The prevalence of symptomatic osteoarthritis (OA) of the hip is ∼3% among adults 30 years and older in the US, and accounts for a significant health care burden (1). Multiple risk factors for OA of the hip, including age, obesity, joint injury, occupational factors, sex, and ethnicity, among others, have been well established (1). Furthermore, it is also known that genetic factors play a strong role in the development of hip OA. Several twin and family studies (2, 3) have demonstrated a significantly increased risk for OA of the hip among siblings of affected individuals. In addition, genome-wide scans, fine-scale mapping, and other association analyses have identified several loci that may be associated with OA of the hip (2, 3).
Recently, type I collagen α1 (COL1A1) has emerged as a candidate gene of interest in OA (3). Type I collagen is a heterotrimer consisting of 2 α1 chains and 1 α2 chain, and is the major protein in bone (4). The gene encoding COL1A1 is an important candidate for the regulation of bone metabolism and bone mass, and mutations in this gene are known to cause osteogenesis imperfecta (4). Grant and colleagues have identified a G-to-T polymorphism in a transcription factor binding site for Sp1 in the first intron of the COL1A1 gene (5). Several studies have examined the relationship of this polymorphism to bone mineral density (BMD), osteoporosis, and fracture (5–8). In addition, higher adjusted BMD increases the risk of OA of the hip (9–11).
Studies of the association of the COL1A1 Sp1 polymorphism and OA have produced conflicting results, with one showing a positive association with OA of the knee and hip (12) and two showing a lack of an association with OA of the spine and hip (3, 13). However, the studies may have been underpowered to detect significant associations. Since the material properties of the subchondral bone are believed to be associated with both the development and the progression of OA (14), and the COL1A1 Sp1 polymorphism increases the risk of osteoporosis due to changes in both bone composition and bone strength (7), we hypothesized that subjects with the COL1A1 Sp1 polymorphism might have a different risk for OA of the hip. To test this hypothesis, we examined the association between the COL1A1 Sp1 binding site polymorphism and radiographic OA of the hip in a large cohort of older postmenopausal women, in an effort to further elucidate the role of COL1A1 in the pathogenesis of OA of the hip.
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The present study addressed the association between the COL1A1 Sp1 binding site polymorphism and the risk of radiographic OA of the hip. While there was no association between the Sp1 polymorphism and radiographic hip OA defined by any of the 3 different criteria or by osteophytosis as the predominant radiographic feature, there was a significant reduction in the odds of radiographic hip OA as characterized by severe JSN among subjects with the T/T genotype. Because joint space narrowing observed by hip radiography is a surrogate measure of articular cartilage loss, we speculate that this effect may reflect the role of the COL1A1 genotype on articular cartilage or subchondral bone metabolism in the development of hip OA.
The relationship between the COL1A1 Sp1 binding site polymorphism and osteoporosis, as well as fracture risk, has been well established (5–8). Moreover, haplotype analysis has demonstrated that the relationship with fracture risk is specific for the Sp1 site, rather than other polymorphisms (8). The Sp1 transcription factor binding site is located in the first intron of the COL1A1 gene, a region that has been identified as important for the regulation of collagen transcription (7). In a series of experiments, Mann et al demonstrated that the G/T genotype was associated with altered production of the collagen protein, with an increased ratio of α1(I) to α2(I) protein chains (7). This result was accompanied by an increase in expression of COL1A1 messenger RNA (mRNA) relative to COL1A2 mRNA and reduced biomechanic strength among those with the G/T genotype versus those with the G/G genotype. In the current study, we found that women with 2 copies of the variant T allele had decreased hip OA risk, but this will have to be evaluated in another study population.
At present, it is unclear how altered collagen production and reduced bone strength as a result of the presence of the T allele contributes to the development of hip OA characterized by severe joint space narrowing. These are recognized subsets of radiographic hip OA, and we don't know about differences in pathogenesis. Higher adjusted levels of BMD are associated with increased odds of radiographic hip OA with osteophytes (9–11) but not radiographic hip OA characterized by JSN alone. Since the T/T genotype is associated with lower BMD and increased risk of fractures, we speculate that it is also associated with radiographic OA of the hip characterized by severe JSN. This association was present, however, even after adjustment for BMD. This suggests that bone strength may be important. While Radin et al found that changes in the subchondral bone strength preceded articular cartilage loss in a rabbit model of OA (13), Burr has shown that increased bone turnover and decreased subchondral bone strength are both important in the development of OA with cartilage loss (19). Since the pathogenesis of hip OA may differ in these 2 subtypes of OA, it is possible that altered collagen in subjects with this COL1A1 polymorphism may result in weaker bone that slows the development of OA. Furthermore, this latter effect appears to be mediated by increased joint space narrowing. Additional work is now required to determine how altered bone composition adjacent to the hip joint may reduce the risk of hip OA.
Two previous studies have investigated the role of COL1A1 in OA. Aerssens et al found no association of the COL1A1 Sp1 polymorphism with hip OA in a case–control study comparing postmenopausal women with THR for OA of the hip and those with no hip OA (14). Given the small sample of only 75 cases, it is possible that the lack of association was due to insufficient power to detect a difference between the groups. The study by Aerssens and colleagues focused on elderly women with THR, while our study focused on women with radiographic OA of the hip and excluded subjects with hip replacement. These differences may also explain our divergent results. In a separate proband–spouse case–control study, Loughlin et al found a weak association of the COL1A1 Sp1 polymorphism with hip or knee OA (12). Compared with female controls, elderly women with OA requiring hip or knee replacement had a significantly different genotype distribution, with a relative increase in the G allele (OR 1.58, 95% CI 1.09–2.29). However, this effect did not remain significant after stratifying by hip or knee replacement (11). It is possible that these results are consistent with ours, in that the G allele may be associated with the development of hip OA, while the T allele may be protective against hip OA. Also, Loughlin et al defined cases by joint replacement, so their results may not be comparable with ours.
This study offers several strengths, including its large community-based cohort of elderly white women and a validated radiographic scoring system making phenotype-specific definitions to fully characterize the extent of radiographic hip OA. However, there are also several potential limitations. Our definitions of radiographic OA of the hip may not be comparable with other grading schemes. Also, despite the large number of subjects in our cohort, we only had 571 subjects with radiographic hip OA, and the numbers of participants were smaller when we subdivided by either genotype or individual radiographic features. Another potential limiting factor is that our study participants were all white women age 65 years and older, and our findings may not be generalizable to other populations.
In summary, we found that the T/T genotype at a binding site for the Sp1 transcription factor in COL1A1 was associated with reduced risk of radiographic OA of the hip as defined by severe joint space narrowing. While our findings require confirmation in other populations, they suggest that the COL1A1 Sp1 genotype may be associated with a reduction in the development of hip OA, and that this effect may be mediated by changes in bone quantity and/or quality. In addition, our results highlight the importance of phenotypic definition in the genetic analyses of OA susceptibility.