteogenic differentiation. In addition, Pls3 knockdown in the murine MLO-Y4 cell line was employed to provide insights in global gene expression. Our results showed that ACTN1 and ACTN4 can rescue the skeletal deformities in zebrafish after pls3 knockdown, but this was inadequate for FSCN1. Patients' fibroblasts showed the same osteogenic transdifferentiation ability as healthy donors. RNA-seq results showed differential expression in Wnt1, Nos1ap, and Myh3 after Pls3 knockdown in MLO-Y4 cells, which were also associated with the Wnt and Th17 cell differentiation pathways. Moreover, WNT2 was significantly increased in patient osteoblast-like cells compared to healthy donors. Altogether, our findings in different bone cell types indicate that the mechanism of PLS3-related pathology extends beyond actin-bundling proteins, implicating broader pathways of bone metabolism. [ABSTRACT FROM AUTHOR]

Published
2024
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30. Meta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function

Author

Xu, Jiayi, Bartz, Traci M, Chittoor, Geetha, Eiriksdottir, Gudny, Manichaikul, Ani W, Sun, Fangui, Terzikhan, Natalie, Zhou, Xia, Booth, Sarah L, Brusselle, Guy G, de Boer, Ian H, Fornage, Myriam, Frazier-Wood, Alexis C, Graff, Mariaelisa, Gudnason, Vilmundur, Harris, Tamara B, Hofman, Albert, Hou, Ruixue, Houston, Denise K, Jacobs, David R, Kritchevsky, Stephen B, Latourelle, Jeanne, Lemaitre, Rozenn N, Lutsey, Pamela L, O’Connor, George, Oelsner, Elizabeth C, Pankow, James S, Psaty, Bruce M, Rohde, Rebecca R, Rich, Stephen S, Rotter, Jerome I, Smith, Lewis J, Stricker, Bruno H, Voruganti, V Saroja, Wang, Thomas J, Zillikens, M Carola, Barr, R Graham, Dupuis, Josée, Gharib, Sina A, Lahousse, Lies, London, Stephanie J, North, Kari E, Smith, Albert V, Steffen, Lyn M, Hancock, Dana B, and Cassano, Patricia A

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Complementary and Integrative Health, Aging, Clinical Research, Adult, Aged, Black People, Cross-Sectional Studies, Female, Forced Expiratory Volume, Genome, Human, Heart, Heart Diseases, Humans, Lung, Lung Diseases, Male, Middle Aged, Molecular Epidemiology, Prospective Studies, Regression Analysis, Respiratory Function Tests, Smoking, Vital Capacity, Vitamin D, White People, 1, 25(OH)D 25-hydroxyvitamin D, AA African ancestry, AGES Age, ARIC Atherosclerosis Risk in Communities Study, Aging, CARDIA Coronary Artery Risk Development in Young Adults Study, CHARGE Cohorts for Heart and Aging Research in Genomic Epidemiology, CHS Cardiovascular Health Study, COPD chronic obstructive pulmonary disease, EA European ancestry, Environment, FEV1 forced expiratory volume in the 1st second, FHS (Gen3) Framingham Heart Study – Generation 3 Cohort, FHS (Offspring) Framingham Heart Study –Offspring Cohort, FVC forced vital capacity, Gene, HABC Health, Iceland, MESA Multi-Ethnic Study of Atherosclerosis, PFT pulmonary function test, RIA radioimmunoassay, Susceptibility Study − Reykjavik, and Body Composition Study, 25-(OH)2D 1, 25-dihydroxyvitamin D, African Americans, Forced expiratory volume, Respiratory function tests, Vital capacity, Whites, Animal Production, Food Sciences, Nutrition & Dietetics, Animal production, Food sciences, Nutrition and dietetics
Abstract

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P

Published
2018

31. Genome‐Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent

Author

Smith, Caren E, Follis, Jack L, Dashti, Hassan S, Tanaka, Toshiko, Graff, Mariaelisa, Fretts, Amanda M, Kilpeläinen, Tuomas O, Wojczynski, Mary K, Richardson, Kris, Nalls, Mike A, Schulz, Christina‐Alexandra, Liu, Yongmei, Frazier‐Wood, Alexis C, van Eekelen, Esther, Wang, Carol, de Vries, Paul S, Mikkilä, Vera, Rohde, Rebecca, Psaty, Bruce M, Hansen, Torben, Feitosa, Mary F, Lai, Chao‐Qiang, Houston, Denise K, Ferruci, Luigi, Ericson, Ulrika, Wang, Zhe, de Mutsert, Renée, Oddy, Wendy H, de Jonge, Ester AL, Seppälä, Ilkka, Justice, Anne E, Lemaitre, Rozenn N, Sørensen, Thorkild IA, Province, Michael A, Parnell, Laurence D, Garcia, Melissa E, Bandinelli, Stefania, Orho‐Melander, Marju, Rich, Stephen S, Rosendaal, Frits R, Pennell, Craig E, Jong, Jessica C Kiefte‐de, Kähönen, Mika, Young, Kristin L, Pedersen, Oluf, Aslibekyan, Stella, Rotter, Jerome I, Mook‐Kanamori, Dennis O, Zillikens, M Carola, Raitakari, Olli T, North, Kari E, Overvad, Kim, Arnett, Donna K, Hofman, Albert, Lehtimäki, Terho, Tjønneland, Anne, Uitterlinden, André G, Rivadeneira, Fernando, Franco, Oscar H, German, J Bruce, Siscovick, David S, Cupples, L Adrienne, and Ordovás, José M

