@article {8016, title = {Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Apr 15}, pages = {491-501}, abstract = {

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 {\texttimes} 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 {\texttimes} 10(-4), Bonferroni corrected), of which six reached P < 5 {\texttimes} 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

}, keywords = {Bone Density, Computational Biology, European Continental Ancestry Group, Extracellular Matrix Proteins, Female, Femur Neck, Fractures, Bone, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, Low Density Lipoprotein Receptor-Related Protein-5, Lumbar Vertebrae, Male, Mitochondrial Membrane Transport Proteins, Osteoporosis, Phosphoproteins, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Spectrin}, issn = {1546-1718}, doi = {10.1038/ng.2249}, author = {Estrada, Karol and Styrkarsdottir, Unnur and Evangelou, Evangelos and Hsu, Yi-Hsiang and Duncan, Emma L and Ntzani, Evangelia E and Oei, Ling and Albagha, Omar M E and Amin, Najaf and Kemp, John P and Koller, Daniel L and Li, Guo and Liu, Ching-Ti and Minster, Ryan L and Moayyeri, Alireza and Vandenput, Liesbeth and Willner, Dana and Xiao, Su-Mei and Yerges-Armstrong, Laura M and Zheng, Hou-Feng and Alonso, Nerea and Eriksson, Joel and Kammerer, Candace M and Kaptoge, Stephen K and Leo, Paul J and Thorleifsson, Gudmar and Wilson, Scott G and Wilson, James F and Aalto, Ville and Alen, Markku and Aragaki, Aaron K and Aspelund, Thor and Center, Jacqueline R and Dailiana, Zoe and Duggan, David J and Garcia, Melissa and Garc{\'\i}a-Giralt, Natalia and Giroux, Sylvie and Hallmans, G{\"o}ran and Hocking, Lynne J and Husted, Lise Bjerre and Jameson, Karen A and Khusainova, Rita and Kim, Ghi Su and Kooperberg, Charles and Koromila, Theodora and Kruk, Marcin and Laaksonen, Marika and LaCroix, Andrea Z and Lee, Seung Hun and Leung, Ping C and Lewis, Joshua R and Masi, Laura and Mencej-Bedrac, Simona and Nguyen, Tuan V and Nogues, Xavier and Patel, Millan S and Prezelj, Janez and Rose, Lynda M and Scollen, Serena and Siggeirsdottir, Kristin and Smith, Albert V and Svensson, Olle and Trompet, Stella and Trummer, Olivia and van Schoor, Natasja M and Woo, Jean and Zhu, Kun and Balcells, Susana and Brandi, Maria Luisa and Buckley, Brendan M and Cheng, Sulin and Christiansen, Claus and Cooper, Cyrus and Dedoussis, George and Ford, Ian and Frost, Morten and Goltzman, David and Gonz{\'a}lez-Mac{\'\i}as, Jes{\'u}s and K{\"a}h{\"o}nen, Mika and Karlsson, Magnus and Khusnutdinova, Elza and Koh, Jung-Min and Kollia, Panagoula and Langdahl, Bente Lomholt and Leslie, William D and Lips, Paul and Ljunggren, Osten and Lorenc, Roman S and Marc, Janja and Mellstr{\"o}m, Dan and Obermayer-Pietsch, Barbara and Olmos, Jos{\'e} M and Pettersson-Kymmer, Ulrika and Reid, David M and Riancho, Jos{\'e} A and Ridker, Paul M and Rousseau, Fran{\c c}ois and Slagboom, P Eline and Tang, Nelson L S and Urreizti, Roser and Van Hul, Wim and Viikari, Jorma and Zarrabeitia, Mar{\'\i}a T and Aulchenko, Yurii S and Castano-Betancourt, Martha and Grundberg, Elin and Herrera, Lizbeth and Ingvarsson, Thorvaldur and Johannsdottir, Hrefna and Kwan, Tony and Li, Rui and Luben, Robert and Medina-G{\'o}mez, Carolina and Palsson, Stefan Th and Reppe, Sjur and Rotter, Jerome I and Sigurdsson, Gunnar and van Meurs, Joyce B J and Verlaan, Dominique and Williams, Frances M K and Wood, Andrew R and Zhou, Yanhua and Gautvik, Kaare M and Pastinen, Tomi and Raychaudhuri, Soumya and Cauley, Jane A and Chasman, Daniel I and Clark, Graeme R and Cummings, Steven R and Danoy, Patrick and Dennison, Elaine M and Eastell, Richard and Eisman, John A and Gudnason, Vilmundur and Hofman, Albert and Jackson, Rebecca D and Jones, Graeme and Jukema, J Wouter and Khaw, Kay-Tee and Lehtim{\"a}ki, Terho and Liu, Yongmei and Lorentzon, Mattias and McCloskey, Eugene and Mitchell, Braxton D and Nandakumar, Kannabiran and Nicholson, Geoffrey C and Oostra, Ben A and Peacock, Munro and Pols, Huibert A P and Prince, Richard L and Raitakari, Olli and Reid, Ian R and Robbins, John and Sambrook, Philip N and Sham, Pak Chung and Shuldiner, Alan R and Tylavsky, Frances A and van Duijn, Cornelia M and Wareham, Nick J and Cupples, L Adrienne and Econs, Michael J and Evans, David M and Harris, Tamara B and Kung, Annie Wai Chee and Psaty, Bruce M and Reeve, Jonathan and Spector, Timothy D and Streeten, Elizabeth A and Zillikens, M Carola and Thorsteinsdottir, Unnur and Ohlsson, Claes and Karasik, David and Richards, J Brent and Brown, Matthew A and Stefansson, Kari and Uitterlinden, Andr{\'e} G and Ralston, Stuart H and Ioannidis, John P A and Kiel, Douglas P and Rivadeneira, Fernando} } @article {6795, title = {Subclinical thyroid dysfunction and fracture risk: a meta-analysis.}, journal = {JAMA}, volume = {313}, year = {2015}, month = {2015 May 26}, pages = {2055-65}, abstract = {

