Polymorphisms in the 5' Flank of COL1A1 Gene and Osteoporosis: Meta-analysis of Published Studies

Overview

Journal Osteoporos Int

Specialties Endocrinology
Orthopedics

Date 2010 Aug 28

PMID 20798928

Citations 22

Authors

H Jin

E Evangelou

J P A Ioannidis

S H Ralston

Affiliations

Soon will be listed here.

Abstract

Unlabelled: A meta-analysis of studies was conducted involving 24,511 participants with 7,864 fractures in which polymorphisms in the 5' flank of COL1A1 (rs1107946, rs2412298, and rs1800012) were related to osteoporosis phenotypes. Polymorphisms of all three sites were associated with BMD, and rs1800012 was associated with fracture but effect sizes were modest.

Introduction And Hypothesis: Polymorphisms in the 5' flank of COL1A1 gene have been implicated as genetic markers for susceptibility to osteoporosis, but previous studies have yielded conflicting results.

Methods: We conducted a meta-analysis of 32 studies including 24,511 participants and 7,864 fractures in which alleles at the -1997G/T (rs1107946), -1663in/delT (rs2412298), and Sp1 binding site polymorphisms (rs1800012) of COL1A1 had been related to bone mineral density (BMD) or fracture.

Results: For the Sp1 polymorphism, BMD values in TT homozygotes were 0.13 units [95% CI, 0.03 to 0.24] lower at the spine (p = 0.01) and 0.16 units [0.10 to 0.23] lower at the hip (p = 1 x 10⁻⁶) than GG homozygotes. Clinical fractures were 1.31-fold [1.04-1.65] increased in TT homozygotes (p = 0.02) and vertebral fractures were 1.34-fold [1.01-1.77] increased (p = 0.04). We also observed associations between spine BMD and allelic variants at the -1997G/T (p = 0.05) and the -1663indelT (p = 0.009) sites. We found no association between alleles at the -1997G/T or -1663indelT sites and fracture but power was limited.

Conclusions: The COL1A1 Sp1 polymorphism is associated with a modest reduction in BMD and an increased risk of fracture, although we cannot fully exclude the possibility that the results may have been influenced by publication bias. Further studies are required to fully evaluate the contribution of the -1997G/T and -1663in/delT sites to these phenotypes and to determine if they interact with the Sp1 polymorphism to regulate susceptibility to osteoporosis.

Citing Articles

The rs1800012 polymorphism is associated with osteoporosis or fracture risk: a meta-analysis of 30 studies.

Xu P, Wang Y, Wu X, Wang W, Wang Q, Lin W Int J Burns Trauma. 2025; 14(6):148-159.

PMID: 39850783 PMC: 11751553. DOI: 10.62347/KKAM3344.

Impact of the Gene Polymorphisms on Pain Perception in Tennis Elbow Patients: A Two-Year Prospective Cohort Study.

Niemiec P, Jarosz A, Nowak T, Balcerzyk-Matic A, Iwanicki T, Iwanicka J Int J Mol Sci. 2024; 25(23).

PMID: 39684930 PMC: 11642392. DOI: 10.3390/ijms252313221.

The Analysis of ECE1 and PPARG Variants in the Development of Osteopenia and Osteoporosis in Postmenopausal Women.

Uzar I, Bogacz A, Luszczynska M, Wolek M, Kotrych K, Modrzejewski A Biomedicines. 2024; 12(7).

PMID: 39062013 PMC: 11274254. DOI: 10.3390/biomedicines12071440.

Tendon and Ligament Genetics: How Do They Contribute to Disease and Injury? A Narrative Review.

Ribbans W, September A, Collins M Life (Basel). 2022; 12(5).

PMID: 35629331 PMC: 9147569. DOI: 10.3390/life12050663.

Association of MTHFR rs1801133 and homocysteine with Legg-Calvé-Perthes disease in Mexican patients.

Buendia-Pazaran J, Hernandez-Zamora E, Rodriguez-Olivas A, Casas-Avila L, Valdes-Flores M, Reyes-Maldonado E Orphanet J Rare Dis. 2022; 17(1):123.

PMID: 35264229 PMC: 8905721. DOI: 10.1186/s13023-022-02264-2.

