Carpal tunnel syndrome: The role of collagen gene variants.

INTRODUCTION: The direct causes of idiopathic carpal tunnel syndrome (CTS) are still unknown. It is suggested that pathology of the tendons and other connective tissue structures within the carpal tunnel may play a role in its aetiology. Variants in genes encoding connective tissue proteins, such as type V collagen, have previously been associated with CTS. Since variants within other collagen genes, such as type I, XI and XII collagen, have previously been associated with modulating the risk of musculoskeletal soft tissue injuries, the aim of this study was to determine whether variants within COL1A1, COL11A1, COL11A2 and COL12A1 were associated with CTS. METHODS: Self-reported Coloured South African participants, with a history of carpal tunnel release surgery (CTS, n=103) and matched control (CON, n=150) participants without any reported history of CTS symptoms were genotyped for COL1A1 rs1800012 (G/T), COL11A1 rs3753841 (T/C), COL11A1 rs1676486 (C/T), COL11A2 rs1799907 (T/A) and COL12A1 rs970547 (A/G). RESULTS: The TT genotype of COL11A1 rs3753841 was significantly over-represented in the CTS group (21.4%) compared to CON group (7.9%, p=0.004). Furthermore, a trend for the T minor allele to be over-represented in the CTS group (p=0.055) with a significant association when only female participants (p=0.036) were investigated was observed. Constructed inferred pseudo-haplotypes including a previously investigated COL5A1 variant, rs71746744 (-/AGGG), suggest gene-gene interactions between COL5A1 and COL11A1 modulate the risk of CTS. DISCUSSION: These findings provide further information of the role of the genetic risk factors and the possible role of variations in collagen fibril composition in the aetiology of CTS. Genetic factors could potential be included in models developed to identify indivisuals at risk of CTS. Strategies that target modifiable risk factors to mitigate the effect of non-modifiable risk factors, such as the genetic risk, could be also developed to reduce incidence and morbidity of CTS.

Matrix metalloproteinase genes on chromosome 11q22 and risk of carpal tunnel syndrome.

Involvement of tendons and/or connective tissue structures in the aetiology of idiopathic carpal tunnel syndrome (CTS) has been proposed. DNA sequence variants within genes encoding structural components of the collagen fibril, the basic structural unit of connective tissue, have been shown to associate with modulating CTS risk. The matrix metalloproteinases (MMPs) play an important role in connective tissue remodelling. Variants within the MMP10, MMP1, MMP3 and MMP12 gene cluster on chromosome 11q22 have been associated with connective tissue injuries. The aim of this study was to investigate whether variants within these MMP genes are associated with CTS. Ninety-seven, self-reported Coloured participants with a history of CTS release surgery and 131 appropriately matched controls were genotyped for MMP10 rs486055 (C/T), MMP1 rs1799750 (G/GG), MMP3 rs679620 (A/G) or MMP12 rs2276109 (A/G) variants. A Pearson's Chi-squared test or a Fisher's exact test was used to determine any significant differences between the genotype distributions or any other categorical data of the groups. An analysis of variance (ANOVA) was used to detect any significant differences between CTS and control groups for continuous data. There were no independent associations between any of the investigated MMP variants and CTS. There were also no significant differences in the relative distributions of the constructed MMP inferred haplotypes between CTS and CON groups. The MMP variants previously associated with other connective tissue injuries were not associated with CTS in this population. These findings do not exclude the possibility that other variants within this locus or other MMP genes are associated with CTS.

Interleukin and growth factor gene variants and risk of carpal tunnel syndrome.

