Polymorphisms in the macrophage migration inhibitory factor gene and bone loss in postmenopausal women.
Osteoporosis is a severe condition in postmenopausal women and a common cause of fracture. Osteoporosis is a complex disease with a strong genetic impact, but susceptibility is determined by many genes with modest effects and environmental factors. Only a handful of genes consistently associated with osteoporosis have been identified so far. Inflammation affects bone metabolism by interfering with the interplay between bone resorption and formation, and many inflammatory mediators are involved in natural bone remodeling. The cytokine macrophage migration inhibitory factor (MIF) has been shown to affect bone density in rodents, and polymorphisms in the human MIF promoter are associated with inflammatory disorders such as rheumatoid arthritis. We investigated the association of polymorphisms in the MIF gene with bone mineral density (BMD) and bone loss in 1002 elderly women using MIF promoter polymorphisms MIF-CATT(5-8) and rs755622(G/C) located -794 and -173 bp upstream of the transcriptional start site. Bone loss was estimated both by the change in BMD over 5 years and by the levels of bone resorption markers in serum measured at four occasions during a 5-year period. The MIF-CATT(7)/rs755622(C) haplotype was associated with increased rate of bone loss during 5 years at the femoral neck (p<0.05) and total hip (p<0.05). In addition, the MIF-CATT(7)/rs755622(C) haplotype carriers had higher levels of the bone turnover marker serum C-terminal cross-linking telopeptide of type I collagen (S-CTX-I, p<0.01) during the 5 year follow-up period. There was no association between MIF-CATT(7)/rs755622(C) and baseline BMD at femoral neck, total hip or lumbar spine. We conclude that MIF promoter polymorphisms have modest effects on bone remodeling and are associated with the rate of bone loss in elderly women.
Swanberg
Maria
M
Clinical and Molecular Osteoporosis Research Unit, Lund University, Department of Clinical Sciences, Malmö University Hospital, Entrance 21, Floor 4, UMAS, SE-20502 Malmö, Sweden.
McGuigan
Fiona
F
Ivaska
Kaisa K
KK
Gerdhem
Paul
P
Lerner
Ulf H
UH
Bucala
Richard
R
Kuchel
George
G
Kenny
Anne
A
Akesson
Kristina
K
D000135:Acid Phosphatase / Q000378:metabolism; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density / Q000235:genetics; D001862:Bone Resorption / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D007527:Isoenzymes / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017698:Postmenopause / Q000235:genetics*; D000071681:Tartrate-Resistant Acid Phosphatase
D015415:Biomarkers; D007527:Isoenzymes; D008263:Macrophage Migration-Inhibitory Factors; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human
FASEB J. 2009 Oct;23(10):3470-81
19564250
Hum Hered. 2000 Mar-Apr;50(2):133-9
10799972
Clin Chem. 2001 Jan;47(1):74-80
11148180
Arthritis Rheum. 2006 Nov;54(11):3661-9
17075815
Cytokine. 1999 Feb;11(2):163-7
10089139
J Clin Endocrinol Metab. 2008 Jul;93(7):2622-32
18460567
Bone. 2009 Oct;45(4):640-9
19591967
Nature. 1986 Feb 6-12;319(6053):516-8
3511389
Osteoporos Int. 2006;17(7):1065-77
16758143
J Immunol. 1985 Oct;135(4):2562-8
3875658
Genes Immun. 2007 Dec;8(8):646-52
17728788
Nat Rev Immunol. 2007 Apr;7(4):292-304
17380158
J Bone Miner Res. 2005 Nov;20(11):1929-35
16234965
Genes Immun. 2003 Oct;4(7):487-91
14551601
FASEB J. 2009 Oct;23(10):3526-38
19546303
J Invest Dermatol. 2004 Sep;123(3):484-7
15304087
Arthritis Rheum. 1999 Aug;42(8):1601-8
10446857
Am J Respir Crit Care Med. 2004 May 1;169(9):1014-8
14962818
PLoS One. 2007 Jul 04;2(7):e586
17611621
Osteoporos Int. 2007 Sep;18(9):1297-305
17440674
Am J Hum Genet. 2001 Apr;68(4):978-89
11254454
Histochem Cell Biol. 2004 Mar;121(3):209-17
14767776
J Clin Invest. 2003 May;111(9):1309-18
12727922
J Bone Miner Res. 2005 Jul;20(7):1195-201
15940372
Clin Chem. 2001 Mar;47(3):597-600
11238321
Arthritis Rheum. 2002 Jan;46(1):232-7
11817596
Maturitas. 2003 Apr 25;44(4):259-65
12697366
Genes Immun. 2006 Jul;7(5):433-6
16724072
Nucleic Acids Res. 2005 Aug 02;33(13):e121
16077028
J Bone Miner Res. 2010 Feb;25(2):393-403
19961336
J Bone Miner Res. 2006 Jun;21(6):876-85
16753018
Lancet. 2002 May 18;359(9319):1761-7
12049882
Arthritis Rheum. 2002 Sep;46(9):2402-9
12355488
Clin Biochem Rev. 2006 Aug;27(3):123-38
17268581
J Bone Miner Res. 2004 Mar;19(3):386-93
15040826
Curr Med Chem. 2009;16(9):1091-114
19275614
Arthritis Rheum. 2003 May;48(5):1398-407
12746913
Nature. 2000 Nov 30;408(6812):600-5
11117749
J Bone Miner Res. 1996 Oct;11(10):1531-8
8889854
Best Pract Res Clin Endocrinol Metab. 2008 Oct;22(5):723-35
19028354
Clin Chem. 2001 Aug;47(8):1410-4
11468230
Arthritis Rheum. 2003 May;48(5):1171-6
12746889
FEBS Lett. 2006 Feb 20;580(5):1251-6
16442103
J Inflamm. 1995-1996;47(1-2):39-51
8913928
J Endocrinol. 2009 Jun;201(3):309-20
19443863
Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14410-5
16186482
Arthritis Rheum. 2005 Oct;52(10):3020-9
16200611
Am J Pathol. 1999 Oct;155(4):1137-46
10514397
J Biol Chem. 2002 Mar 8;277(10):7865-74
11751895
Genes Immun. 2002 May;3(3):170-6
12070782
Clin Infect Dis. 2005 Nov 15;41 Suppl 7:S513-9
16237655