TY - JOUR
T1 - Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes
T2 - the GENOMOS study
AU - Ralston, Stuart H
AU - Uitterlinden, Andre G
AU - Brandi, Maria Luisa
AU - Balcells, Susana
AU - Langdahl, Bente L
AU - Lips, Paul
AU - Lorenc, Roman
AU - Obermayer-Pietsch, Barbara
AU - Scollen, Serena
AU - Bustamante, Mariona
AU - Husted, Lise Bjerre
AU - Carey, Alisoun H
AU - Diez-Perez, Adolfo
AU - Dunning, Alison M.
AU - Falchetti, Alberto
AU - Karczmarewicz, Elzbieta
AU - Kruk, Marcin
AU - van Leeuwen, Johannes P T M
AU - van Meurs, Joyce B J
AU - Mangion, Jon
AU - McGuigan, Fiona E A
AU - Mellibovsky, Leonardo
AU - del Monte, Francesca
AU - Pols, Huibert A P
AU - Reeve, Jonathan
AU - Reid, David M
AU - Renner, Wilfried
AU - Rivadeneira, Fernando
AU - van Schoor, Natasja M
AU - Sherlock, Rachael E
AU - Ioannidis, John P A
AU - GENOMOS Invest
PY - 2006/2/21
Y1 - 2006/2/21
N2 - 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.
Methods and Findings 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/cm(2) (CI, 16 to 34 mg/cm(2)) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm(2) (CI, 1 to 42 mg/cm(2)), (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.
AB - 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.
Methods and Findings 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/cm(2) (CI, 16 to 34 mg/cm(2)) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm(2) (CI, 1 to 42 mg/cm(2)), (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.
KW - bone-mineral density
KW - vertebral deformity
KW - binding site
KW - in vitro
KW - women
KW - gene
KW - men
KW - association
KW - population
KW - fractures
U2 - 10.1371/journal.pmed.0030090
DO - 10.1371/journal.pmed.0030090
M3 - Article
SN - 1549-1277
VL - 3
JO - PLoS Medicine
JF - PLoS Medicine
IS - 4
M1 - e90
ER -