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. 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/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.

[1]  J. Ioannidis,et al.  Local Literature Bias in Genetic Epidemiology: An Empirical Evaluation of the Chinese Literature , 2005, PLoS medicine.

[2]  J. Ioannidis,et al.  Why Most Published Research Findings Are False , 2005, PLoS medicine.

[3]  R. Aspden,et al.  Association of COLIA1 Sp1 Alleles with Defective Bone Nodule Formation In Vitro and Abnormal Bone Mineralization In Vivo , 2005, Calcified Tissue International.

[4]  M. Brown,et al.  Genetic Studies of Osteoporosis — A Rethink Required , 2005, Calcified Tissue International.

[5]  A. Díez-Pérez,et al.  In vitro functional assay of alleles and haplotypes of two COL1A1-promoter SNPs. , 2005, Bone.

[6]  A. Uitterlinden,et al.  Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study. , 2005, Human molecular genetics.

[7]  A. Uitterlinden,et al.  Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. , 2004, JAMA.

[8]  J. Long,et al.  Common variants at the PCOL2 and Sp1 binding sites of the COL1A1 gene and their interactive effect influence bone mineral density in Caucasians , 2004, Journal of Medical Genetics.

[9]  A. Uitterlinden,et al.  Collagen type I α1 Sp1 polymorphism, osteoporosis, and intervertebral disc degeneration in older men and women , 2003 .

[10]  S. Ralston,et al.  Meta-analysis of COL1A1 Sp1 polymorphism in relation to bone mineral density and osteoporotic fracture. , 2003, Bone.

[11]  Yao-Zhong Liu,et al.  Molecular studies of identification of genes for osteoporosis: the 2002 update. , 2003, The Journal of endocrinology.

[12]  John P A Ioannidis,et al.  Genetic associations: false or true? , 2003, Trends in molecular medicine.

[13]  G. Leb,et al.  Normative data of bone mineral density in an unselected adult Austrian population , 2003, European journal of clinical investigation.

[14]  Alphonso Brown,et al.  Meta-analysis, Decision Analysis and Cost-Effectiveness Analysis: Methods for Quantitative Synthesis in Medicine , 2002 .

[15]  A. Díez-Pérez,et al.  Two New Single‐Nucleotide Polymorphisms in the COL1A1 Upstream Regulatory Region and Their Relationship to Bone Mineral Density , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[16]  J. Ioannidis,et al.  Replication validity of genetic association studies , 2001, Nature Genetics.

[17]  J. Ioannidis,et al.  Association of Collagen Iα 1 Sp1 Polymorphism with the Risk of Prevalent Fractures: A Meta‐Analysis , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[18]  R M Aspden,et al.  A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. , 2001, The Journal of clinical investigation.

[19]  A R Feinstein,et al.  Clinical epidemiological quality in molecular genetic research: the need for methodological standards. , 1999, JAMA.

[20]  A Hofman,et al.  Risk factors for increased bone loss in an elderly population: the Rotterdam Study. , 1998, American journal of epidemiology.

[21]  G. Smith,et al.  Meta-analysis Spurious precision? Meta-analysis of observational studies , 1998, BMJ.

[22]  D. Torgerson,et al.  Randomized trial of osteoporosis screening. Use of hormone replacement therapy and quality-of-life results. , 1997, Archives of internal medicine.

[23]  S. Grant,et al.  Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I α 1 gene , 1996, Nature Genetics.

[24]  F. Rousset,et al.  Testing heterozygote excess and deficiency. , 1995, Genetics.

[25]  Diana B. Petitti,et al.  Meta-Analysis, Decision Analysis, and Cost-Effectiveness Analysis: Methods for Quantitative Synthesis in Medicine , 1994 .

[26]  T. Spector,et al.  The assessment of vertebral deformity: A method for use in population studies and clinical trials , 1993, Osteoporosis International.

[27]  P. Easterbrook,et al.  Publication bias in clinical research , 1991, The Lancet.

[28]  Banaras Hindu.  The Institute of Medical Sciences , 1905, The Hospital.

[29]  A. Uitterlinden,et al.  Cross-calibration of dual-energy X-ray densitometers for a large, multi-center genetic study of osteoporosis , 2005, Osteoporosis International.

[30]  A. Uitterlinden,et al.  Collagen type I alpha1 Sp1 polymorphism, osteoporosis, and intervertebral disc degeneration in older men and women. , 2004, Annals of the rheumatic diseases.

[31]  Stacey S Cherny,et al.  The impact of genotyping error on family-based analysis of quantitative traits , 2001, European Journal of Human Genetics.

[32]  A. Hofman,et al.  RELATION OF ALLELES OF THE COLLAGEN TYPE I a 1 GENE TO BONE DENSITY AND THE RISK OF OSTEOPOROTIC FRACTURES IN POSTMENOPAUSAL WOMEN , 2000 .

[33]  A. Silman,et al.  Validity of Self-Report of Fractures: Results from a Prospective Study in Men and Women Across Europe , 2000, Osteoporosis International.

[34]  A. Silman,et al.  Mortality Associated with Vertebral Deformity in Men and Women: Results from the European Prospective Osteoporosis Study (EPOS) , 1998, Osteoporosis International.