Rs2073711

The rs2073711 SNP (1184T→C ) is located in exon 8 of the cartilage intermediate layer protein gene (CILP). However, CILP gene is primarily known to be expressed abundantly in intervertebral discs, and was reported to have increased expression when degeneration occurs. For the rs2073711 SNP, the ancestral allele is T and the disease associated risk allele is C. A study of Asian patients with lumbar disc disease (LDD) implicates each copy of a (C) allele of SNP rs2073711 (as oriented with respect to dbSNP) as increasing risk about 1.6 fold.

Background
Low back pain (LBP) is an enervating condition that affects 70-85% of all people during their lifetime. It can lead to decreased physical activity and quality of life, presenting considerable negative socioeconomic and health impacts on many levels. Various studies have shown that although LBP is attributed to many factors, lumbar disc degeneration is a strong contributing factor especially among young individuals.

Lumbar disc degeneration (LDD) is one of the leading causes of disability in the working-age population. Numerous studies have been conducted to understand the causes of lumbar disc degeneration. Although the etiology of the LDD is not fully understood, it is believed that both genetic and environmental factors are involved in development of the disease, and that genetic factors play a more prominent role than environmental factors. Indeed, LDD shows strong familial predisposition, and identical twins exhibit similar degeneration on magnetic resonance imaging (MRI) studies as well. Recent genetic studies reported association of several genes with LDD, supporting the idea that genetic factors are important in the etiology of LDD.

Studies
In 2005 Seki et. al, used a candidate gene case-control association study of Japanese individuals with symptomatic disc disease (N=467) and controls (N=654). The intervertebral disc contains abundant extracellular matrix proteins that play crucial roles in homeostasis. The researchers selected 30 sequences variations in 20 such genes that encode matrix proteins in intervertebral disc.

rs2073711 showed significant association with LDD ((OR 1.61, [CI 1.31 -1.98], p = 0.00020) . The rs2073711 SNP (1184T→C ) is located in exon 8 of the cartilage intermediate layer protein gene (CILP), which is expressed abundantly in intervertebral discs, and was reported to have increased expression when degeneration occurs . For the rs2073711 SNP, the ancestral allele is T and the disease associated risk allele is C. The allelic change results in a substitution of amino acid Ile395Thr. CILP proteins interact directly with TGF- β1 mediated extracellular matrix protein synthesis and functional analysis showed that the C allele was associated with increased binding and inhibition of TGF- β1, suggesting that regulation of TGF- β1 signaling by CILP might have an important role in symptomatic disc disease.

However, in 2007, another group failed to identify any relationship between the CILP 1184T/C allele and LDD in Finnish and Chinese subjects. They made the argument that if the association between the CILP 1184T/C and LDD exists, the same association would be replicable in distinct populations. They included Finnish subjects (case =243, control 259) with symptoms of LDD and Chinese individuals with MRI-defined LDD only (case = 348, control = 343) and analyzed the rs2073711 SNP as well as flanking SNPs. Their results showed that the CILP 1184T/C allele was not a major risk factor for symptoms of LDD in Finnish subjects (OR =1.35, 95% CI 0.97 to 1.87; P=0.14) or in the Chinese population (OR=1.05, 95% CI 0.77 to 1.43; P=0.71).

This study shows no evidence of association of CILP and LDD in both Finnish and Chinese population, suggesting that cartilage intermediate layer protein gene is not a risk factor for symptoms of LDD in general population. As a result, this contradictory study compelled researchers to conduct more detailed investigation on the association of CILP and LDD, especially in different ethnic populations.

A later study in 2009 on lumbar disc degeneration in Japanese collegiate judo athletes revealed that there is a significant association of the 1184T/C SNP variant at the CILP gene. The study involved 89 Japanese judo athletes, and they used MRI to define LDD and DNA sequencing to perform genotyping of the 1184T/C SNP. They calculated the odds ratio of lumbar disc degeneration with the CILP to be 2.4, with 95% confidence interval of 1.13-5.11 and p-value of 0.02, which indicates the significant risk factor of CILP for lumbar disc degeneration occurrence in Japanese collegiate judo athletes.

Another study of intervertebral disc degeneration among young Finnish adults was undertaken to assess the association between relevant candidate gene polymorphisms and moderate LDD. They investigated the associations of 19 SNPs in 16 genes with LDD among 538 young adults (46% control, 54% case). The risk of LDD was significantly higher in subjects with an allele G in IL6 SNPs rs1800795 (OR 1.45, 95% CI 1.07-1.96, p-value 0.042) and rs1800797 (OR 1.37, 95% CI 1.02-1.85, p-value 0.074). There is also association between LDD and SKT rs16924573 (OR 0.27, 95% CI 0.07-0.96, p-value 0.023) and CILP rs2073711 in woman only (OR 2.04, 95% CI 1.07-3.89, p-value 0.025).

The most recent study (2012) searching for susceptibility genes in LDD validated some association of SNPs and LDD by examining both Finnish and Danish young individual populations (Eskola, 2012). The study showed that among Finnish individuals, polymorphisms in IL6 (G-allele OR 1.45, [95% CI 1.07–1.96], p=0.042), SKT (OR 0.27 [95% CI 0.07–0.96], p=0.024) and CILP (only in women: CC/TT vs. CC genotype OR 2.04 [CI 1.07–3.89], and p=0.025) were associated with moderate LDD, but the association in CILP was significant only in woman. The results support most of earlier findings on genes in LDD association studies; however, there are unexpected differences between genders observed.

Summary
The results emphasize the complexity and some conditional specificity of LDD development, and the important role of further study in populations with different ethnic, age, and especially on gender specificity backgrounds. A thorough understanding of the contribution of variation is valuable, and this genetic information could be used to help patients predict their risks of developing LDD throughout their lifetime based on their variation in the genomes. Overall, SNP rs2073711 has shown some level of association with LDD especially in women populations and Japanese population, and functional analysis of related cartilage intermediate layer protein gene also provides some evidence of its potential role in LDD development. Further studies should be conducted to verify the association in distinct populations with different backgrounds.