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Impact of common variation in bone-related genes on type 2 diabetes and related traits.

TitleImpact of common variation in bone-related genes on type 2 diabetes and related traits.
Publication TypeJournal Article
Year of Publication2012
AuthorsBillings LK, Hsu Y-H, Ackerman RJ, Dupuis J, Voight BF, Rasmussen-Torvik LJ, Hercberg S, Lathrop M, Barnes D, Langenberg C, Hui J, Fu M, Bouatia-Naji N, Lecoeur C, An P, Magnusson PK, Surakka I, Ripatti S, Christiansen L, Dalgård C, Folkersen L, Grundberg E, Eriksson P, Kaprio J, Kyvik KOhm, Pedersen NL, Borecki IB, Province MA, Balkau B, Froguel P, Shuldiner AR, Palmer LJ, Wareham N, Meneton P, Johnson T, Pankow JS, Karasik D, Meigs JB, Kiel DP
Secondary AuthorsFlorez JC
Corporate AuthorsMAGIC Investigators, DIAGRAM + Consortium, MuTHER Consortium, ASCOT Investigators, GEFOS Consortium
JournalDiabetes
Volume61
Issue8
Pagination2176-86
Date Published2012 Aug
ISSN1939-327X
KeywordsAdipose Tissue, Adult, Blood Glucose, Body Mass Index, Bone Density, Diabetes Mellitus, Type 2, Endonucleases, Female, Fractures, Bone, Genome-Wide Association Study, Humans, Insulin, Integrin alpha1, Linkage Disequilibrium, Liver, Microfilament Proteins, Nuclear Proteins, Osteoporosis, Polymorphism, Single Nucleotide
Abstract

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 ∼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, β-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.

DOI10.2337/db11-1515
Alternate JournalDiabetes
PubMed ID22698912
PubMed Central IDPMC3402303
Grant ListR01 DK078616 / DK / NIDDK NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
5-R01-HL-08770003 / HL / NHLBI NIH HHS / United States
U01-HL-72515 / HL / NHLBI NIH HHS / United States
R01-HL-086694 / HL / NHLBI NIH HHS / United States
T32 DK007028 / DK / NIDDK NIH HHS / United States
UL1 TR000150 / TR / NCATS NIH HHS / United States
R21-AR-056405 / AR / NIAMS NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
UL1-RR-025005 / RR / NCRR NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
R01-DK-04261 / DK / NIDDK NIH HHS / United States
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R01 HL059367 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
R01-HL-087641 / HL / NHLBI NIH HHS / United States
R01-DK-078616 / DK / NIDDK NIH HHS / United States
HHSN268201100009C / / PHS HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
P30 DK079637 / DK / NIDDK NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
R01 AR041398 / AR / NIAMS NIH HHS / United States
HHSN268201100010C / / PHS HHS / United States
1-L30-DK-089944-01 / DK / NIDDK NIH HHS / United States
MC_U106179471 / / Medical Research Council / United Kingdom
R01-HL-59367 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
HHSN268201100012C / / PHS HHS / United States
G1002084 / / Medical Research Council / United Kingdom
L30 DK089944 / DK / NIDDK NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
P60 DK079637 / DK / NIDDK NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
5-R01-DK-07568102 / DK / NIDDK NIH HHS / United States
1-S10-RR-163736-01A1 / RR / NCRR NIH HHS / United States
5-R01-DK-06833603 / DK / NIDDK NIH HHS / United States
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HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100011C / / PHS HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
T32-DK-007028-35 / DK / NIDDK NIH HHS / United States
M01-RR-16500 / RR / NCRR NIH HHS / United States
R21 AR056405 / AR / NIAMS NIH HHS / United States
HHSN268201100006C / / PHS HHS / United States
R01-AG-18728 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
U01-HG-004402 / HG / NHGRI NIH HHS / United States
/ / Wellcome Trust / United Kingdom
R01-AR/AG-41398 / AG / NIA NIH HHS / United States
R01 AG018728 / AG / NIA NIH HHS / United States
G0900339 / / Medical Research Council / United Kingdom
5-R01-HL-08821502 / HL / NHLBI NIH HHS / United States