References

Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson B, Hsu Y, Richards J . Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet. 2009; 41(11):1199-206. PMC: 2783489. DOI: 10.1038/ng.446. View

Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N . Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst. 2004; 96(6):434-42. PMC: 7713993. DOI: 10.1093/jnci/djh075. View

Efstathiadou Z, Kranas V, Ioannidis J, Georgiou I, Tsatsoulis A . The Sp1 COLIA1 gene polymorphism, and not vitamin D receptor or estrogen receptor gene polymorphisms, determines bone mineral density in postmenopausal Greek women. Osteoporos Int. 2001; 12(4):326-31. DOI: 10.1007/s001980170123. View

Mann V, Ralston S . Meta-analysis of COL1A1 Sp1 polymorphism in relation to bone mineral density and osteoporotic fracture. Bone. 2003; 32(6):711-7. DOI: 10.1016/s8756-3282(03)00087-5. View

Bustamante M, Nogues X, Enjuanes A, Elosua R, Garcia-Giralt N, Perez-Edo L . COL1A1, ESR1, VDR and TGFB1 polymorphisms and haplotypes in relation to BMD in Spanish postmenopausal women. Osteoporos Int. 2006; 18(2):235-43. DOI: 10.1007/s00198-006-0225-8. View

Harris S, Patel M, Cole D, Dawson-Hughes B . Associations of the collagen type Ialpha1 Sp1 polymorphism with five-year rates of bone loss in older adults. Calcif Tissue Int. 2000; 66(4):268-71. DOI: 10.1007/pl00005842. View

Michaelsson K, Melhus H, Ferm H, Ahlbom A, Pedersen N . Genetic liability to fractures in the elderly. Arch Intern Med. 2005; 165(16):1825-30. DOI: 10.1001/archinte.165.16.1825. View

Efstathiadou Z, Tsatsoulis A, Ioannidis J . Association of collagen Ialpha 1 Sp1 polymorphism with the risk of prevalent fractures: a meta-analysis. J Bone Miner Res. 2001; 16(9):1586-92. DOI: 10.1359/jbmr.2001.16.9.1586. View

Ralston S, Galwey N, Mackay I, Albagha O, Cardon L, Compston J . Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study. Hum Mol Genet. 2005; 14(7):943-51. DOI: 10.1093/hmg/ddi088. View

10.

Lau J, Ioannidis J, Schmid C . Quantitative synthesis in systematic reviews. Ann Intern Med. 1998; 127(9):820-6. DOI: 10.7326/0003-4819-127-9-199711010-00008. View

11.

Aerssens J, Dequeker J, Peeters J, Breemans S, Broos P, Boonen S . Polymorphisms of the VDR, ER and COLIA1 genes and osteoporotic hip fracture in elderly postmenopausal women. Osteoporos Int. 2000; 11(7):583-91. DOI: 10.1007/s001980070079. View

12.

Ioannidis J . Why most published research findings are false. PLoS Med. 2005; 2(8):e124. PMC: 1182327. DOI: 10.1371/journal.pmed.0020124. View

13.

Yamada Y, Ando F, Niino N, Shimokata H . Association of a -1997G-->T polymorphism of the collagen Ialpha1 gene with bone mineral density in postmenopausal Japanese women. Hum Biol. 2005; 77(1):27-36. DOI: 10.1353/hub.2005.0035. View

14.

Bernad M, Martinez M, Escalona M, Gonzalez M, Gonzalez C, Garces M . Polymorphism in the type I collagen (COLIA1) gene and risk of fractures in postmenopausal women. Bone. 2002; 30(1):223-8. DOI: 10.1016/s8756-3282(01)00639-1. View

15.

Styrkarsdottir U, Halldorsson B, Gretarsdottir S, Gudbjartsson D, Walters G, Ingvarsson T . New sequence variants associated with bone mineral density. Nat Genet. 2008; 41(1):15-7. DOI: 10.1038/ng.284. View

16.

van Meurs J, Trikalinos T, Ralston S, Balcells S, Brandi M, Brixen K . Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA. 2008; 299(11):1277-90. PMC: 3282142. DOI: 10.1001/jama.299.11.1277. View

17.

Ashford R, Luchetti M, McCloskey E, Gray R, Pande K, Dey A . Studies of bone density, quantitative ultrasound, and vertebral fractures in relation to collagen type I alpha 1 alleles in elderly women. Calcif Tissue Int. 2001; 68(6):348-51. DOI: 10.1007/s002230010010. View

18.

Ioannidis J, Trikalinos T . An exploratory test for an excess of significant findings. Clin Trials. 2007; 4(3):245-53. DOI: 10.1177/1740774507079441. View

19.

Heegaard A, Jorgensen H, Vestergaard A, Hassager C, Ralston S . Lack of influence of collagen type Ialpha1 Sp1 binding site polymorphism on the rate of bone loss in a cohort of postmenopausal danish women followed for 18 years. Calcif Tissue Int. 2000; 66(6):409-13. DOI: 10.1007/s002230010083. View

20.

Gerdhem P, Brandstrom H, Stiger F, Obrant K, Melhus H, Ljunggren O . Association of the collagen type 1 (COL1A 1) Sp1 binding site polymorphism to femoral neck bone mineral density and wrist fracture in 1044 elderly Swedish women. Calcif Tissue Int. 2003; 74(3):264-9. DOI: 10.1007/s00223-002-2159-2. View