Impact of Common Variation in Bone-Related Genes on Type 2 Diabetes and Related Traits

被引：33

作者：

Billings, Liana K. ^{[1
,2
,3
]}

Hsu, Yi-Hsiang ^{[4
,5
,6
,7
]}

Ackerman, Rachel J. ^{[1
]}

Dupuis, Josee ^{[7
,8
]}

Voight, Benjamin F. ^{[1
,2
,9
]}

Rasmussen-Torvik, Laura J. ^{[10
]}

Hercberg, Serge ^{[11
]}

Lathrop, Mark ^{[12
]}

Barnes, Daniel ^{[13
]}

Langenberg, Claudia ^{[13
]}

Hui, Jennie ^{[14
,15
,16
,17
]}

Fu, Mao ^{[18
]}

Bouatia-Naji, Nabila ^{[19
]}

Lecoeur, Cecile ^{[19
]}

An, Ping ^{[20
,21
]}

Magnusson, Patrik K. ^{[22
]}

Surakkaza, Ida ^{[23
,24
]}

Ripatti, Samuli ^{[23
,24
]}

Christiansen, Lene ^{[25
]}

Dalgard, Christine ^{[26
]}

Folkersen, Lasse ^{[27
]}

Grundberg, Elin ^{[28
,29
]}

Eriksson, Per ^{[27
]}

Kaprio, Jaakko ^{[23
,31
,32
]}

Kyvik, Kirsten Ohm ^{[33
,34
]}

Pedersen, Nancy L. ^{[22
]}

Borecki, Ingrid B. ^{[20
,21
]}

Province, Michael A. ^{[22
]}

Balkau, Beverley ^{[35
,36
]}

Froguel, Philippe ^{[19
,37
]}

Shuldiner, Alan R. ^{[18
,38
]}

Palmer, Lyle J. ^{[39
]}

Wareham, Nick ^{[13
]}

Meneton, Pierre ^{[40
]}

Johnson, Toby ^{[41
]}

Pankow, James S. ^{[42
]}

Karasik, David ^{[4
,5
,7
]}

Meigs, James B. ^{[2
,7
]}

Kiel, Douglas P. ^{[2
,4
,5
,7
]}

Florez, Jose C. ^{[1
,2
,3
,9
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[2] Harvard Sch Med, Dept Med, Boston, MA 02115 USA

[3] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA

[4] Hebrew Senior Life Inst Aging Res, Boston, MA USA

[5] Harvard Med Sch, Boston, MA USA

[6] Harvard Sch Publ Hlth, Mol & Integrat Physiol Sci Program, Boston, MA USA

[7] Framingham Heart Dis Epidemiol Study, Framingham, MA USA

[8] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA USA

[9] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA

[10] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL USA

[11] Univ Paris, INSERM, Natl Inst Agron Res, Bobigny, France

[12] Atom Energy Commiss, Natl Genotyping Ctr, Inst Genom, Evry, France

[13] Addenbrookes Hosp, Inst Metab Sci, Med Res Council Epidemiol Unit, Cambridge, England

[14] PathWest Lab Med Western Australia, Mol Genet, Nedlands, WA, Australia

[15] Univ Western Australia, Sch Populat Hlth, Nedlands, WA, Australia

[16] Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA, Australia

[17] Sir Charles Gairdner Hosp, Busselton Populat Med Res Fdn, Nedlands, WA, Australia

[18] Univ Maryland, Sch Med, Dept Med, Baltimore, MD USA

[19] Lille Nord France Univ, Natl Ctr Sci Res, UMR 8199, Lille Pasteur Inst,Genom & Metab Dis, Lille, France

[20] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO USA

[21] Washington Univ, Sch Med, Dept Genet, St Louis, MO USA

[22] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[23] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland

[24] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland

[25] Univ Southern Denmark, Inst Publ Hlth, Danish Twin Registry, Odense, Denmark

[26] Univ Southern Denmark, Dept Environm Med, Inst Publ Hlth, Odense, Denmark

[27] Karolinska Inst, Dept Med, Atherosclerosis Res Unit, Stockholm, Sweden

[28] Wellcome Trust Sanger Inst, Hinxton, England

[29] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England

[30] Erasmus Med Coll, Coordinating Ctr, Rotterdam, Netherlands

[31] Natl Inst Hlth & Welf, Unit Child & Adolescent Mental Hlth, Helsinki, Finland

[32] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland

[33] Univ Southern Denmark, Inst Reg Hlth Serv Res, Odense, Denmark

[34] Odense Univ Hosp, Odense Patient Data Explorat Network, Odense, Denmark

[35] INSERM, CESP Ctr Res Epidemiol & Hlth Populat, U1018, Epidemiol Diabet Obes & Chron Kidney Dis Life Cou, Villejuif, France

[36] Univ Paris Sud 11, UMRS 1018, Villejuif, France

[37] Imperial Coll London, Hammersmith Hosp, Genom Med, London, England

[38] Baltimore VA Med Ctr, Geriatr Res Educ & Clin Ctr, Baltimore, MD USA

[39] Ontario Inst Canc Res, Toronto, ON, Canada

[40] INSERM, Cordeliers Ctr Res, Paris, France

[41] Queen Mary Univ London, Clin Pharmacol & Genome Ctr, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England

[42] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA

来源：

DIABETES | 2012年 / 61卷 / 08期

基金：

英国医学研究理事会; 瑞典研究理事会; 美国国家卫生研究院; 英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; FRACTURE RISK; MINERAL DENSITY; OSTEOPOROTIC FRACTURES; GLUCOSE-HOMEOSTASIS; INSULIN-RESISTANCE; FASTING GLUCOSE; LOCI; EXPRESSION; MELLITUS;

D O I：

10.2337/db11-1515

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Exploring genetic pleiotropy can provide clues to a mechanism underlying the observed epidemiological association between type 2 diabetes and heightened fracture risk. We examined genetic variants associated with bone mineral density (BMD) for association with type 2 diabetes and glycemic traits in large well-phenotyped and -genotyped consortia. We undertook follow-up analysis in similar to 19,000 individuals and assessed gene expression. We queried single nucleotide polymorphisms (SNPs) associated with BMD at levels of genome-wide significance, variants in linkage disequilibrium (r(2) > 0.5), and BMD candidate genes. SNP rs6867040, at the ITGA1 locus, was associated with a 0.0166 mmol/L (0.004) increase in fasting glucose per C allele in the combined analysis. Genetic variants in the ITGA1 locus were associated with its expression in the liver but not in adipose tissue. ITGA1 variants appeared among the top loci associated with type 2 diabetes, fasting insulin, beta-cell function by homeostasis model assessment, and 2-h post-oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion, and bone healing lends credence to its contribution to both osteoporosis and type 2 diabetes. These findings further underscore the link between skeletal and glucose metabolism and highlight a locus to direct future investigations. Diabetes 61:2176-2186, 2012

引用

页码：2176 / 2186

页数：11

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