IMPORTANCE: Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking.

OBJECTIVE: To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures.

DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures.

DATA EXTRACTION: Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH >=4.50-19.99 mIU/L) with normal thyroxine concentrations.

MAIN OUTCOME AND MEASURES: The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes.

RESULTS: Among 70,298 participants, 4092 (5.8\%) had subclinical hypothyroidism and 2219 (3.2\%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6\%; 12 studies), any fracture in 2528 participants (9.0\%; 8 studies), nonspine fracture in 2018 participants (8.4\%; 8 studies), and spine fracture in 296 participants (1.3\%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95\% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95\% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95\% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95\% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95\% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95\% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95\% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95\% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95\% CI, 1.19-1.93) for hip fracture, 1.42 (95\% CI, 1.16-1.74) for any fracture, and 1.74 (95\% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk.

CONCLUSIONS AND RELEVANCE: Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Female, Fractures, Bone, Hip Fractures, Humans, Hyperthyroidism, Hypothyroidism, Male, Middle Aged, Risk Factors, Spinal Fractures, Thyrotropin, Young Adult}, issn = {1538-3598}, doi = {10.1001/jama.2015.5161}, author = {Blum, Manuel R and Bauer, Douglas C and Collet, Tinh-Hai and Fink, Howard A and Cappola, Anne R and da Costa, Bruno R and Wirth, Christina D and Peeters, Robin P and Asvold, Bj{\o}rn O and den Elzen, Wendy P J and Luben, Robert N and Imaizumi, Misa and Bremner, Alexandra P and Gogakos, Apostolos and Eastell, Richard and Kearney, Patricia M and Strotmeyer, Elsa S and Wallace, Erin R and Hoff, Mari and Ceresini, Graziano and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Stott, David J and Westendorp, Rudi G J and Khaw, Kay-Tee and Langhammer, Arnuf and Ferrucci, Luigi and Gussekloo, Jacobijn and Williams, Graham R and Walsh, John P and J{\"u}ni, Peter and Aujesky, Drahomir and Rodondi, Nicolas} } @article {9748, title = {Associations of Serum GDF-15 Levels with Physical Performance, Mobility Disability, Cognition, Cardiovascular Disease, and Mortality in Older Adults.}, journal = {medRxiv}, year = {2024}, month = {2024 Aug 08}, abstract = {

BACKGROUND: Growth differentiation factor 15 (GDF-15) is a member of the TGFβ superfamily secreted by many cell types and found at higher blood concentrations as chronological age increases (1). Given the emergence of GDF-15 as a key protein associated with aging, it is important to understand the multitude of conditions with which circulating GDF-15 is associated.

METHODS: We pooled data from 1,174 randomly selected Health ABC Study (Health ABC) participants and 1,503 Cardiovascular Health Study (CHS) participants to evaluate the risk of various conditions and age-related outcomes across levels of GDF-15. The primary outcomes were (1) risk of mobility disability and falls; (2) impaired cognitive function; (3) and increased risk of cardiovascular disease and total mortality.

RESULTS: The pooled study cohort had a mean age of 75.4 +/-4.4 years. Using a Bonferroni-corrected threshold, our analyses show that high levels of GDF-15 were associated with a higher risk of severe mobility disability (HR: 2.13 [1.64, 2.77]), coronary heart disease (HR: 1.47 [1.17, 1.83]), atherosclerotic cardiovascular disease (HR: 1.56 [1.22, 1.98]), heart failure (HR: 2.09 [1.66, 2.64]), and mortality (HR: 1.81 [1.53, 2.15]) when comparing the highest and lowest quartiles. For CHS participants, analysis of extreme quartiles in fully adjusted models revealed a 3.5-fold higher risk of dementia (HR: 3.50 [1.97, 6.22]).

CONCLUSIONS: GDF-15 is associated with several age-related outcomes and diseases, including mobility disability, impaired physical and cognitive performance, dementia, cardiovascular disease, and mortality. Each of these findings demonstrates the importance of GDF-15 as a potential biomarker for many aging-related conditions.

}, doi = {10.1101/2024.08.07.24311629}, author = {Webber, Katey and Patel, Sheena and Kizer, Jorge R and Eastell, Richard and Psaty, Bruce M and Newman, Anne B and Cummings, Steven R} }