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

Abstract

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.

Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing

“…Furthermore, Mio and collaborators (13) recently identified an association between an allelic variant of COL11A1 (rs1676486) and disc herniation in a Japanese population. COL11A1 was found to be highly expressed in intervertebral discs, but its expression was decreased in patients with disc herniation.…”

“…Among the 11 genes that have been investigated in 21 studies previously performed, 9 (AGC1, COL1A1, COL9A2, COL5A1, COL9A3, COL11A2, IL1, IL2, and MMP3) were associated with disc degeneration, pathologic changes, or associated symptoms in at least 1 study (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). However, phenotypes vary widely, and the studies included both symptoms assumed to be associated with disc pathology and qualitative assessments of disc degeneration.…”

Association between collagen type XI α1 gene polymorphisms and papillary thyroid cancer in a Korean population

“…In a previous study, the T allele of rs1676486 (C/T) of the COL11A1 gene exhibited a significant association with an increased risk of lumbar disc herniation (LDH) in a Japanese population (25). In addition, the mRNA expression level of COL11A1, which was decreased according to the severity of degeneration in patients with LDH, was lower in the intervertebral discs of patients with minor allele T allele than with major allele C allele (25).…”

Evidence for an Inherited Predisposition to Lumbar Disc Disease

“…Studies have evaluated the components of the extracellular matrix and the genes that encode them as contributors to lumbar disc disease. These biochemical studies have shown an association between genes that code for type-XI collagen 21 , type-IX collagen 20 , and multiple intervertebral disc proteins 22 and symptomatic lumbar disc herniations.…”

“…Recently, genetic abnormalities in the extracellular matrix of the intervertebral disc have been implicated as a possible mechanism to explain these observations 21 . Studies have evaluated the components of the extracellular matrix and the genes that encode them as contributors to lumbar disc disease.…”