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Ann Rheum Dis. 2018 Mar;77(3):378-385. doi: 10.1136/annrheumdis-2017-212469. Epub 2017 Nov 23.

Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density.

Author information

1
Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
2
Departments of Internal Medicine and Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
3
Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar.
4
Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
5
Department of Clinical Biochemistry, Lovisenberg Diakonale Hospital, Oslo, Norway.
6
Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
7
Centre for Genomic and Experimental Medicine, IGMM, University of Edinburgh, Edinburgh, UK.
8
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
9
Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, Oregon, USA.
10
Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
11
BROAD Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
12
Musculoskeletal Research Center, Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts, USA.
13
Harvard Medical School, Boston, Massachusetts, USA.
14
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
15
Centre for Evidence Synthesis in Health, Department of Health Services, Policy and Practice, School of Public Health, Brown University, Rhode Island, USA.
16
Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
17
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
18
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
19
Department of Medicine, Stanford School of Medicine, Stanford, California, USA.
20
Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
21
Institute of Ageing and Chronic Disease, The MRC-Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing, University of Liverpool, Liverpool, UK.
22
Department of Internal Medicine, Hospital UM Valdecilla, University of Cantabria, IDIVAL, RETICEF, Santander, Spain.
23
Department of Endocrinology and Internal Medicine THG, Aarhus University Hospital, Aarhus, Denmark.
24
Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
25
Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.
26
Department of Endocrinology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
27
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
28
Department of Public Health and Primary Care, School of Medicine, University of Cambridge, Cambridge, UK.
29
Molecular Medicine Unit, Department of Medicine and Biomedical Research Institute of Salamanca (IBSAL), University Hospital of Salamanca, University of Salamanca - CSIC, Salamanca, Spain.
30
School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.
31
Centre for Kidney Research, School of Public Health, University of Sydney, Sydney, New South Wales, Australia.
32
School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia.
33
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.
34
Gerontology and Bone Metabolic Diseases Unit, Department of Medical Science, University of Torino, Torino, Italy.
35
Department of Internal Medicine, Hospital del Mar-IMIM, RETICEF, Universitat Autonoma de Barcelona, Barcelona, Spain.
36
Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
37
Osteoporosis and Bone Biology Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
38
Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
39
Edinburgh/British Heart Foundation Centre for Cardiovascular Science, QMRI, University of Edinburgh, Edinburgh, UK.
40
MRC Human Genetics Unit, MRC, IGMM, University of Edinburgh, Edinburgh, UK.
41
Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
42
Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council of Italy, Naples, Italy.
43
Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.
44
Grup de Recerca en Genètica i Epidemiologia Cardiovascular, IMIM, Barcelona, Spain.

Abstract

OBJECTIVES:

To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis.

METHODS:

Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies.

RESULTS:

A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures.

CONCLUSION:

We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.

KEYWORDS:

bone mineral density; gene polymorphism; osteoporosis

PMID:
29170203
PMCID:
PMC5912156
DOI:
10.1136/annrheumdis-2017-212469
[Indexed for MEDLINE]
Free PMC Article

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