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Genetics, Prevention, Nutrition, Obesity, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Cancer, Metabolic and endocrine, Actins, Adult, Aged, Body Mass Index, Cohort Studies, Cross-Sectional Studies, Dairy Products, Female, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Myosin-Light-Chain Phosphatase, Polymorphism, Single Nucleotide, White People, body mass index, CHARGE consortium, dairy intake, genome-wide interaction study, meta-analysis, Food Sciences, Public Health and Health Services, Food Science, Nutrition & Dietetics, Food sciences, Nutrition and dietetics
Abstract

ScopeBody weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption.Methods and resultsA genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction

Published
2018

32. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author

Jiang, Xia, O’Reilly, Paul F, Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A, Albanes, Demetrius, Lutsey, Pamela L, Yao, Lu, Tang, Weihong, Econs, Michael J, Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I, Michos, Erin D, Boerwinkle, Eric, Weinstein, Stephanie J, Freedman, Neal D, Huang, Wen-Yi, Van Schoor, Natasja M, van der Velde, Nathalie, Groot, Lisette CPGM de, Enneman, Anke, Cupples, L Adrienne, Booth, Sarah L, Vasan, Ramachandran S, Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G, Shea, M Kyla, Houston, Denise K, Kritchevsky, Stephen B, Liu, Yongmei, Lohman, Kurt K, Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E, März, Winfried, de Boer, Ian H, Wood, Alexis C, Rotter, Jerome I, Rich, Stephen S, Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K, Wilson, James F, Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M Carola, Uitterlinden, Andre G, Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M, Timofeeva, Maria, Dunlop, Malcolm G, Valdes, Ana M, Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T, Mikkilä, Vera, Ikram, M Arfan, Sattar, Naveed, Jukema, J Wouter, Wareham, Nicholas J, Langenberg, Claudia, Forouhi, Nita G, Gundersen, Thomas E, Khaw, Kay-Tee, Butterworth, Adam S, Danesh, John, and Spector, Timothy

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Amidohydrolases, Autoimmune Diseases, Cohort Studies, Female, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Vesicular Transport Proteins, Vitamin D, White People
Abstract

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

Published
2018

33. Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects

Author

Medina-Gomez, Carolina, Kemp, John P, Trajanoska, Katerina, Luan, Jian’an, Chesi, Alessandra, Ahluwalia, Tarunveer S, Mook-Kanamori, Dennis O, Ham, Annelies, Hartwig, Fernando P, Evans, Daniel S, Joro, Raimo, Nedeljkovic, Ivana, Zheng, Hou-Feng, Zhu, Kun, Atalay, Mustafa, Liu, Ching-Ti, Nethander, Maria, Broer, Linda, Porleifsson, Gudmar, Mullin, Benjamin H, Handelman, Samuel K, Nalls, Mike A, Jessen, Leon E, Heppe, Denise HM, Richards, J Brent, Wang, Carol, Chawes, Bo, Schraut, Katharina E, Amin, Najaf, Wareham, Nick, Karasik, David, Van der Velde, Nathalie, Ikram, M Arfan, Zemel, Babette S, Zhou, Yanhua, Carlsson, Christian J, Liu, Yongmei, McGuigan, Fiona E, Boer, Cindy G, Bønnelykke, Klaus, Ralston, Stuart H, Robbins, John A, Walsh, John P, Zillikens, M Carola, Langenberg, Claudia, Li-Gao, Ruifang, Williams, Frances MK, Harris, Tamara B, Akesson, Kristina, Jackson, Rebecca D, Sigurdsson, Gunnar, Heijer, Martin den, van der Eerden, Bram CJ, van de Peppel, Jeroen, Spector, Timothy D, Pennell, Craig, Horta, Bernardo L, Felix, Janine F, Zhao, Jing Hua, Wilson, Scott G, de Mutsert, Renée, Bisgaard, Hans, Styrkársdóttir, Unnur, Jaddoe, Vincent W, Orwoll, Eric, Lakka, Timo A, Scott, Robert, Grant, Struan FA, Lorentzon, Mattias, van Duijn, Cornelia M, Wilson, James F, Stefansson, Kari, Psaty, Bruce M, Kiel, Douglas P, Ohlsson, Claes, Ntzani, Evangelia, van Wijnen, Andre J, Forgetta, Vincenzo, Ghanbari, Mohsen, Logan, John G, Williams, Graham R, Bassett, JH Duncan, Croucher, Peter I, Evangelou, Evangelos, Uitterlinden, Andre G, Ackert-Bicknell, Cheryl L, Tobias, Jonathan H, Evans, David M, and Rivadeneira, Fernando

