COLIA1 (Collagen type I α1 Sp1 polymorphism in LASA)


Contact: Natasja van Schoor

The collagen type I α1 gene (COLIA1) gene encodes a part of type I collagen, which is the major protein in bone. Mutations in this gene cause the connective tissue disorders Ehlers-Danlos syndrome, characterised by cutis laxa, hypertension of the joints and low bone mass, and osteogenesis imperfecta (OI), characterised by very low bone mass and an increased fracture risk [1]. In 1996, Grant et al. [2] described a guanine (G)-to-thymidine (T) polymorphism affecting a binding site for the transcription factor Sp1 in the first intron of COLIA1. This study showed that the T-allele was more prevalent in patients with osteoporosis than in controls. Therefore, the COLIA1 Sp1 polymorphism seems a likely candidate gene to be involved in osteoporosis or joint disorders.

Measurements in LASA

Blood collection
Blood samples were obtained from respondents who participated in the medical interview of the second data collection cycle of LASA (1995/96), who were born in 1930 or before (aged 65 years and older as of January 1, 1996) and were living in Amsterdam, Zwolle and Oss and surroundings (n=1509). At the visit in the hospital or health care center, morning blood samples (EDTA-blood) were obtained (n=1321), centrifuged and frozen at -80° C until DNA isolation and COLIA1 genotyping in 1999/2000. Adequate buffy coats for DNA isolation were obtained in 966 respondents. At the Endocrine Laboratory of the VUMC (HW van Essen), the G to T polymorphism in the Sp1 binding site in the COLIA1 gene was detected by a PCR-based method, described by Uitterlinden et al. [3]. Briefly, DNA was extracted from buffy coats by standard phenol extraction methods. PCR was performed with mismatch primers as described by Grant et al. [2], which introduce a restriction site for MscI if the polymorphism is present. After digestion with MscI and gelelectrophoresis, the alleles were defined as G or T according to the absence or presence of the restriction site, respectively. The genotypes were named GG, GT or TT, which correspond with SS, Ss and ss, respectively, the designation previously used.

Measurement procedure & variable information
There are two ways to classify the COLIA1 Sp1 polymorphism: 1) by genotype (GG, GT, TT) (Table 2) or 2) by allele (G or T). Some studies [2,3] suggest that there may be a dose-response relationship between the collagen type I α1 (COLIA1) Sp1 and osteoporosis, but results are inconsistent. If one is interested to examine a dose-response association, the polymorphism must be classified by genotype, because the strongest association may be found for the TT genotype. To increase power, the classification by allele can be used.

Availability of data per wave

Table 1. Numbers per wave








All regions





*  2B=baseline second cohort;
    3B=baseline third cohort

Table 2. COLIA1 Sp1 polymorphism by genotype














Previous use in LASA
In LASA, Pluijm et al. (2004) examined the association between collagen type I α1 (COLIA1) Sp1 polymorphism and osteoporosis and/or intervertebral disc degeneration in older men and women. In this study, it was demonstrated that persons with a Sp1 polymorphism of the COLIA1 gene had an increased risk of intervertebral disc degeneration. Although the results indicate that male carriers of the T-allele had higher levels of serum osteocalcin, the COLIA1 Sp1 polymorphism was not associated with any other measure of osteoporosis in men and women. However, Ralston et al. (2006) demonstrated in a multicentre study that the COLIA1 SP1 polymorphism was associated with reduced BMD and and could predispose to incident vertebral fractures in women, independent of BMD. 

  • Pluijm SM, van Essen HW, Bravenboer N, Uitterlinden AG, Smit JH, Pols HA, Lips P. Collagen type I alpha1 Sp1 polymorphism, osteoporosis, and intervertebral disc degeneration in older men and women. Ann Rheum Dis 2004;63:71-7.
  • Ralston SH, Uitterlinden AG, Brandi ML, Balcells S, Langdahl BL, Lips P, Lorenc R, Obermayer-Pietsch B, Scollen S, Bustamante M, Husted LB, Carey AH,Diez-Perez A, Dunning AM, Falchetti A, Karczmarewicz E, Kruk M, van Leeuwen JP, van Meurs JB, Mangion J, McGuigan FE, Mellibovsky L, del Monte F, Pols HA, Reeve J, Reid DM, Renner W, Rivadeneira F, van Schoor NM, Sherlock RE, Ioannidis JP; GENOMOS Investigators. Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study. PloS Medicine 2006; 3(4):e90.


  1. Byers PH. Brittle bones--fragile molecules: disorders of collagen gene structure and expression. Trends Genet 1990;6:293-300.
  2. Grant SF, Reid DM, Blake G, Herd R, Fogelman I, Ralston SH. Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene. Nat Genet 1996;14:203-5.
  3. Uitterlinden AG, Burger H, Huang Q, Yue F, McGuigan FE, Grant SF et al. Relation of alleles of the collagen type Ialpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women. N Engl J Med 1998; 338:1016-21.
  4. Pluijm SM, van Essen HW, Bravenboer N, Uitterlinden AG, Smit JH, Pols HA, Lips P. Collagen type I alpha1 Sp1 polymorphism, osteoporosis, and intervertebral disc degeneration in older men and women. Ann Rheum Dis. 2004;63:71-7.