**6. Collagen, type II, alpha 1 (COL2A1) gene**

Solomon *et al.* [80] suggest that the human type II collagen gene, COL2A1, has been assigned to chromosome 12.

Law et al. [81, 82] said a cosmid clone containing the entire human type II alpha one collagen gene (COL2A1) was used as a probe in the Southern analysis of DNA from a panel of human/hamster somatic cell hybrids containing different portions of human chromosome 12. Two of the hybrids exhibited a similar terminal deletion q14.3----qt, but one was positive for the gene while the other was negative. Therefore, the gene must reside in the region q14.3.

Holderbaum *et al.* [83, 84] referred a single base change resulting in the substitution of Cys for Arg at position 519 of the type II collagen triple helix is a predisposing factor in the pathogenesis of a precocious-onset form of familial Osteoarthritis associated with a mild chondrodysplasia. Cartilage obtained at the time of total knee replacement in a patient with the Arg-Cys519 mutation was used to investigate the expression of Col2A1 alleles. Using PCR assisted amplification of mRNA with specific amplification of a region of Col2A1 message encompassing exons 31-34, followed by single-strand conformation polymorphism and sequence analyses, we have found transcription products of both mutant and normal type II collagen alleles. Further analysis of the sequence of these exons provides evidence that the Arg-Cys519 mutation arose independently in at least two of the three known affected families. The presence of both mutant and normal alleles of Col2A1 in cDNA derived from cartilage obtained from this patient suggests that Cys519-containing type II collagen may continue to be produced even in advanced stages of Osteoarthritis.

**233**

*Genetics in Osteoarthritis Knee*

chondrogenesis [85].

of the knee [86–89].

*DOI: http://dx.doi.org/10.5772/intechopen.93890*

On the other hand, mutations in Type II procollagen (COL2A1) can cause a hereditary form of the joint disorder with a broad spectrum of phenotypes ranging from primary OA with mild chondrodysplasia, mild spondyloepiphyseal dysplasia and osteonecrosis to severe generalized OA, including achondrogenesis and hypo-

The COL2A1 gene appears to play a crucial role in OA pathogenesis because the protein encoded is the most abundant in articular cartilage. However, results of the studies searching for a relationship between COL2A1 and OA are controversial, due to that an association with specific genotypes has been reported in some studies, whereas others have denied this. We found no association between OA of the knee and COL2A1 gene polymorphism in the overall sample. Nevertheless, when the association was analyzed according to radiologic grade, a significant relationship was denoted in OA grade 4 with allele p (Pp/pp) [OR (95% CI) 4.1 (1.2¡14.6)] independently of gender, age, and BMI; this indicates that in Mexican Mestizo population, a COL2A1 gene polymorphism is associated with advanced stages of OA

The study of Mu *et al.* [90] does not fully support that COL2A1 could be implicated in primary OA of other non-Asian ethnic groups since ethnic variability in gene susceptibility is very well documented. The clinical features of early-onset OA, mild clinical phenotypes and one patient with osteonecrosis of the femoral head strongly suggested that COL2A1 may also be the underlying cause of OA in our family. Linkage analysis and direct sequencing of COL2A1, however, clearly rule out this possibility. Kannu *et al.* [91] have been described COL2A1 mutations in association with bilateral hip disease and Osteoarthritis in the second decade of life but without ocular abnormalities or short stature. Xu *et al.* [92] investigate the relationships between two COL2A1 single nucleotide polymorphisms (SNPs; T2088C and

Loughlin *et al.* [93] said that IL-1 is the primary catabolic cytokine of the OA joint and can stimulate the synthesis of several proteinases, which can result in the breakdown of cartilage extracellular matrix proteins. The 2 IL-1 genes (*IL1A* and *IL1B*) and the gene encoding IL-1Ra (*IL1RN*) are located on chromosome 2q13 within a 430-kb genomic fragment [94]. Loughlin *et al.* 2002 reported that IL-1R antagonist (IL-1Ra) competes with IL-1 for binding to the IL-1 receptors and can act as an inhibitor of cartilage loss. When the catabolic and anabolic activities of the cytokines are balanced, cartilage integrity is maintained. If there is an imbalance favoring catabolism, however, cartilage destruction can proceed, resulting in OA. It is, therefore, reasonable to propose that a proportion of the genetic susceptibility to OA may be encoded for by variation in the activity of interleukins and that for chromosome 2q this susceptibility could reside within the IL-1 gene clusters. Stern *et al.* [95] reported that IL1B 5810 G > A SNP genotypes marker were not in Hardy-Weinberg equilibrium (p < 0.05 in both non-erosive and erosive hand OA subgroups). Statistically significant association with the IL1B 5810 AA genotype was found in the erosive hand OA subgroup (relative risk 3.8, p = 0.007). This IL1B 5810 AA genotype association was also significant between erosive and non-erosive hand OA subjects (relative risk 4.01, p = 0.008). As expected, significant linkage disequilibrium was present between IL1B 5810 SNP and IL1A (−)889 SNP, other IL1B SNPs, and the nearest IL1RN SNP examined. The IL1B 5810A allele occurs most frequently on haplotypes with the SNP alleles IL1B 1423C, IL1B 1903 T, IL1B 5887C, and IL1A (−)889C. Genotypes at null loci failed to show evidence suggesting

G4006A) and Osteoarthritis (OA) in Han Chinese women.

**7. Interleukin 1 beta (IL1B) gene**

#### *Genetics in Osteoarthritis Knee DOI: http://dx.doi.org/10.5772/intechopen.93890*

On the other hand, mutations in Type II procollagen (COL2A1) can cause a hereditary form of the joint disorder with a broad spectrum of phenotypes ranging from primary OA with mild chondrodysplasia, mild spondyloepiphyseal dysplasia and osteonecrosis to severe generalized OA, including achondrogenesis and hypochondrogenesis [85].

The COL2A1 gene appears to play a crucial role in OA pathogenesis because the protein encoded is the most abundant in articular cartilage. However, results of the studies searching for a relationship between COL2A1 and OA are controversial, due to that an association with specific genotypes has been reported in some studies, whereas others have denied this. We found no association between OA of the knee and COL2A1 gene polymorphism in the overall sample. Nevertheless, when the association was analyzed according to radiologic grade, a significant relationship was denoted in OA grade 4 with allele p (Pp/pp) [OR (95% CI) 4.1 (1.2¡14.6)] independently of gender, age, and BMI; this indicates that in Mexican Mestizo population, a COL2A1 gene polymorphism is associated with advanced stages of OA of the knee [86–89].

The study of Mu *et al.* [90] does not fully support that COL2A1 could be implicated in primary OA of other non-Asian ethnic groups since ethnic variability in gene susceptibility is very well documented. The clinical features of early-onset OA, mild clinical phenotypes and one patient with osteonecrosis of the femoral head strongly suggested that COL2A1 may also be the underlying cause of OA in our family. Linkage analysis and direct sequencing of COL2A1, however, clearly rule out this possibility. Kannu *et al.* [91] have been described COL2A1 mutations in association with bilateral hip disease and Osteoarthritis in the second decade of life but without ocular abnormalities or short stature. Xu *et al.* [92] investigate the relationships between two COL2A1 single nucleotide polymorphisms (SNPs; T2088C and G4006A) and Osteoarthritis (OA) in Han Chinese women.
