A Functional Polymorphism in COL11A1, Which Encodes the α1 Chain of Type XI Collagen, Is Associated with Susceptibility to Lumbar Disc Herniation

Laboratory for Bone and Joint Diseases, School of Medicine, Keio University, Tokyo.
The American Journal of Human Genetics (Impact Factor: 10.93). 12/2007; 81(6):1271-7. DOI: 10.1086/522377
Source: PubMed


Lumbar disc herniation (LDH), degeneration and herniation of the nucleus pulposus of the intervertebral disc (IVD) of the lumbar spine, is one of the most common musculoskeletal diseases. Its etiology and pathogenesis, however, remain unclear. Type XI collagen is important for cartilage collagen formation and for organization of the extracellular matrix. We identified an association between one of the type XI collagen genes, COL11A1, and LDH in Japanese populations. COL11A1, which encodes the alpha 1 chain of type XI collagen, was highly expressed in IVD, but its expression was decreased in the IVD of patients with LDH. The expression level was inversely correlated with the severity of disc degeneration. A single-nucleotide polymorphism (c.4603C-->T [rs1676486]) had the most significant association with LDH (P=3.3 x 10(-6)), and the transcript containing the disease-associated allele was decreased because of its decreased stability. These observations indicate that type XI collagen is critical for IVD metabolism and that its decrease is related to LDH.