Subjects
Rare Diseases, Aging, Human Genome, Osteoporosis, Clinical Research, Genetics, Aetiology, 2.1 Biological and endogenous factors, Musculoskeletal, Good Health and Well Being, Adolescent, Age Factors, Animals, Bone Density, Child, Child, Preschool, Genetic Loci, Genome-Wide Association Study, Humans, Infant, Infant, Newborn, Mice, Knockout, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Regression Analysis, BMD, CREB3L1, ESR1, GWASs, RANKL, age-dependent effects, bone mineral density, fracture, genetic correlation, genome-wide association studies, meta-regression, total-body DXA, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

Published
2018

34. Dairy Consumption and Body Mass Index Among Adults: Mendelian Randomization Analysis of 184802 Individuals from 25 Studies

Author

Huang, Tao, Ding, Ming, Bergholdt Helle, KM, Wang, Tiange, Heianza, Yoriko, Sun, Dianjianyi, Frazier-Wood Alexis, C, Aslibekyan, Stella, North Kari, E, Voortman, Trudy, Graff, Mariaelisa, Smith Caren, E, Lai, Chao-Qiang, Varbo, Anette, Lemaitre, Rozenn N, de Jonge, M Ester AL, Fumeron, Frédéric, Corella, Dolores, Wang, Carol A, Tjønneland, Anne, Overvad, Kim, Sørensen, Thorkild IA, Feitosa, Mary F, Wojczynski, Mary K, Kähönen, Mika, Renström, Frida, Psaty, Bruce M, Siscovick, David S, Barroso, Inês, Johansson, Ingegerd, Hernandez, Dena, Ferrucci, Luigi, Bandinelli, Stefania, Linneberg, Allan, Zillikens, M Carola, Sandholt, Camilla Helene, Pedersen, Oluf, Hansen, Torben, Schulz, Christina-Alexandra, Sonestedt, Emily, Orho-Melander, Marju, Chen, Tzu-An, Rotter, Jerome I, Allison, Mathew A, Rich, Stephen S, Sorlí, Jose V, Coltell, Oscar, Pennell, Craig E, Eastwood, Peter, Hofman, Albert, Uitterlinden, Andre G, van Rooij, Frank JA, Chu, Audrey Y, Rose, Lynda M, Ridker, Paul M, Viikari, Jorma, Raitakari, Olli, Lehtimäki, Terho, Mikkilä, Vera, Willett, Walter C, Wang, Yujie, Tucker, Katherine L, Ordovas, Jose M, Kilpeläinen, Tuomas O, Province, Michael A, Franks, Paul W, Arnett, Donna K, Tanaka, Toshiko, Toft, Ulla, Ericson, Ulrika, Franco, Oscar H, Mozaffarian, Dariush, Hu, Frank B, Chasman, Daniel I, Nordestgaard, Børge G, Ellervik, Christina, and Qi, Lu

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Prevention, Genetics, Adult, Body Mass Index, Body Weight, Cross-Sectional Studies, Dairy Products, Genotype, Humans, Mendelian Randomization Analysis, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Prospective Studies, Mendelian Randomization of Dairy Consumption Working Group, Medical Biotechnology, Medical Biochemistry and Metabolomics, Clinical Sciences, General Clinical Medicine, Clinical sciences, Medical biochemistry and metabolomics
Abstract

