Polymorphisms in the 5' flank of COL1A1 gene and osteoporosis: meta-analysis of published studies.
A meta-analysis of studies was conducted involving 24,511 participants with 7,864 fractures in which polymorphisms in the 5' flank of COL1A1 (rs1107946, rs2412298, and rs1800012) were related to osteoporosis phenotypes. Polymorphisms of all three sites were associated with BMD, and rs1800012 was associated with fracture but effect sizes were modest.


OBJECTIVE
Polymorphisms in the 5' flank of COL1A1 gene have been implicated as genetic markers for susceptibility to osteoporosis, but previous studies have yielded conflicting results.


METHODS
We conducted a meta-analysis of 32 studies including 24,511 participants and 7,864 fractures in which alleles at the -1997G/T (rs1107946), -1663in/delT (rs2412298), and Sp1 binding site polymorphisms (rs1800012) of COL1A1 had been related to bone mineral density (BMD) or fracture.


RESULTS
For the Sp1 polymorphism, BMD values in TT homozygotes were 0.13 units [95% CI, 0.03 to 0.24] lower at the spine (p = 0.01) and 0.16 units [0.10 to 0.23] lower at the hip (p = 1 x 10⁻⁶) than GG homozygotes. Clinical fractures were 1.31-fold [1.04-1.65] increased in TT homozygotes (p = 0.02) and vertebral fractures were 1.34-fold [1.01-1.77] increased (p = 0.04). We also observed associations between spine BMD and allelic variants at the -1997G/T (p = 0.05) and the -1663indelT (p = 0.009) sites. We found no association between alleles at the -1997G/T or -1663indelT sites and fracture but power was limited.


CONCLUSIONS
The COL1A1 Sp1 polymorphism is associated with a modest reduction in BMD and an increased risk of fracture, although we cannot fully exclude the possibility that the results may have been influenced by publication bias. Further studies are required to fully evaluate the contribution of the -1997G/T and -1663in/delT sites to these phenotypes and to determine if they interact with the Sp1 polymorphism to regulate susceptibility to osteoporosis.
Jin
H
H
Rheumatic Disease Unit, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH42XU, UK.
Evangelou
E
E
Ioannidis
J P A
JP
Ralston
S H
SH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density / Q000235:genetics*; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D005260:Female; D005272:Femur Neck / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006801:Humans; D008159:Lumbar Vertebrae / Q000502:physiology; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics*; D058866:Osteoporotic Fractures / Q000235:genetics*; D011110:Polymorphism, Genetic; D016103:Spinal Fractures / Q000235:genetics; D055815:Young Adult
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain
Nat Genet. 2009 Nov;41(11):1199-206
19801982
J Natl Cancer Inst. 2004 Mar 17;96(6):434-42
15026468
Osteoporos Int. 2001;12(4):326-31
11420783
Bone. 2003 Jun;32(6):711-7
12810179
Osteoporos Int. 2007 Feb;18(2):235-43
17021946
Calcif Tissue Int. 2000 Apr;66(4):268-71
10742443
Arch Intern Med. 2005 Sep 12;165(16):1825-30
16157825
J Bone Miner Res. 2001 Sep;16(9):1586-92
11547828
Hum Mol Genet. 2005 Apr 1;14(7):943-51
15746152
Ann Intern Med. 1997 Nov 1;127(9):820-6
9382404
Osteoporos Int. 2000;11(7):583-91
11069192
PLoS Med. 2005 Aug;2(8):e124
16060722
Hum Biol. 2005 Feb;77(1):27-36
16114814
Bone. 2002 Jan;30(1):223-8
11792589
Nat Genet. 2009 Jan;41(1):15-7
19079262
JAMA. 2008 Mar 19;299(11):1277-90
18349089
Calcif Tissue Int. 2001 Jun;68(6):348-51
11685422
Clin Trials. 2007;4(3):245-53
17715249
Calcif Tissue Int. 2000 Jun;66(6):409-13
10821875
Calcif Tissue Int. 2004 Mar;74(3):264-9
14595528
J Bone Miner Res. 2007 Feb;22(2):173-183
17228994
N Engl J Med. 1998 Apr 9;338(15):1016-21
9535665
Osteoporos Int. 2000;11(4):338-43
10928224
Arthritis Rheum. 1999 Feb;42(2):285-90
10025922
J Bone Miner Res. 1998 May;13(5):813-7
9610745
J Bone Miner Res. 2003 Aug;18(8):1525-30
12929943
Adv Genet. 2008;60:311-34
18358326
Nat Genet. 2003 Feb;33(2):177-82
12524541
Calcif Tissue Int. 2007 Jul;81(1):18-25
17551768
Am J Epidemiol. 2008 Aug 15;168(4):374-83; discussion 384-90
18611956
J Clin Endocrinol Metab. 2006 Sep;91(9):3575-83
16804049
PLoS Med. 2006 Apr;3(4):e90
16475872
Stat Med. 2006 Oct 30;25(20):3443-57
16345038
Rheumatology (Oxford). 2000 Nov;39(11):1222-5
11085801
Osteoporos Int. 2001;12(2):91-6
11303720
Calcif Tissue Int. 2002 Jun;70(6):457-62
12016463
Ann Intern Med. 2006 Aug 15;145(4):255-64
16908916
Kidney Int Suppl. 2003 Jun;(85):S14-8
12753258
J Bone Miner Res. 1999 Aug;14(8):1411-9
10457274
Bone. 2008 May;42(5):969-81
18284942
J Bone Miner Res. 2009 Mar;24(3):448-54
19016596
Nat Genet. 1996 Oct;14(2):203-5
8841196
Osteoporos Int. 1999;9(4):346-50
10550452
BMJ. 1997 Sep 13;315(7109):629-34
9310563
Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3871-6
19202052
Genetika. 2008 Feb;44(2):219-25
18619040
J Clin Endocrinol Metab. 2005 Dec;90(12):6575-9
16159929
J Bone Miner Res. 1997 Dec;12(12):2076-81
9421240
Osteoporos Int. 2001;12(10):895-901
11716195
Osteoporos Int. 2002;13(6):506-12
12107666
Arthritis Rheum. 1998 Jan;41(1):187-8
9433891
J Bone Miner Res. 2001 Nov;16(11):1962-71
11697792
Calcif Tissue Int. 2005 Feb;76(2):98-106
15570400
Lancet. 2008 May 3;371(9623):1505-12
18455228
Calcif Tissue Int. 1998 Oct;63(4):293-5
9744986
Eur J Intern Med. 2001 Feb;12(1):48-56
11173011
J Clin Invest. 2001 Apr;107(7):899-907
11285309
Calcif Tissue Int. 2000 Nov;67(5):361-366
11136533
J Bone Miner Res. 2002 Mar;17(3):384-93
11874231
N Engl J Med. 2008 May 29;358(22):2355-65
18445777
Am J Hum Genet. 2005 Nov;77(5):807-23
16252240
Calcif Tissue Int. 2009 Feb;84(2):85-96
19082910
Hum Mol Genet. 2009 Aug 1;18(15):2729-38
19429913
Ann Intern Med. 2009 Oct 20;151(8):528-37
19841454
BMJ. 2007 Nov 3;335(7626):914-6
17974687