rs1800012
badMag 4.5This is a intron variant variant in the COL1A1 gene.
Key Literature Trait Associations
Osteoporosis
The T allele ('s' allele) at rs1800012 reduces Sp1-binding-driven COL1A1 transcription, producing weaker bone matrix. A landmark meta-analysis of 32 studies (24,511 participants, 7,864 fractures) found TT homozygotes had significantly lower lumbar spine BMD (−0.13 units, p=0.01) and femoral neck BMD (−0.16 units, p=1×10⁻⁶), with 1.31-fold increased clinical fracture risk and 1.34-fold increased vertebral fracture risk. A more recent meta-analysis of 30 studies (2,943 cases, 4,724 controls, 2024) confirmed significant associations across allelic, dominant, and heterozygote models, particularly in European cohorts. Effects are modest and may be subject to publication bias.
Soft Tissue Injury Susceptibility
rs1800012 (Sp1 binding site polymorphism, +1245 G>T) in COL1A1 affects type I collagen production. The rare T allele alters an Sp1 transcription factor binding site in intron 1, increasing the alpha1(I)-to-alpha2(I) collagen chain ratio. This produces altered collagen fibril architecture in tendons and ligaments. Paradoxically, the T allele appears protective against cruciate ligament rupture (OR ~0.43) and shoulder dislocations, but is associated with reduced bone mineral density and increased osteoporotic fracture risk.
Intervertebral disc degeneration
The G allele at rs1800012 is associated with higher susceptibility to intervertebral disc degeneration (IVDD). A meta-analysis of 7 studies (1,339 cases, 5,406 controls) found the GG genotype was associated with significantly greater IVDD risk compared to TT homozygotes (dominant model OR=0.31 for TT/GT vs GG, p=0.008), with consistent effects also observed for severe IVDD. No significant association with osteoarthritis was found in the same meta-analysis, suggesting the effect is specific to disc pathology rather than joint cartilage.
Cervical insufficiency
A Turkish case-control study (93 cervical insufficiency patients, 103 healthy controls) found significant differences in rs1800012 genotype frequencies between groups (p=0.049), with the TT genotype conferring protection against cervical insufficiency. The G allele (GG/GT genotypes) was overrepresented in cases. Carriers of TT genotype also showed a lower rate of cerclage history (p=0.010). This is a single small study and findings require independent replication before clinical relevance can be established.
▶ClinVar annotation
Bone mineral density variation quantitative trait locus
View on ClinVar →▶Research that mentions this SNP (7)
▶Exploring new genetic variants within COL5A1 intron 4‐exon 5 region and TGF‐β family with risk of anterior cruciate ligament rupturesReviewN=9,720Mary‐Jessica N. Laguette et al.(2020)· Journal of Orthopaedic Research
This systematic review analyzed 24 studies examining 31 genes and 62 genetic variants associated with anterior cruciate ligament rupture (ACLR). Key findings show mixed evidence for collagen variants: COL1A1 rs1800012 showed protective association in European ancestry populations (OR=2.8, p=0.040), while COL1A2 rs42524 and rs2621215 conferred increased risk (OR=5.73 and 4.29 respectively). VEGFA polymorphisms rs2010963 and rs699947 showed conflicting associations across studies, and most major variants in IL6, IL1B, MMP genes, and inflammatory markers showed no consistent associations with ACLR across populations, highlighting the need for gender and ancestry-stratified analyses.
▶A haplotype derived from the common variants at the −1997G/T and Sp1 binding site of the COL1A1 gene influences risk of postmenopausal osteoporosis in IndiaAssociationN=349Monica Singh et al.(2013)· Rheumatology International
This case-control study examined two COL1A1 SNPs (rs1107946 and rs1800012) in 349 postmenopausal Indian women (145 osteoporotic, 87 osteopenic, 117 normal). The GT haplotype conferred a threefold higher risk of osteoporosis (OR 3.12, 95% CI 1.24-8.88, P=0.008) after adjusting for age, BMI, and years since menopause. Individual SNP analysis showed allele dose effects with lumbar spine and femoral neck BMD.
▶Investigation of variants within the COL27A1 and TNC genes and Achilles tendinopathy in two populationsAssociationN=890Colleen J. Saunders et al.(2013)· Journal of Orthopaedic Research
PhD dissertation examining genetic variants in collagen genes (COL22A1, COL27A1, COL11A1) and anterior cruciate ligament injury risk in Polish athletes. Paper 1 is a systematic review of genetic determinants of ACL rupture. Papers 2 and 3 are case-control association studies finding no significant associations between SNPs rs11784270/rs6577958 (COL22A1), rs946053 (COL27A1), and rs3753841 (COL11A1) and non-contact ACL injury risk in Polish athletes.
▶COL1A1 haplotypes and hip fractureAssociationN=600Roser Urreizti et al.(2012)· Journal of Bone and Mineral Research
A case-control study of 203 Spanish hip fracture patients and 397 controls examined three COL1A1 SNPs (rs1107946, rs11327935, rs1800012) for association with fracture risk. The study failed to replicate a previously reported T-delT-T haplotype association but found a weak but significant (p=0.03) association with the rare G-insT-T haplotype, which was 2.5-fold overrepresented in fracture cases (3.0% vs 1.2%).
▶Polymorphisms in the 5′ flank of COL1A1 gene and osteoporosis: meta-analysis of published studiesMeta-analysisN=24,511Jin H. et al.(2011)· Osteoporosis International
A meta-analysis of 32 studies including 24,511 participants and 7,864 fractures examined three polymorphisms in the 5' flanking region of COL1A1. The Sp1 binding site polymorphism (rs1800012) showed modest associations with reduced BMD (0.13-0.16 units lower at spine and hip in TT vs GG homozygotes, p=0.01 to 1×10⁻⁶) and increased fracture risk (OR 1.31 for all fractures, OR 1.34 for vertebral fractures in females). The -1997G/T (rs1107946) and -1663in/delT (rs2412298) polymorphisms showed limited association with BMD but insufficient data for fracture analysis.
▶The role of cigarette smoking and statins in the development of postmenopausal osteoporosis: a pilot study utilizing the Marshfield Clinic Personalized Medicine CohortAssociationN=602Giampietro PF et al.(2010)· Osteoporosis International
A nested case-control study of 309 postmenopausal osteoporotic women and 293 controls found that the IL6 -634G>C SNP (rs1800796) was associated with osteoporosis (OR 2.51, p=0.0047), independent of smoking or statin use. Additionally, the LRP5 C135242T SNP (rs545382) showed association with osteoporosis specifically in cigarette smokers (OR 2.8, p=0.03), suggesting a gene-environment interaction.
▶Genetic Variation in Candidate Osteoporosis Genes, Bone Mineral Density, and Fracture Risk: The Study of Osteoporotic FracturesAssociationN=6,752Gregory J. Tranah et al.(2008)· Calcified Tissue International
A candidate gene association study of 6,752 women from the Study of Osteoporotic Fractures examined 31 polymorphisms in 18 candidate osteoporosis genes for associations with fracture risk and bone mineral density. ALOX15_G48924T (rs7220870) T/T genotype was associated with 33% higher hip fracture risk (HR=1.33, 95% CI 1.00-1.77); PRL_T228C (rs7739889) C alleles reduced nonvertebral fracture risk by ~20%; BMP2_A125611G (rs235764) G/G showed 51% higher vertebral fracture risk (OR=1.51, 95% CI 1.03-2.23); and MMP2_C595T (rs243865) T allele carriers had reduced vertebral fracture risk. No significant associations were found with total hip BMD.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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