BackgroundAssociations between dairy intake and body mass index (BMI) have been inconsistently observed in epidemiological studies, and the causal relationship remains ill defined.MethodsWe performed Mendelian randomization (MR) analysis using an established dairy intake-associated genetic polymorphism located upstream of the lactase gene (LCT-13910 C/T, rs4988235) as an instrumental variable (IV). Linear regression models were fitted to analyze associations between (a) dairy intake and BMI, (b) rs4988235 and dairy intake, and (c) rs4988235 and BMI in each study. The causal effect of dairy intake on BMI was quantified by IV estimators among 184802 participants from 25 studies.ResultsHigher dairy intake was associated with higher BMI (β = 0.03 kg/m2 per serving/day; 95% CI, 0.00-0.06; P = 0.04), whereas the LCT genotype with 1 or 2 T allele was significantly associated with 0.20 (95% CI, 0.14-0.25) serving/day higher dairy intake (P = 3.15 × 10-12) and 0.12 (95% CI, 0.06-0.17) kg/m2 higher BMI (P = 2.11 × 10-5). MR analysis showed that the genetically determined higher dairy intake was significantly associated with higher BMI (β = 0.60 kg/m2 per serving/day; 95% CI, 0.27-0.92; P = 3.0 × 10-4).ConclusionsThe present study provides strong evidence to support a causal effect of higher dairy intake on increased BMI among adults.

Published
2018

39. Erratum: Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

Author

Zillikens, M Carola, Demissie, Serkalem, Hsu, Yi-Hsiang, Yerges-Armstrong, Laura M, Chou, Wen-Chi, Stolk, Lisette, Livshits, Gregory, Broer, Linda, Johnson, Toby, Koller, Daniel L, Kutalik, Zoltán, Luan, Jian'an, Malkin, Ida, Ried, Janina S, Smith, Albert V, Thorleifsson, Gudmar, Vandenput, Liesbeth, Hua Zhao, Jing, Zhang, Weihua, Aghdassi, Ali, Åkesson, Kristina, Amin, Najaf, Baier, Leslie J, Barroso, Inês, Bennett, David A, Bertram, Lars, Biffar, Rainer, Bochud, Murielle, Boehnke, Michael, Borecki, Ingrid B, Buchman, Aron S, Byberg, Liisa, Campbell, Harry, Campos Obanda, Natalia, Cauley, Jane A, Cawthon, Peggy M, Cederberg, Henna, Chen, Zhao, Cho, Nam H, Jin Choi, Hyung, Claussnitzer, Melina, Collins, Francis, Cummings, Steven R, De Jager, Philip L, Demuth, Ilja, Dhonukshe-Rutten, Rosalie AM, Diatchenko, Luda, Eiriksdottir, Gudny, Enneman, Anke W, Erdos, Mike, Eriksson, Johan G, Eriksson, Joel, Estrada, Karol, Evans, Daniel S, Feitosa, Mary F, Fu, Mao, Garcia, Melissa, Gieger, Christian, Girke, Thomas, Glazer, Nicole L, Grallert, Harald, Grewal, Jagvir, Han, Bok-Ghee, Hanson, Robert L, Hayward, Caroline, Hofman, Albert, Hoffman, Eric P, Homuth, Georg, Hsueh, Wen-Chi, Hubal, Monica J, Hubbard, Alan, Huffman, Kim M, Husted, Lise B, Illig, Thomas, Ingelsson, Erik, Ittermann, Till, Jansson, John-Olov, Jordan, Joanne M, Jula, Antti, Karlsson, Magnus, Khaw, Kay-Tee, Kilpeläinen, Tuomas O, Klopp, Norman, Kloth, Jacqueline SL, Koistinen, Heikki A, Kraus, William E, Kritchevsky, Stephen, Kuulasmaa, Teemu, Kuusisto, Johanna, Laakso, Markku, Lahti, Jari, Lang, Thomas, Langdahl, Bente L, Launer, Lenore J, Lee, Jong-Young, Lerch, Markus M, Lewis, Joshua R, Lind, Lars, Lindgren, Cecilia, and Liu, Yongmei

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics
Abstract

A correction to this article has been published and is linked from the HTML version of this article.

Published
2017

40. Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis

Author

Manousaki, Despoina, Dudding, Tom, Haworth, Simon, Hsu, Yi-Hsiang, Liu, Ching-Ti, Medina-Gómez, Carolina, Voortman, Trudy, van der Velde, Nathalie, Melhus, Håkan, Robinson-Cohen, Cassianne, Cousminer, Diana L, Nethander, Maria, Vandenput, Liesbeth, Noordam, Raymond, Forgetta, Vincenzo, Greenwood, Celia MT, Biggs, Mary L, Psaty, Bruce M, Rotter, Jerome I, Zemel, Babette S, Mitchell, Jonathan A, Taylor, Bruce, Lorentzon, Mattias, Karlsson, Magnus, Jaddoe, Vincent VW, Tiemeier, Henning, Campos-Obando, Natalia, Franco, Oscar H, Utterlinden, Andre G, Broer, Linda, van Schoor, Natasja M, Ham, Annelies C, Ikram, M Arfan, Karasik, David, de Mutsert, Renée, Rosendaal, Frits R, Heijer, Martin den, Wang, Thomas J, Lind, Lars, Orwoll, Eric S, Mook-Kanamori, Dennis O, Michaëlsson, Karl, Kestenbaum, Bryan, Ohlsson, Claes, Mellström, Dan, de Groot, Lisette CPGM, Grant, Struan FA, Kiel, Douglas P, Zillikens, M Carola, Rivadeneira, Fernando, Sawcer, Stephen, Timpson, Nicholas J, and Richards, J Brent

