Estrogen receptor-α gene haplotype is associated with primary knee osteoarthritis in Korean population

Abstract

Estrogen and estrogen receptors (ERs) are known to play important roles in the pathophysiology of osteoarthritis (OA). To investigate ER-α gene polymorphisms for its associations with primary knee OA, we conducted a case-control association study in patients with primary knee OA (n = 151) and healthy individuals (n = 397) in the Korean population. Haplotyping analysis was used to determine the relationship between three polymorphisms in the ER-α gene (intron 1 T/C, intron 1 A/G and exon 8 G/A) and primary knee OA. Genotypes of the ER-α gene polymorphism were determined by PCR followed by restriction enzyme digestion (PvuII for intron 1 T/C, XbaI for intron 1 A/G, and BtgI for exon 8 G/A polymorphism). There was no significant difference between primary knee OA patients and healthy control individuals in the distribution of any of the genotypes evaluated. However, we found that the allele frequency for the exon 8 G/A BtgI polymorphism (codon 594) was significantly different between primary knee OA patients and control individuals (odds ratio = 1.38, 95% confidence interval = 1.01-1.88; P = 0.044). In haplotype frequency estimation analysis, there was a significant difference between primary knee OA patients and control individuals (degrees of freedom = 7, χ 2 = 21.48; P = 0.003). Although the number OA patients studied is small, the present study shows that ER-α gene haplotype may be associated with primary knee OA, and genetic variations in the ER-α gene may be involved in OA.

Association of Single Nucleotide Polymorphisms in Estrogen Receptor Alpha Gene with Susceptibility to Knee Osteoarthritis: A Case-Control Study in a Chinese Han Population

“…Noteworthy, the C allele frequency of rs2234693 and the G allele frequency of rs9340799 in controls were 0.379 and 0.185, respectively, which were similar to those observed in the Japanese and Korean populations [13, 15] whereas different from those in European and American Caucasians to a certain degree [17, 18]. We also proposed the predisposing roles of T allele of rs2234693 in the etiology of knee OA, and this was partially in concordance with the protective effects of C allele in Japanese and Caucasians [17, 18] but against the observation that CC genotype was a risk factor of radiographic knee OA in a Rotterdam study [14].…”

Expression of Genes and Their Polymorphism Influences the Risk of Knee Osteoarthritis

“…Our data has shown significant alterations in the distribution of variant alleles of GDF-5, ESR- α , and CALM-1 in OA cases when compared to the controls. Similar to the case control studies involving Caucasians and Oriental people [ 9 , 11 , 16 – 18 , 27 ], an increase in the frequency of A allele (rs 2228480) was observed in OA patients when compared with the controls. Significant increase in the frequency of risk allele (T) of GDF-5 in cases of osteoarthritis is consistent with previous report demonstrating association of polymorphism in GDF-5 with OA [ 9 , 11 ].…”

“…Polymorphism in ESR- α gene was detected by the method of Jin et al 2004 [ 16 ]. In brief the PCR product formed was digested with BtgI for identifying (rs2228480) polymorphism.…”

“…Likewise, polymorphism in ESR- α is reported to be significantly associated with risk to OA development. A significant increase in the frequency of A allele (ESR- α , rs2228480) in patients has been associated with reduced cartilage formation that may lead to increased risk to OA [ 15 , 16 ]. Functional analysis has also indicated that the variant allele (rs12885713) of CALM-1 reduces the expression of the major cartilage matrix genes (Col 2a1 and Agc 1) that enhances the susceptibility for osteoarthritis through modulation of chondrogenic activity [ 17 ].…”

OPN gene polymorphisms influence the risk of knee OA and OPN levels in synovial fluid in a Chinese population

“…Inheritance studies involving family groups and twin pairs have demonstrated that a large proportion of OA cases can be attributed to genetic factors, suggesting that the etiology of OA clearly has a genetic component [9,10]. In recent years, a number of gene polymorphisms involved in development of knee OA have been identified, such as those localized in, or adjacent to the encoding sequences for the vitamin D receptor [11], estrogen receptor alpha [12] or calcitonin [13]. …”