Increased Expression of Netrin-1 and Its Deleted in Colorectal Cancer Receptor in Human Diseased Lumbar Intervertebral Disc Compared With Autopsy Control

Bu, Guoyun; Hou, Shuxun; Ren, Dazhong; Wu, Ye; Shang, Wei-lin; Huang, Wei

doi:10.1097/brs.0b013e31825d4ebc

Cited by 10 publications

(11 citation statements)

References 34 publications

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“…[ 52 , 53 ] Increased expression of netrin-1 and DCC occurs in degenerate human intervertebral discs compared to healthy control discs, and in nucleus pulposus compared to annulus fibrosis. [ 54 ] Netrin-1/DCC might therefore mediate neurovascular ingrowth into the intervertebral disc, which has long been implicated as a possible mechanism of chronic discogenic back pain. [ 54 , 55 ] Given the well-known phenotypic correlation between depression and CBP[ 56 ], however, another possible explanation for the link between CBP and DCC (suggested by the cross-phenotype association of rs4384683 with depressive symptoms) is pleiotropy.…”

Section: Discussionmentioning

confidence: 99%

“…[ 54 ] Netrin-1/DCC might therefore mediate neurovascular ingrowth into the intervertebral disc, which has long been implicated as a possible mechanism of chronic discogenic back pain. [ 54 , 55 ] Given the well-known phenotypic correlation between depression and CBP[ 56 ], however, another possible explanation for the link between CBP and DCC (suggested by the cross-phenotype association of rs4384683 with depressive symptoms) is pleiotropy. Netrin-1/ DCC interactions are also known to play a role in pain processing in the spinal cord in animal models of mechanical allodynia.…”

Section: Discussionmentioning

confidence: 99%

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Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain

et al. 2018

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Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3–6 months; non-cases were included as comparisons (“controls”). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10−8. Suggestive (p<5×10−7) and genome-wide significant (p<5×10−8) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10−10). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10−11), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10−19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10−13), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10−10). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain

et al. 2018

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“…(56, 57) Increased expression of netrin-1 and DCC occurs in degenerate human intervertebral discs compared to healthy control discs, and in nucleus pulposus compared to annulus fibrosis. (58) Netrin-1/DCC might therefore mediate neurovascular ingrowth into the intervertebral disc, which has long been implicated as a possible mechanism of chronic discogenic back pain. (58, 59) Netrin-1/DCC interactions also play a role in pain processing in the spinal cord in animal models of mechanical allodynia.…”

Section: Discussionmentioning

confidence: 99%

“…(58) Netrin-1/DCC might therefore mediate neurovascular ingrowth into the intervertebral disc, which has long been implicated as a possible mechanism of chronic discogenic back pain. (58, 59) Netrin-1/DCC interactions also play a role in pain processing in the spinal cord in animal models of mechanical allodynia. (56) Taken together, these findings suggest nociceptive and/or neuropathic mechanisms connecting lumbar intervertebral disc degeneration (including disc herniation) with CBP.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide Meta-analysis of 158,000 Individuals of European Ancestry Identifies Three Loci Associated with Chronic Back Pain

Suri

Palmer

Tsepilov

et al. 2018

Preprint

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OBJECTIVES To conduct a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). METHODS Adults of European ancestry were included from 16 cohorts in Europe and North America. CBP cases were defined as those reporting back pain present for >3-6 months; non-cases were included as comparisons (“controls”). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10−8. Suggestive (p<5×10−7) and genome-wide significant (p<5×10−8) variants were carried forward for replication or further investigation in an independent sample. RESULTS The discovery sample was comprised of 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p=7.2×10−10). This was subsequently replicated in an independent sample of 283,752 subjects, including 50,915 cases (OR 1.06, p=5.3×10−11), and exceeded genome-wide significance in joint meta-analysis (OR=1.07, p=4.5×10−19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p=4.4×10−13), and an intronic variant, rs4384683, in DCC (OR 0.97, p=2.4×10−10). DISCUSSION In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

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“…Compared to healthy human IVDs, expression of both these genes is greater in degraded discs. They are also found less frequently in the annulus fibrosus than in the nucleus pulposus [25]. Neurovascular ingrowth into the IVD may be mediated by netrin-1 and DCC, which is a mechanism that has long been implicated in chronic discogenic back pain [25,26].…”

Section: (Deleted In Colorectal Carcinoma)mentioning

confidence: 99%

Can Implementation of Genetics and Pharmacogenomics Improve Treatment of Chronic Low Back Pain?

et al. 2020

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Etiology of back pain is multifactorial and not completely understood, and for the majority of people who suffer from chronic low back pain (cLBP), the precise cause cannot be determined. We know that back pain is somewhat heritable, chronic pain more so than acute. The aim of this review is to compile the genes identified by numerous genetic association studies of chronic pain conditions, focusing on cLBP specifically. Higher-order neurologic processes involved in pain maintenance and generation may explain genetic contributions and functional predisposition to formation of cLBP that does not involve spine pathology. Several genes have been identified in genetic association studies of cLBP and roughly, these genes could be grouped into several categories, coding for: receptors, enzymes, cytokines and related molecules, and transcription factors. Treatment of cLBP should be multimodal. In this review, we discuss how an individual’s genotype could affect their response to therapy, as well as how genetic polymorphisms in CYP450 and other enzymes are crucial for affecting the metabolic profile of drugs used for the treatment of cLBP. Implementation of gene-focused pharmacotherapy has the potential to deliver select, more efficacious drugs and avoid unnecessary, polypharmacy-related adverse events in many painful conditions, including cLBP.

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Increased Expression of Netrin-1 and Its Deleted in Colorectal Cancer Receptor in Human Diseased Lumbar Intervertebral Disc Compared With Autopsy Control

Abstract: The increased expression of netrin-1 and DCC in diseased IVDs compared with controls suggested that they might play an important role in the process of neurovascular ingrowth.

Cited by 10 publications

References 34 publications

Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain

Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain

Genome-wide Meta-analysis of 158,000 Individuals of European Ancestry Identifies Three Loci Associated with Chronic Back Pain

Can Implementation of Genetics and Pharmacogenomics Improve Treatment of Chronic Low Back Pain?

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