Subjects
Biological Sciences, Health Sciences, Genetics, Prevention, Multiple Sclerosis, Nutrition, Autoimmune Disease, Neurodegenerative, Human Genome, Neurosciences, Brain Disorders, 2.1 Biological and endogenous factors, Neurological, Cholestanetriol 26-Monooxygenase, Cytochrome P450 Family 2, Gene Frequency, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk Factors, Vitamin D, Vitamin D Deficiency, GWAS, low-frequency genetic variants, multiple sclerosis, vitamin D, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10-88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10-12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10-5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

Published
2017

41. Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

Author

Zillikens, M Carola, Demissie, Serkalem, Hsu, Yi-Hsiang, Yerges-Armstrong, Laura M, Chou, Wen-Chi, Stolk, Lisette, Livshits, Gregory, Broer, Linda, Johnson, Toby, Koller, Daniel L, Kutalik, Zoltán, Luan, Jian'an, Malkin, Ida, Ried, Janina S, Smith, Albert V, Thorleifsson, Gudmar, Vandenput, Liesbeth, Hua Zhao, Jing, Zhang, Weihua, Aghdassi, Ali, Åkesson, Kristina, Amin, Najaf, Baier, Leslie J, Barroso, Inês, Bennett, David A, Bertram, Lars, Biffar, Rainer, Bochud, Murielle, Boehnke, Michael, Borecki, Ingrid B, Buchman, Aron S, Byberg, Liisa, Campbell, Harry, Campos Obanda, Natalia, Cauley, Jane A, Cawthon, Peggy M, Cederberg, Henna, Chen, Zhao, Cho, Nam H, Jin Choi, Hyung, Claussnitzer, Melina, Collins, Francis, Cummings, Steven R, De Jager, Philip L, Demuth, Ilja, Dhonukshe-Rutten, Rosalie AM, Diatchenko, Luda, Eiriksdottir, Gudny, Enneman, Anke W, Erdos, Mike, Eriksson, Johan G, Eriksson, Joel, Estrada, Karol, Evans, Daniel S, Feitosa, Mary F, Fu, Mao, Garcia, Melissa, Gieger, Christian, Girke, Thomas, Glazer, Nicole L, Grallert, Harald, Grewal, Jagvir, Han, Bok-Ghee, Hanson, Robert L, Hayward, Caroline, Hofman, Albert, Hoffman, Eric P, Homuth, Georg, Hsueh, Wen-Chi, Hubal, Monica J, Hubbard, Alan, Huffman, Kim M, Husted, Lise B, Illig, Thomas, Ingelsson, Erik, Ittermann, Till, Jansson, John-Olov, Jordan, Joanne M, Jula, Antti, Karlsson, Magnus, Khaw, Kay-Tee, Kilpeläinen, Tuomas O, Klopp, Norman, Kloth, Jacqueline SL, Koistinen, Heikki A, Kraus, William E, Kritchevsky, Stephen, Kuulasmaa, Teemu, Kuusisto, Johanna, Laakso, Markku, Lahti, Jari, Lang, Thomas, Langdahl, Bente L, Launer, Lenore J, Lee, Jong-Young, Lerch, Markus M, Lewis, Joshua R, Lind, Lars, Lindgren, Cecilia, and Liu, Yongmei

Subjects
Humans, Thinness, 17-Hydroxysteroid Dehydrogenases, Aldehyde Oxidoreductases, Extracellular Matrix Proteins, Body Composition, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Regulatory Elements, Transcriptional, Versicans, Genome-Wide Association Study, Insulin Receptor Substrate Proteins, ADAMTS Proteins, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Human Genome, Genetics, 1.1 Normal biological development and functioning
Abstract

