Our study has shown the statistically significant association between polymorphism in promoter of GDF5 gene (rs143383) and knee osteoarthritis in Thai population. We found that T allele in GDF5 polymorphism was a significant risk factor for knee osteoarthritis with Odds ratio 1.53 (95%C.I. = 1.01-2.31). When analysed by genotype, it was found that the TT genotype increased risk of knee OA, whereas TC has not shown any correlation. Regarding these finding, it suggests that this polymorphic gene might be expressed as the autosomal recessive type. The GDF5 gene is located on the chromosome 20q11.2 and it regulates the expression of GDF5 protein. It is categorised in the class of bone morphogenetic protein (BMP) . It involves in development of bone and cartilage, particularly in endochondral ossification process [24, 25]. The mutation of GDF5 associates with generalised osteoarthritis and skeletal-related congenital diseases. Acromesomelic chondrodysplasia; Grebe type and Hunter-Thompson type is autosomal recessive form which is rare hereditary skeletal disorders. They are presented by short status, abnormal limbs development. Brachydactyly type A1, A2 and C and symphalangism proximal syndrome are inherited malformation presented with abnormal morphology of hand and finger. Multiple synostoses syndrome type 2 is an autosomal dominant condition characterised by progressive joint fusions and progressive conductive deafness. Du Pan syndrome is a rare autosomal recessive; the patient presents with absence of the fibulae and severe acromesomelic limb shortening with small, non-functional toes. These abnormal conditions have been reported that they have a mutation in GDF5 gene, thus they support that GDF5 plays a role in skeletal development [26, 27]. Recently, it has been reported that GDF5 deficiency mice had the delay fracture healing process that impaired the cartilaginous matrix deposition in the callus and reduced callus cross-sectional area .
The functional study of this polymorphism has been demonstrated; T allele in rs143383 was associated with the decrease of GFD5 molecule expression and might increase susceptibility to osteoarthritis . Moreover, it has been report that the differential binding of deformed epidermal autoregulatory factor 1 (DEAF-1) can modulate the expression of GDF5 via this polymorphism . It is believed that GDF5 plays role in the regulation of the chondrogenic cell growth and differentiation. These evidences support the function of GDF5 gene which might indicate the importance of this polymorphism in osteoarthritis etiology. As the result, many scientists have been working for study the association of this polymorphism in GDF5 gene. Recently, a large scale association study between GDF5 gene and osteoarthritis has revealed the genetic susceptibility of polymorphism in the GDF5; rs143383 with odds ratio 1.12 (95%CI 0.99-1.31) . This study included the data from diverse ethnics which have been reported in the recent literatures. However, the magnitude of this association is smaller than the Asian ethnic, it has been reported from Japan that odds ratio is 1.79 (P = 1.18 × 10-13) for GDF5 polymorphism with per-risk allele (T) odds ratio by Miyamoto et al . The magnitude of the association of GDF5 polymorphism is different between Caucasian ethnic and Asian ethnic. Furthermore, the association of this polymorphism from Greek and Korean study cannot demonstrate the association of GDF5 polymorphism [20, 30]. We have also reported the polymorphism in ESR1, which is associated with knee OA in Korean population. However, our result did not show any statistically significant difference . Thus, these evidences can imply that the association of ethic and genetic susceptibility in osteoarthritis might not be consistent among the different populations and cannot be applied to others.
In addition, there is a report that GDF5 polymorphism (rs143383) also predisposes to Lumbar disc degeneration in women. Lumbar disc degeneration which is defined by disc space narrowing and the presence of osteophytes significantly associates with GDF5 polymorphism from cohorts from Northern Europe in women, with an odds ratio (OR) of 1.72 (95% CI 1.15-2.57) . The genome-wide association study from Finland and Sardinia shows the common variants in GDF5 contribute to height difference . The GDF5 gene might be involved skeletal growth and development and GDF5 variants might play role in pathogenesis of bone and cartilage diseases.
Although the sample size in our study was small when compared to previous studies, these limited samples were sufficient for demonstrating the statistically significant association of rs143383 in GDF5 core promotor area. Furthermore, the population in our study was in homogeneity and the distribution between the case and control groups was in the Hardy Weinberg's equilibrium. Therefore, our study can represent the significant susceptibility of GDF5 in knee osteoarthritis in Thai ethnic. Our findings have emphasized this association that the susceptibility of the polymorphism in GDF5 among the Asian population because the magnitude of association is close to Japan and Chinese population. It is possible that Thai population ethnic is believed to be close to Chinese ancestry. Finally, we decide to leave some suggestions in genetic susceptibility study. Firstly, it is important to study the genetic susceptibility in common disease as this might be valuable for further investigation in order to understand the disease at molecular level or even apply to use for disease screening. More important, the association between polymorphism and disease might not similar in different ethics; therefore the genetic susceptibility from different ethics is required and the meta-analysis should be conducted in the adjacent area or similar genetic background. Lastly, other modern technology such as microarray technique should be employed for investigation of genetic susceptibility in osteoarthritis.