Analysis of low back pain through the methylation process in specific genes. Systematic review

Moroti-Perugini, Layse Rafaela; Cônsolo, Isadora Fernandes; Bello, Valeria Aparecida; Poli, Regina Célia

doi:10.5935/2595-0118.20230039-en

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REVIEW ARTICLE • BrJP 6 (2) • Apr-Jun 2023 • https://doi.org/10.5935/2595-0118.20230039-en copy

Analysis of low back pain through the methylation process in specific genes. Systematic review

Authorship SCIMAGO INSTITUTIONS RANKINGS

HIGHLIGHTS

Several low back pain-related genes show different levels of DNA methylation;
There are different genes involved on low back pain in men and women, and their methylation level is also different according to gender and exercise practice;
There is still no epigenetic biomarker for low back pain, which indicates the need for further studies to clarify the role of epigenetics in low back pain.

ABSTRACT

BACKGROUND AND OBJECTIVES:

Low back pain is one of the most common complaints. Epigenetics represents a mechanism where the environment can modify gene expression without alterations in the primary DNA sequence. This can be seen in the process of DNA methylation, histone modification, and chromatin reorganization. The objective of this study was to conduct a systematic review on DNA methylation processes related to low back pain.

Data were collected up to March 2023. The search was conducted on the following article search platforms: Scielo, Pubmed, Regional Portal of BVS, and LILACS. Pre-defined keywords were used in Portuguese or English: low back pain, DNA methylation, epigenomics, and epigenetics. All chosen words were verified through Health Sciences Descriptors (DeCS), and English words were verified in MesHterms. Bias risk analysis was identified. 61 genes were highlighted in the 8 articles that met the inclusion criteria. Only 2 studies presented genes in common, but one of them was in animal samples. Each analyzed gene has its particularity in performing processes, thus presenting differences in how it could generate low back pain. All studies included in this review were assessed for risk of bias.

CONCLUSION:

The identified genes contribute significantly to the development of treatments and scientific knowledge. However, as the topic addressed is relatively new, further studies should be developed.