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p

Published
2017

42. A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

Author

Vandenput, L, Johansson, H, McCloskey, EV, Liu, E, Schini, M, Åkesson, KE, Anderson, FA, Azagra, R, Bager, CL, Beaudart, C, Bischoff-Ferrari, HA, Biver, E, Bruyère, O, Cauley, JA, Center, JR, Chapurlat, R, Christiansen, C, Cooper, C, Crandall, CJ, Cummings, SR, da Silva, JAP, Dawson-Hughes, B, Diez-Perez, A, Dufour, AB, Eisman, JA, Elders, PJM, Ferrari, S, Fujita, Y, Fujiwara, S, Glüer, C-C, Goldshtein, I, Goltzman, D, Gudnason, V, Hall, J, Hans, D, Hoff, M, Hollick, RJ, Huisman, M, Iki, M, Ish-Shalom, S, Jones, G, Karlsson, MK, Khosla, S, Kiel, DP, Koh, W-P, Koromani, F, Kotowicz, MA, Kröger, H, Kwok, T, Lamy, O, Langhammer, A, Larijani, B, Lippuner, K, McGuigan, FEA, Mellström, D, Merlijn, T, Nguyen, TV, Nordström, A, Nordström, P, O'Neill, TW, Obermayer-Pietsch, B, Ohlsson, C, Orwoll, ES, Pasco, JA, Rivadeneira, F, Schott, A-M, Shiroma, EJ, Siggeirsdottir, K, Simonsick, EM, Sornay-Rendu, E, Sund, R, Swart, KMA, Szulc, P, Tamaki, J, Torgerson, DJ, van Schoor, NM, van Staa, TP, Vila, J, Wareham, NJ, Wright, NC, Yoshimura, N, Zillikens, M, Zwart, M, Harvey, NC, Lorentzon, M, Leslie, WD, Kanis, JA, Vandenput, L, Johansson, H, McCloskey, EV, Liu, E, Schini, M, Åkesson, KE, Anderson, FA, Azagra, R, Bager, CL, Beaudart, C, Bischoff-Ferrari, HA, Biver, E, Bruyère, O, Cauley, JA, Center, JR, Chapurlat, R, Christiansen, C, Cooper, C, Crandall, CJ, Cummings, SR, da Silva, JAP, Dawson-Hughes, B, Diez-Perez, A, Dufour, AB, Eisman, JA, Elders, PJM, Ferrari, S, Fujita, Y, Fujiwara, S, Glüer, C-C, Goldshtein, I, Goltzman, D, Gudnason, V, Hall, J, Hans, D, Hoff, M, Hollick, RJ, Huisman, M, Iki, M, Ish-Shalom, S, Jones, G, Karlsson, MK, Khosla, S, Kiel, DP, Koh, W-P, Koromani, F, Kotowicz, MA, Kröger, H, Kwok, T, Lamy, O, Langhammer, A, Larijani, B, Lippuner, K, McGuigan, FEA, Mellström, D, Merlijn, T, Nguyen, TV, Nordström, A, Nordström, P, O'Neill, TW, Obermayer-Pietsch, B, Ohlsson, C, Orwoll, ES, Pasco, JA, Rivadeneira, F, Schott, A-M, Shiroma, EJ, Siggeirsdottir, K, Simonsick, EM, Sornay-Rendu, E, Sund, R, Swart, KMA, Szulc, P, Tamaki, J, Torgerson, DJ, van Schoor, NM, van Staa, TP, Vila, J, Wareham, NJ, Wright, NC, Yoshimura, N, Zillikens, M, Zwart, M, Harvey, NC, Lorentzon, M, Leslie, WD, and Kanis, JA

Abstract

UNLABELLED: The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. INTRODUCTION: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). METHODS: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. RESULTS: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1

