Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study.
BACKGROUND
Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes.


RESULTS
Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm2 (CI, 16 to 34 mg/cm2) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm2 (CI, 1 to 42 mg/cm2), (p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses.


CONCLUSIONS
Allowing for the inevitable heterogeneity between participating teams, this study-which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene-demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.
Rheumatic Diseases Unit, University of Edinburgh, Western General Hospital Edinburgh, Edinburgh, United Kingdom.
Stuart H
SH
Ralston
André G
AG
Uitterlinden
Maria Luisa
ML
Brandi
Susana
S
Balcells
Bente L
BL
Langdahl
Paul
P
Lips
Roman
R
Lorenc
Barbara
B
Obermayer-Pietsch
Serena
S
Scollen
Mariona
M
Bustamante
Lise Bjerre
LB
Husted
Alisoun H
AH
Carey
Adolfo
A
Diez-Perez
Alison M
AM
Dunning
Alberto
A
Falchetti
Elzbieta
E
Karczmarewicz
Marcin
M
Kruk
Johannes P T M
JP
van Leeuwen
Joyce B J
JB
van Meurs
Jon
J
Mangion
Fiona E A
FE
McGuigan
Leonardo
L
Mellibovsky
Francesca
F
del Monte
Huibert A P
HA
Pols
Jonathan
J
Reeve
David M
DM
Reid
Wilfried
W
Renner
Fernando
F
Rivadeneira
Natasja M
NM
van Schoor
Rachael E
RE
Sherlock
John P A
JP
Ioannidis
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density; D016022:Case-Control Studies; D024042:Collagen Type I / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000188:drug therapy / Q000235:genetics*; D011110:Polymorphism, Genetic; D012307:Risk Factors; D016103:Spinal Fractures / Q000209:etiology / Q000235:genetics*
D024042:Collagen Type I