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.
Ralston
Stuart H
SH
Rheumatic Diseases Unit, University of Edinburgh, Western General Hospital Edinburgh, Edinburgh, United Kingdom.
Uitterlinden
André G
AG
Brandi
Maria Luisa
ML
Balcells
Susana
S
Langdahl
Bente L
BL
Lips
Paul
P
Lorenc
Roman
R
Obermayer-Pietsch
Barbara
B
Scollen
Serena
S
Bustamante
Mariona
M
Husted
Lise Bjerre
LB
Carey
Alisoun H
AH
Diez-Perez
Adolfo
A
Dunning
Alison M
AM
Falchetti
Alberto
A
Karczmarewicz
Elzbieta
E
Kruk
Marcin
M
van Leeuwen
Johannes P T M
JP
van Meurs
Joyce B J
JB
Mangion
Jon
J
McGuigan
Fiona E A
FE
Mellibovsky
Leonardo
L
del Monte
Francesca
F
Pols
Huibert A P
HA
Reeve
Jonathan
J
Reid
David M
DM
Renner
Wilfried
W
Rivadeneira
Fernando
F
van Schoor
Natasja M
NM
Sherlock
Rachael E
RE
Ioannidis
John P A
JP
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