Published
2024

43. A meta-analysis of previous falls and subsequent fracture risk in cohort studies

Author

Vandenput, L., Johansson, H., McCloskey, E. V., Liu, E., Schini, M., Åkesson, K.E., Anderson, F. A., Azagra, R., Bager, C. L., Beaudart, C., Bischoff-Ferrari, H. A., Biver, E., Bruyère, O., Cauley, J. A., Center, J. R., Chapurlat, R., Christiansen, C., Cooper, C., Crandall, C. J., Cummings, S. R., da Silva, J. A. P., Dawson-Hughes, B., Diez-Perez, A., Dufour, A. B., Eisman, J. A., Elders, P. J. M., Ferrari, S., Fujita, Y., Fujiwara, S., Glüer, C. -C, Goldshtein, I., Goltzman, D., Gudnason, V., Hall, J., Hans, D., Hoff, M., Hollick, R. J., Huisman, M., Iki, M., Ish-Shalom, S., Jones, G., Karlsson, M. K., Khosla, S., Kiel, D. P., Koh, W. -P, Koromani, F., Kotowicz, M. A., Kröger, H., Kwok, T., Lamy, O., Langhammer, A., Larijani, B., Lippuner, K., McGuigan, F. E. A., Mellström, D., Merlijn, T., Nguyen, T. V., Nordström, Anna, Nordström, P., O’Neill, T. W., Obermayer-Pietsch, B., Ohlsson, C., Orwoll, E. S., Pasco, J. A., Rivadeneira, F., Schott, A. -M, Shiroma, E. J., Siggeirsdottir, K., Simonsick, E. M., Sornay-Rendu, E., Sund, R., Swart, K. M. A., Szulc, P., Tamaki, J., Torgerson, D. J., van Schoor, N. M., van Staa, T. P., Vila, J., Wareham, N. J., Wright, N. C., Yoshimura, N., Zillikens, M. C., Zwart, M., Harvey, N. C., Lorentzon, M., Leslie, W. D., Kanis, J. A., Vandenput, L., Johansson, H., McCloskey, E. V., Liu, E., Schini, M., Åkesson, K.E., Anderson, F. A., Azagra, R., Bager, C. L., Beaudart, C., Bischoff-Ferrari, H. A., Biver, E., Bruyère, O., Cauley, J. A., Center, J. R., Chapurlat, R., Christiansen, C., Cooper, C., Crandall, C. J., Cummings, S. R., da Silva, J. A. P., Dawson-Hughes, B., Diez-Perez, A., Dufour, A. B., Eisman, J. A., Elders, P. J. M., Ferrari, S., Fujita, Y., Fujiwara, S., Glüer, C. -C, Goldshtein, I., Goltzman, D., Gudnason, V., Hall, J., Hans, D., Hoff, M., Hollick, R. J., Huisman, M., Iki, M., Ish-Shalom, S., Jones, G., Karlsson, M. K., Khosla, S., Kiel, D. P., Koh, W. -P, Koromani, F., Kotowicz, M. A., Kröger, H., Kwok, T., Lamy, O., Langhammer, A., Larijani, B., Lippuner, K., McGuigan, F. E. A., Mellström, D., Merlijn, T., Nguyen, T. V., Nordström, Anna, Nordström, P., O’Neill, T. W., Obermayer-Pietsch, B., Ohlsson, C., Orwoll, E. S., Pasco, J. A., Rivadeneira, F., Schott, A. -M, Shiroma, E. J., Siggeirsdottir, K., Simonsick, E. M., Sornay-Rendu, E., Sund, R., Swart, K. M. A., Szulc, P., Tamaki, J., Torgerson, D. J., van Schoor, N. M., van Staa, T. P., Vila, J., Wareham, N. J., Wright, N. C., Yoshimura, N., Zillikens, M. C., Zwart, M., Harvey, N. C., Lorentzon, M., Leslie, W. D., and Kanis, J. A.

Abstract

Summary: The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. Introduction: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). Methods: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. Results: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33–1.51) and men (HR 1.53, 95% CI 1.41–1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27–1.84) in men vs. HR 1.32

Published
2024
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44. ERN BOND:The key European network leveraging diagnosis, research, and treatment for rare bone conditions

Author

Casareto, Lorena, Appelman-Dijkstra, Natasha M., Brandi, Maria Luisa, Chapurlat, Roland, Cormier-Daire, Valérie, Hamdy, Neveen A.T., Heath, Karen E., Horn, Joachim, Mantovani, Giovanna, Mohnike, Klaus, Sousa, Sérgio Bernardo, Travessa, André, Wekre, Lena Lande, Zillikens, M. Carola, Sangiorgi, Luca, Casareto, Lorena, Appelman-Dijkstra, Natasha M., Brandi, Maria Luisa, Chapurlat, Roland, Cormier-Daire, Valérie, Hamdy, Neveen A.T., Heath, Karen E., Horn, Joachim, Mantovani, Giovanna, Mohnike, Klaus, Sousa, Sérgio Bernardo, Travessa, André, Wekre, Lena Lande, Zillikens, M. Carola, and Sangiorgi, Luca

Abstract

There is no universally accepted definition for rare diseases: in Europe a disease is considered to be rare when affecting fewer than 1 in 2000 people. European Reference Networks (ERNs) have been the concrete response to address the unmet needs of rare disease patients and many pan-European issues in the field, reducing inequities, and significantly increasing accessibility to high-quality healthcare across Europe. ERNs are virtual networks, involving centres and patient representatives with the general scope to facilitate discussion on complex cases requiring highly specialised competences and trained expertise. ERN BOND - the European Reference Network on rare BONe Diseases - is one of these 24 approved networks with the specific ongoing mission to implement measures facilitating multidisciplinary, holistic, continuous, patient-centred, and participative care provision to patients, and supporting them in the full realisation of their fundamental human rights. ERN BOND includes in 2023 a total of 53 centres of expertise from 20 European countries. Its governing structure installed in March 2017 includes decision-making, operative and consultative committees, which comprise experts in the field and patient representatives ensuring patient's voice and perspectives are taken into account. Over the years, ERN BOND has worked hard to achieve its mission and valuably contribute to the advancement of diagnosis, management, treatment, and research in rare diseases. The network activities are mainly related to (i) the provision of care which collectively involves averagely 2800 patients diagnosed per year, (ii) the development of education for and training of the healthcare personnel consisting until now in the realisation of 7 thematic workshops and 19 webinars, (iii) the dissemination and exchange and spread of knowledge via network's website (https://ernbond.eu/), social media channels, and newsletters, (iv) the management of related data through a disease registry c

