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

被引：23

作者：

Alonso, Nerea ^{[1
]}

Estrada, Karol ^{[2
,3
]}

Albagha, Omar M. E. ^{[1
,4
]}

Herrera, Lizbeth ^{[2
,3
]}

Reppe, Sjur ^{[5
,6
,7
]}

Olstad, Ole K. ^{[5
]}

Gautvik, Kaare M. ^{[6
,7
]}

Ryan, Niamh M. ^{[8
]}

Evans, Kathryn L. ^{[8
,9
]}

Nielson, Carrie M. ^{[10
]}

Hsu, Yi-Hsiang ^{[11
,12
,13
,14
]}

Kiel, Douglas P. ^{[12
,13
,14
]}

Markozannes, George ^{[15
]}

Ntzani, Evangelia E. ^{[15
,16
]}

Evangelou, Evangelos ^{[15
,17
]}

Feenstra, Bjarke ^{[18
]}

Liu, Xueping ^{[18
]}

Melbye, Mads ^{[18
,19
,20
]}

Masi, Laura ^{[21
]}

Brandi, Maria Luisa ^{[21
]}

Riches, Philip ^{[13
]}

Daroszewska, Anna ^{[1
,22
]}

Olmos, Jose Manuel ^{[23
]}

Valero, Carmen ^{[23
]}

Castillo, Jesus ^{[23
]}

Riancho, Jose A. ^{[23
]}

Husted, Lise B. ^{[24
]}

Langdahl, Bente L. ^{[23
]}

Brown, Matthew A. ^{[25
]}

Duncan, Emma L. ^{[25
,26
,27
]}

Kaptoge, Stephen ^{[28
]}

Khaw, Kay-Tee ^{[29
]}

Usategui-Martin, Ricardo ^{[30
,31
]}

Del Pino-Montes, Javier ^{[30
,31
]}

Gonzalez-Sarmiento, Rogelio ^{[30
,31
]}

Lewis, Joshua R. ^{[32
,33
,34
]}

Prince, Richard L. ^{[32
,35
]}

D'Amelio, Patrizia ^{[36
]}

Garcia-Giralt, Natalia ^{[37
]}

Nogues, Xavier ^{[37
]}

Mencej-Bedrac, Simona ^{[38
]}

Marc, Janja ^{[38
]}

Wolstein, Orit ^{[39
]}

Eisman, John A. ^{[39
]}

Oei, Ling ^{[2
,3
]}

Medina-Gomez, Carolina ^{[2
,3
]}

Schraut, Katharina E. ^{[40
,41
]}

Navarro, Pau ^{[42
]}

Wilson, James F. ^{[40
,42
]}

Davies, Gail ^{[9
]}

机构：

[1] Univ Edinburgh, Ctr Genom & Expt Med, Inst Genet & Mol Med, Rheumatol & Bone Dis Unit, Edinburgh, Midlothian, Scotland

[2] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[3] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[4] Hamad Bin Khalifa Univ, Qatar Biomed Res Inst, Doha, Qatar

[5] Oslo Univ Hosp, Dept Med Biochem, Oslo, Norway

[6] Lovisenberg Diakonale Hosp, Dept Clin Biochem, Oslo, Norway

[7] Univ Oslo, Inst Basic Med Sci, Dept Mol Med, Oslo, Norway

[8] Univ Edinburgh, Ctr Genom & Expt Med, IGMM, Edinburgh, Midlothian, Scotland

[9] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland

[10] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA

[11] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA

[12] Harvard Med Sch, Boston, MA USA

[13] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[14] Hebrew Seniorlife, Inst Aging Res, Musculoskeletal Res Ctr, Boston, MA USA

[15] Univ Ioannina, Dept Hyg & Epidemiol, Sch Med, Ioannina, Greece

[16] Brown Univ, Ctr Evidence Synth Hlth, Dept Hlth Serv Policy & Publ Hlth, Sch Publ Hlth, Providence, RI 02912 USA

[17] Imperial Coll London, Dept Epidemiol & Biostat, London, England

[18] Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark

[19] Univ Copenhagen, Dept Clin Med, Fac Hlth & Med Sci, Copenhagen, Denmark

[20] Stanford Sch Med, Dept Med, Stanford, CA USA

[21] Univ Florence, Dept Surg & Translat Med, Florence, Italy

[22] Univ Liverpool, MRC Arthrit Res UK Ctr Integrated Res Musculoskel, Inst Ageing & Chron Dis, Liverpool, Merseyside, England

[23] Univ Cantabria, Hosp Valdecilla, Dept Internal Med, RETICEF, Santander, Spain

[24] Aarhus Univ Hosp, Dept Endocrinol & Internal Med THG, Aarhus, Denmark

[25] Queensland Univ Technol, Princess Alexandra Hosp, Inst Hlth & Biomed Innovat, Translat Res Inst, Brisbane, Qld, Australia

[26] Univ Queensland, Fac Med, Brisbane, Qld, Australia

[27] Royal Brisbane & Womens Hosp, Dept Endocrinol, Brisbane, Qld, Australia

[28] Univ Cambridge, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge, England

[29] Univ Cambridge, Sch Med, Dept Publ Hlth & Primary Care, Cambridge, England

[30] Univ Salamanca, Univ Hosp Salamanca, Dept Med, Mol Med Unit,CSIC, Salamanca, Spain

[31] Univ Salamanca, Univ Hosp Salamanca, Biomed Res Inst Salamanca IBSAL, CSIC, Salamanca, Spain

[32] Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia

[33] Univ Sydney, Ctr Kidney Res, Sch Publ Hlth, Sydney, NSW, Australia

[34] Edith Cowan Univ, Sch Med & Hlth Sci, Joondalup, WA, Australia

[35] Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Perth, WA, Australia

[36] Univ Torino, Dept Med Sci, Gerontol & Bone Metab Dis Unit, Turin, Italy

[37] Univ Autonoma Barcelona, Hosp del Mar IMIM, Dept Internal Med, RETICEF, Barcelona, Spain

[38] Univ Ljubljana, Fac Pharm, Dept Clin Biochem, Ljubljana, Slovenia

[39] Garvan Inst Med Res, Osteoporosis & Bone Biol Program, Sydney, NSW, Australia

[40] Univ Edinburgh, Ctr Global Hlth Res, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland

[41] Univ Edinburgh, Edinburgh British Heart Fdn, QMRI, Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland

[42] Univ Edinburgh, MRC Human Genet Unit, IGMM, Edinburgh, Midlothian, Scotland

[43] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA

[44] Natl Res Council Italy, Inst Genet & Biophys Adrian Buzzati Traverso, Naples, Italy

[45] Univ Siena, Dept Med Surg & Neurosci, Siena, Italy

[46] IMIM, Grp Recerca Genet & Epidemiol Cardiovasc, Barcelona, Spain

来源：

ANNALS OF THE RHEUMATIC DISEASES | 2018年 / 77卷 / 03期

基金：

英国生物技术与生命科学研究理事会; 英国医学研究理事会; 新加坡国家研究基金会;

关键词：

GENOME-WIDE ASSOCIATION; MINERAL DENSITY; PHOSPHATE-TRANSPORT; RISK; EXPRESSION; VARIANTS; RECEPTOR; WOMEN; GENE; OSTEOPOROSIS;

D O I：

10.1136/annrheumdis-2017-212469

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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=1.04x10-9) 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.

引用

页码：378 / 385

页数：8

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