TNF-α and TNF-β Polymorphisms are Associated with Susceptibility to Osteoarthritis in a Korean Population.

Osteoarthritis (OA) is a slowly progressive degenerative joint disease of the articular cartilage that generally occurs in weight-bearing joints and fingers of elderly individuals. OA is characterized by the destruction of the articular cartilage, subchondral bone alterations, and synovitis. Clinical manifestations of OA may include joint pain, swelling, stiffness, and even the loss of some bodily function. The development of OA is a multifactorial process associated with a variety of risk factors, including genetic predispositions, aging, obesity, inflammation, and excessive mechanical loading. In Korea, radiographic and symptomatic knee OA affects 37.3% and 24.2% of elderly individuals, respectively.1 Given the high morbidity and huge economic and personal burdens of OA, there is an urgent need for defining the pathogenesis that contributes to OA development. Recently, new single-nucleotide polymorphisms (SNPs) in the human leukocyte antigen (HLA) class II/III region have been associated with susceptibility to knee OA,2,3 implicating immunologic and inflammatory mechanisms in the etiology and pathophysiology of OA. Both the tumor necrosis factor (TNF)-α and TNF-β genes are located on chromosome 6p21.3 and are closely linked to the HLA.4 This close genetic linkage indicates the possible involvement of the TNF in inflammatory autoimmune diseases.4,5 In addition, polymorphic major histocompatibility complex ancestral haplotypes influence TNF activity.6 Thus, the activity of TNF-α and TNF-β genes may play an important role in the development of knee OA in the Korean population. The TNF is known as a multifunctional pro-inflammatory cytokine that is involved not only in various physiological processes but also in pathological processes, including inflammation, immunoregulation, proliferation, and apoptosis. TNF-α (also known as cachectin) and TNF-β (formerly known as lymphotoxin) are members of the TNF superfamily. Some of the biological properties of TNF-α and TNF-β suggest that these cytokines may be involved in the destruction of cartilages.7 TNF-α levels are elevated in OA patients' synovial fluid, synovial membrane, subchondral bone, and cartilage.8 However, TNF-β levels are detected differently in inflammatory and autoimmune diseases. SNPs include some differences or variations in the genome between individuals. Some of these polymorphic variants are functionally expressed, suggesting that SNPs are among the factors associated with susceptibility to diseases. The transcriptional regulation of the TNF gene is essential for avoiding the deleterious effects of the inappropriate or excessive synthesis of the TNF.9 Therefore, genetic variations within the TNF promoter may influence the transcription and expression of the TNF. Polymorphisms in the promoter region of the TNF gene have been detected at -G238A, -G308A, -C863A, and -C857A in the TNF-α promoter and at +G252A and +G318C in intron 1 of the TNF-β gene. The up-regulation of TNF-α expression is involved in the pathogenesis of a large variety of illnesses with inflammatory and autoimmune components. Previous research has demonstrated that TNF-α production is higher in carriers of the -308A allele than in -308G carriers, indicating that this polymorphism has functional implications for transcriptional activation and subsequent increases in inflammation.10 The TNFB +252G allele has been associated with higher TNF-β production at both the mRNA and protein levels.11,12 However, some studies have found that the TNFB +252A allele is more likely to increase TNF-α secretory capacity and plasma TNF-α levels than the TNFB +252G allele.13 In view of these considerations, this study focuses on the genetic susceptibility of TNF-α and TNF-β polymorphisms for OA. To determine the relationships between TNF-α and TNF-β gene polymorphisms and individual susceptibility to OA in a Korean population, this study examines the percentages of genotypes and alleles for the TNF-α polymorphism (TNFA -G308A) by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the TNF-β polymorphism (TNFB +G252A) by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) in 301 patients with OA and 291 healthy individuals.