Published
2024

45. Osteopetrosis and related osteoclast disorders in adults:A review and knowledge gapsOn behalf of the European calcified tissue society and ERN BOND

Author

Funck-Brentano, Thomas, Zillikens, M. Carola, Clunie, Gavin, Siggelkow, Heide, Appelman-Dijkstra, Natasha M., Cohen-Solal, Martine, Funck-Brentano, Thomas, Zillikens, M. Carola, Clunie, Gavin, Siggelkow, Heide, Appelman-Dijkstra, Natasha M., and Cohen-Solal, Martine

Abstract

Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of fracture is high, particularly in the long bones. Osteopetrosis was classically categorized by inheritance pattern into autosomal recessive forms (ARO), which are severe and diagnosed within the first years of life, an intermediate form and an autosomal dominant (ADO) form; the latter with variable clinical severity and typically diagnosed during adolescence or in young adulthood. Subsequently, the AD form was shown to be a result of mutations in the gene CLCN7 encoding for the ClC-7 chloride channel). Traditionally, the diagnosis of osteopetrosis was made on radiograph appearance alone, but recent molecular and genetic advances have enabled a greater fidelity in classification of osteopetrosis subtypes. In the more severe ARO forms (e.g., malignant infantile osteopetrosis MIOP) typical clinical features have severe consequences and often result in death in early childhood. Major complications of ADO are atypical fractures with delay or failure of repair and challenge in orthopedic management. Bone marrow failure, dental abscess, deafness and visual loss are often underestimated and neglected in relation with lack of awareness and expertise. Accordingly, the care of adult patients with osteopetrosis requires a multidisciplinary approach ideally in specialized centers. Apart from hematopoietic stem cell transplantation in certain infantile forms, the treatment of patients with osteopetrosis, has not been standardized and remains supportive. Further clinical studies are needed to improve our knowledge of the natural history, optimum management and impact of osteopetrosis on the lives of patients living with the disorder.

Published
2024

46. Diuretic Use and Serum Phosphate:Rotterdam Study and UK Biobank

Author

Bosman, Ariadne, Campos-Obando, Natalia, De Keyser, Catherine E., Stricker, Bruno H., Zillikens, M. Carola, Bosman, Ariadne, Campos-Obando, Natalia, De Keyser, Catherine E., Stricker, Bruno H., and Zillikens, M. Carola

Abstract

Purpose: Hypophosphatemia (serum phosphate < 0.80 mmol/L) leads to musculoskeletal complaints. The most common drugs linked to hypophosphatemia are thiazide and loop diuretics, but studies in the general population are lacking. Our aim was to study associations between diuretic use and serum phosphate in the Rotterdam Study (RS), a population-based cohort study, with replication in UK Biobank (UKBB).Methods: Associations between thiazide and loop diuretic use and serum phosphate and odds of hypophosphatemia were analyzed with cross-sectional multivariate linear and logistic regression in participants without chronic kidney disease in the RS and UKBB. Analyses were adjusted for age, sex, and body mass index (BMI) and pooled in 3 RS cohorts with further adjustment for cohort and serum potassium, which was not available in UKBB. Results: Thiazide diuretics were associated with lower serum phosphate in both sexes. This association lost significance in RS females after adjustment for BMI and in males after adjustment for serum potassium. Thiazide diuretics increased odds of hypophosphatemia in females in both cohorts and in males in UKBB only. Loop diuretics were associated with lower serum phosphate in females but not males. Adjustment for BMI attenuated these associations. Associations between loop diuretics and increased odds of hypophosphatemia in females lost significance after BMI adjustment. Conclusion: Thiazides, but not loop diuretics, and increased BMI and decreased serum potassium should be considered as contributing factors in subjects with hypophosphatemia. Further studies are needed to replicate the findings and elucidate the potential role of hypokalemia as a mediator of this effect.

Published
2024

47. A dens fracture case solved

Author

Oei, Ling, Li, Jiawei, Karim, A. Faiz, Verdijk, Robert M., Oei, Edwin H. G., van Laar, Jan A. M., Ten Cate, David, Haitsma, Iain, Monserez, Dominiek A., Zillikens, M. Carola, Oei, Ling, Li, Jiawei, Karim, A. Faiz, Verdijk, Robert M., Oei, Edwin H. G., van Laar, Jan A. M., Ten Cate, David, Haitsma, Iain, Monserez, Dominiek A., and Zillikens, M. Carola

Abstract

Graphical Abstract

Published
2024

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