Recent research has identified DNA sequence variants within genes encoding structural components of the collagen fibril, the basic structural unit of tendons, to modify the risk of carpal tunnel syndrome (CTS). Since the expression of these previously associated genes are regulated by cytokine and growth factor signalling pathways, the aim of this study was to determine whether variants within these cell signalling pathway genes, namely interleukin 1ß (IL-1ß), IL-6, interleukin 6 receptor (IL-6R) and vascular endothelial growth factor A(VEGFA), are also associated with CTS. One hundred and three self-reported Coloured participants, with a history of carpal tunnel release surgery (CTS) and 149 matched control participants (CON) without any reported history of CTS symptoms were genotyped for the functional IL-1ß rs16944 (-511C/T), IL-6 rs1800795 (-174G/C), IL-6R rs2228145 (C/A) and VEGFA rs699947 (-2578C/A) variants. Only the IL-6R variant was significantly associated with CTS (p=0.005, OR=0.41, 95% CI 0.22-0.75). When the previously reported associated COL5A1 and BGN variants were included in the analysis, gene-gene interactions were also shown to significantly modulate the risk of CTS. In conclusion, the AA genotype of IL-6R rs2228145 was independently associated with reduced risk of CTS in a South African Coloured population. The IL-6R variant interacted with the previously reported COL5A1 and BGN variants to modulate CTS risk. This highlights that interleukin and growth factor gene variants should also be considered, in addition to the extracellular matrix proteins, for future research in determining the aetiology of CTS.

The COL5A1 gene is associated with increased risk of carpal tunnel syndrome.

The direct causes of idiopathic carpal tunnel syndrome (CTS), a common upper limb entrapment neuropathy, remain unknown. It is however generally accepted that an increase in pressure within the carpal tunnel structure, which contains nine flexor tendons, causes compression of the median nerve. The involvement of these tendons in the aetiology of CTS cannot be excluded. Variants within the collagen, type V, alpha 1 (COL5A1) gene, which encodes for the α1 chain of type V collagen, an important regulator of fibril assembly in tendons, have previously been associated with Achilles tendinopathy. The aim of this study was to determine whether these COL5A1 variants are also associated with CTS. One hundred and three self-reported coloured participants, with a history of carpal tunnel release surgery (CTS) and 150 matched control (CON) participants without any reported history of CTS symptoms were genotyped for the COL5A1 rs13946 (C/T), rs14774622 (C/T)/rs55748801 (G/A) (W/M where W = CG), rs12722 (C/T) and rs71746744 (-/AGGG) variants. The TT genotype of COL5A1 rs13946 was significantly over-represented (p = 0.007) in the CON (69.3 %) compared to that in the CTS (50.6 %) group. When the combined rs14774622/rs55748801 and rs12722 genotypes were analysed, the WW + CC (41.7 %, p = 0.008) and WW + CT (40.3 %, p = 0.009) genotypes were significantly over- and under-represented in the CON group, respectively, when compared to the CTS group (24.5 % WW + CC, 59.2 % WW + CT). Furthermore, the T-W-C (51.2 %, p < 0.001) and C-W-C (15.9 %, p = 0.005) inferred haplotypes were significantly over- and under-represented in the CON compared to the CTS (34.9 % T-W-C, 26.8 % C-W-C). In conclusion, this is the first study to report that variants within the functional COL5A1 3'-untranslated region are associated with the CTS. Further studies are required to replicate these findings.

The BGN and ACAN genes and carpal tunnel syndrome.

The causes of idiopathic carpal tunnel syndrome (CTS) remain unknown and the involvement of the tendons within the carpal tunnel structure in the aetiology of CTS cannot be excluded. Variants within the COL5A1 gene, an important regulator of fibril assembly in tendons, have previously been associated with modulating the risk of CTS. Furthermore, proteoglycans are also important structural components of tendons and variants within the aggrecan gene are associated with musculoskeletal soft tissue injuries. The aim of this study was to determine whether ACAN and BGN variants are associated with CTS. Self-reported Coloured participants (n=99), with a history of CTS release surgery (CTS), and 136 control participants, with no history of CTS symptoms (CON), were genotyped for ACAN rs1516797(G/T) and BGN rs1126499(C/T) variants. The BGN CC genotype was significantly over-represented (p=0.0498; OR=0.545, 95% CI=0.30-0.99) in the CON group (71.8%) versus the CTS (58.1%) group. When the previously reported associated COL5A1 genotypes were included in the analysis, COL5A1 and BGN gene-gene interactions were also shown to significantly modulate the risk of CTS in females. In conclusion this is the first study to report that variants within the BGN gene, independently and by interacting with COL5A1 variants, are associated with CTS. Further studies are required to replicate these findings.