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Enhancement of Absolute Fracture Risk Prognosis with Genetic Marker: The Collagen I Alpha 1 Gene

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Abstract

An important objective of genetic research in osteoporosis is to translate genotype data into the prognosis of fracture. The present study sought to develop a prognostic model for predicting osteoporotic fracture by using information from a genetic marker and clinical risk factors. It was designed as a prospective epidemiological study which involved 894 women of Caucasian background aged 60+ years who had been followed for a median of 9 years (from 1989 and 2008, range 0.2–18 years). During the follow-up period, fragility fracture was ascertained by X-ray reports for all women. Bone mineral density (BMD) at the femoral neck was measured by dual-energy X-ray absorptiometry. Genotypes of the Sp1 binding site in the first intron of the collagen I alpha 1 (COLIA1) gene polymorphism were determined by polymerase chain reaction, digestion with BalI restriction enzyme, and agarose gel electrophoresis. The relationship between COL1A1 genotype and fracture was assessed by the Cox proportional hazards model, from which nomograms were developed for individualizing the risk of fracture. The distribution of COL1A1 genotypes was consistent with the Hardy-Weinberg equilibrium law: GG (63.8%), GT (32.6%), and TT (3.6%). During the follow-up period, there were 322 fractures, including 77 hip and 127 vertebral fractures. There was an overrepresentation of the TT genotype in the fracture group (6.2%) compared with the nonfracture group (2.3%). Compared with carriers of GT and GG, women carrying the TT genotype had increased risk of any fracture (relative risk [RR] = 1.91, 95% CI 1.21–3.00), hip fracture (RR = 3.67, 95% CI 1.69–8.00), and vertebral fracture (RR = 3.36, 95% CI 1.81–6.24). The incorporation of COL1A1 genotypes improved the risk reclassification by 2% for any fragility fracture, 4% for hip fracture, and 5% for vertebral fracture, beyond age, BMD, prior fracture, and fall. Three nomograms were constructed for predicting fracture risk in an individual woman based on age, BMD, and COLIA1 genotypes. These data suggest that the COLIA1 Sp1 polymorphism is associated with the risk of fragility fracture in Caucasian women and that the polymorphism could enhance the predictive accuracy of fracture prognosis. The nonograms presented here can be useful for individualizing the short- and intermediate-term prognosis of fracture risk and help identify high-risk individuals for intervention for appropriate management of osteoporosis.

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Acknowledgements

This work was supported by the National Health and Medical Research Council of Australia. We appreciate the expert assistance of Janet Watters and Donna Reeves in interviewing, data collection, and measurement of BMD. We also appreciate the invaluable help of the Dubbo community. We thank Mr. J. McBride and the IT group of the Garvan Institute of Medical Research for the management and maintenance of the database. We also thank Chehani Alles for her assistance in the genotyping. J. A. E.’s research, including the Dubbo Osteoporosis Epidemiology Study, has been supported by and/or he has provided consultation to Amgen, deCode, Eli Lilly, GE Lunar, Merck Sharp and Dohme, Novartis, Roche-GSK, Sanofi-Aventis, Servier, and Wyeth Australia. J. R. C. has been supported by and/or given educational talks for Eli Lilly, Merck Sharp and Dohme, and Sanofi-Aventis. T. V. N. is supported by a senior research fellowship from the Australian National Health and Medical Research Council. N. D. N. is supported by a grant from the AMBeR (Australian Medical Bioinformatics Resource).

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Authors and Affiliations

  1. Osteoporosis and Bone Biology Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, 2010, Sydney, NSW, Australia

    Bich N. H. Tran, Nguyen D. Nguyen, Jacqueline R. Center, John A. Eisman & Tuan V. Nguyen

  2. Faculty of Medicine, St. Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia

    Jacqueline R. Center, John A. Eisman & Tuan V. Nguyen

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  1. Bich N. H. Tran
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  2. Nguyen D. Nguyen
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Correspondence to Tuan V. Nguyen.

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Tran, B.N.H., Nguyen, N.D., Center, J.R. et al. Enhancement of Absolute Fracture Risk Prognosis with Genetic Marker: The Collagen I Alpha 1 Gene. Calcif Tissue Int 85, 379–388 (2009). https://doi.org/10.1007/s00223-009-9296-9

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