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Available from: Yoshiharu Kawaguchi
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    • "Association studies of genes encoding for structural and functional components of intervertebral disc have highlighted the participation of polymorphisms in IDD [18, 20– 22], including collagens I [23], IX [24], and XI [25], aggrecan [26], cartilage intermediate layer protein (CILP) [27], ECM-degrading enzymes such as MMP-3 [28] and MMP9, thrombospondin-2 (THBS2) [29], inflammatory cytokines interleukin-1 alpha (IL-1í µí»¼) [30], IL-18 [21], IL-6, and tumor necrosis factor alpha (TNF-í µí»¼) [31], and vitamin D receptor (VDR) [32]. The hormonal form of vitamin D (calcitriol) plays a key role in mineralization of bone, absorption of calcium from the gut, control of calcium and phosphate homeostasis , and regulation of parathyroid hormone secretion and may affect intervertebral disc maintenance by altering the sulfation of glycosaminoglycans as well as other changes relating to the nucleus pulposus ECM. "
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    ABSTRACT: Intervertebral disc degeneration (IDD) is the most common diagnosis in patients with back pain, a leading cause of musculoskeletal disability worldwide. Several conditions, such as occupational activities, gender, age, and obesity, have been associated with IDD. However, the development of this disease has strong genetic determinants. In this study, we explore the possible association between rs1800587 (c.-949C>T) of interleukin-1 alpha (IL1A) and rs2228570 (c.2T>V) and rs731236 (c.1056T>C) of vitamin D receptor (VDR) gene polymorphisms and the development of IDD in northwestern Mexican Mestizo population. Gene polymorphisms were analyzed by polymerase chain reaction followed by restriction fragment length polymorphism, in two groups matched by age and gender: patients with symptomatic lumbar IDD (n = 100) and subjects with normal lumbar-spine MRI-scans (n = 100). Distribution of the mutated alleles in patients and controls was 27.0% versus 28.0% (P = 0.455) for T of rs1800587 (IL1A); 53.0% versus 58.0% (P = 0.183) for V of rs2228570 (VDR); and 18.0% versus 21.0% (P = 0.262) for C of rs731236 (VDR). Our results showed no association between the studied polymorphisms and IDD in this population. This is the first report on the contribution of gene polymorphisms on IDD in a Mexican population.
    Full-text · Article · Nov 2014 · International Journal of Plant Genomics
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    • "Several previous studies have described the potential gene markers for lumbar disc diseases, including collagen 9A2 [6, 7], vitamin D receptor [8], matrix metalloproteinase (MMP)-3 [9], cartilage intermediate layer protein [10], collagen 11A1 [11], thrombospondin (THBS2) [12], sickle tail (SKT) [13], MMP-9 [12], asporin (ASPN) [14], and carbohydrate sulfotransferase [15]. Systematic reviews demonstrated that there is moderate evidence of correlation of ASPN, COLXIA1, SKT, THBS2, and MMP-9 with HD [16]. "
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    ABSTRACT: Lumbar herniated discs commonly occur in patients 20-40 years of age, and result in acute symptoms of shooting and intractable pain in the low back and/or lower extremities. However, the prognosis of these patients is considered to be very good. Moreover, 70 % of these patients have been reported to be free from sciatica at approximately 6 months after the first onset. Magnetic resonance imaging (MRI) studies have described the spontaneous resorption process of herniated discs, which is a major cause of the reduction of symptoms in patients. New advancements in MRI have recently been developed that have facilitated the examination of nerve tract fibers and identification of symptomatic nerve tissue. Furthermore, the mechanism underlying the resorption process of a herniated disc has been determined. Inflammatory cytokines such as TNF (tumor necrosis factor)-α, angiogenic factors such as vascular endothelial growth factor, and enzymes such as matrix metalloproteinases are intricately related to each other. In our previous studies, matrix metalloproteinase-7 (MMP-7) has been shown to play a crucial role in the initiation of herniated disc resorption. Therefore, we developed recombinant human MMP-7 for intradiscal therapy through an industry-university joint research program. We have already performed in vitro and in vivo experiments to confirm its efficacy; this therapy avoids the side effects associated with surgery, such as nerve tissue damage. Moreover, the phase 1/2 studies of recombinant human (rh) MMP-7 are currently ongoing in the United States, and careful monitoring is required for these clinical trials. In conclusion, patients with lumbar herniated discs may benefit from the development of a less invasive treatment for disc herniation, which can be applied even immediately after the onset of disease symptoms.
    Preview · Article · Apr 2014 · Journal of Orthopaedic Science
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    • "Lumbar disc herniation (LDH) and lumbar disc degeneration (LDD) can be viewed as having similar aetiological routes to OA, with each condition being age-associated and involving the degeneration of cartilage, albeit of different types, with OA being hyaline and LDH/LDD being fibrocartilage. The common non-synonymous SNP rs1676486, which is located in exon 62 of COL11A1, has been reported to associate with LDH in a Japanese population [9]. rs1676486 is a C-T transition that results in a proline to serine substitution. "
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    ABSTRACT: The single nucleotide polymorphism (SNP) rs2615977 is associated with osteoarthritis (OA) and is located in intron 31 of COL11A1, a strong candidate gene for this degenerative musculoskeletal disease. Furthermore, the common non-synonymous COL11A1 SNP rs1676486 is associated with another degenerative musculoskeletal disease, lumbar disc herniation (LDH). rs1676486 is a C-T transition mediating its affect on LDH susceptibility by modulating COL11A1 expression. The risk T-allele of rs1676486 leads to reduced expression of the COL11A1 transcript, a phenomenon known as allelic expression imbalance (AEI). We were keen therefore to assess whether the effect that rs1676486 has on COL11A1 expression in LDH is also observed in OA and whether the rs2615977 association to OA also marked AEI. Using RNA from OA cartilage, we assessed whether either SNP correlated with COL11A1 AEI by 1) measuring COL11A1 expression and stratifying the data by genotype at each SNP; and 2) quantifying the mRNA transcribed from each allele of the two SNPs. We also assessed whether rs1676486 was associated with OA susceptibility using a case-control cohort of over 18,000 individuals. We observed significant AEI at rs1676486 (p < 0.0001) with the T-allele correlating with reduced COL11A1 expression. This corresponded with observations in LDH but the SNP was not associated with OA. We did not observe AEI at rs2615977. COL11A1 is subject to AEI in OA cartilage. AEI at rs1676486 is a risk factor for LDH, but not for OA. These two diseases therefore share a common functional phenotype, namely AEI of COL11A1, but this appears to be a disease risk only in LDH. Other functional effects on COL11A1 presumably account for the OA susceptibility that maps to this gene.
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