Keywords:
DNA; Epigenomics; Low back pain; Methylation

Authors	Type of study	Biological sample	Sample size (n)	Gender	Age (years)	Genetic analysis	LBP identification	Significance
Aroke et al.¹⁵15 Aroke EN, Overstreet DS, Penn TM, Crossman DK, Jackson P, Tollefsbol TO, Quinn TL, Yi N, Goodin BR. Identification of DNA methylation associated enrichment pathways in adults with non-specific chronic low back pain. Mol Pain. 2020;16:1744806920972889.	Transversal	Human peripheral blood	50	Both	52	DNA methylation by bisulfite	Self-report, medical records - American Colleges of Physicians e American Pain Society, Brief Pain Inventory (BPI) - Short Form	Yes
Cao et al.²⁴	Transversal	Human ligamentum flavum	10	Both	63.5	EZ DNA methylation kit, cell culture in DMEM medium	Examinations and surgical needs	Yes
Grégoire, et al.¹⁰10 Grégoire S, Cheishvili D, Salmon-Divon M, Dymov S, Topham L, Calderon V, Shir Y, Szyf M, Stone LS. Epigenetic signature of chronic low back pain in human T cells. Pain Rep. 2021;3;6(4):e960.	Transversal	Human peripheral blood	75	Both	43.4	DNA methylation by bisulfite	Self-report - Canadian adaptation of the NIH Low Back Pain Taskforce	Yes
Jiang et al.²⁰20 Adhikari B, Starkweather A, Xu W, Acabchuk Rl, Ramesh D, Eze B, Yang Y, Yang Gs, Walker J, Laubenbacher R, Park CL. A feasibility study on yoga’s mechanism of action for chronic low back pain: psychological and neurophysiological changes, including global gene expression and DNA methylation, following a yoga intervention for chronic low back pain. Pilot Feasibility Stud. 2022;8(1):142.	Longitudinal	Cartilaginous end plate (CEP) mice/human - when performed surgery	15 mice 18 human	Male	6 weeks	Quantitative RT-PCR, Western blotting, metilação de DNA	Mice - Pfirrmann grade - to check impact Human - sample through surgery in the lumbar region	Yes
Luo et al.²⁵	Longitudinal	Lumbar disc samples from mice	60 mice	Male	2 months	RT-qPCR, Western blot, flow cytometry, methylation, ELISA	None - performed surgical techniques exclusively for analysis	Yes
Adhikari et al.²⁰20 Adhikari B, Starkweather A, Xu W, Acabchuk Rl, Ramesh D, Eze B, Yang Y, Yang Gs, Walker J, Laubenbacher R, Park CL. A feasibility study on yoga’s mechanism of action for chronic low back pain: psychological and neurophysiological changes, including global gene expression and DNA methylation, following a yoga intervention for chronic low back pain. Pilot Feasibility Stud. 2022;8(1):142.	Longitudinal	Human peripheral blood	11	Both	34	bisulfite sequencing, EZ DNA methylation kit, RNA sequencing by Illumina NextSeq 550 system	Self-report - brief 40-iten byTaskforce on Research Standards for cLBP; Brief Pain Inventory (BPI); Emotion Regulation Questionnaire (ERQ)	No
Li et al. ²⁷	Transversal	Tissue of nucleus pulposus	95	Both	55	Intervertebral disc RNA-seq, RNA scope, RT-PCR, Western blot	None - performed surgical techniques, due to operative need	Yes
Sukenaga et al.¹⁹19 Sukenaga N, Ikeda-Miyagawa Y, Tanada D, Tunetoh T, Nakano S, Inui T, Satoh K, Okutani H, Noguchi K, Hirose M. Correlation between DNA methylation of TRPA1 and chronic pain states in human whole blood cells. Pain Med. 2016;17(10):1906-10.	Transversal	Total human blood	12	Both	62.5	Illumina HumanMethylation450 BeadChip, SurePrint G3 Human Gene Expression 8x60K v2 microarray kit	DN4 (Douleur Neuropathique 4), SF-MPQ (Short-Form McGill Pain Questionnaire)	Yes

Authors	Genes
Aroke et al.¹⁵15 Aroke EN, Overstreet DS, Penn TM, Crossman DK, Jackson P, Tollefsbol TO, Quinn TL, Yi N, Goodin BR. Identification of DNA methylation associated enrichment pathways in adults with non-specific chronic low back pain. Mol Pain. 2020;16:1744806920972889.	CELSR1, MFGE8, NR2F2, GPAT2, WDR5, CIof127, DYRK3, PAX5, HTRA3, MINK1, K1F11, NAV1,DAD1, FAM101B, TCF25, OLFM1, FBRS
Cao et al.²¹21 Cao Y, Zhan Y, Qiu S, Chen Z, Gong K, Ni S, Duan Y. Integrative analysis of genome-wide DNA methylation and single-nucleotide polymorphism identified ACSM5 as a suppressor of lumbar ligamentum flavum hypertrophy. Arthritis Res Ther. 2021;23(1):251.	COL4A3, MACC1, PIGC, ACSM5, HSPA6
Grégoire et. ¹⁰10 Grégoire S, Cheishvili D, Salmon-Divon M, Dymov S, Topham L, Calderon V, Shir Y, Szyf M, Stone LS. Epigenetic signature of chronic low back pain in human T cells. Pain Rep. 2021;3;6(4):e960.	Woman- LGALS8, FRMD4A, KLRC4-KLRK1, RAMP1, COL21A1, TACSTD2, RPH3AL, NINJ2, MR1, DTHD1 Man - MYT1L, MYO1D, PTPRE, ACBD5, EDIL3, PGAM2, NUP35, NOTCH1, ZNF718, PLD6
Jiang et al.¹⁴14 Jiang C, Guo Q, Jin Y, Xu JJ, Sun ZM, Zhu DC, Lin JH, Tian NF, Sun LJ, Zhang XL, Wu YS. Inhibition of EZH2 ameliorates cartilage endplate degeneration and attenuates the progression of intervertebral disc degeneration via demethylation of Sox-9. EBioMedicine. 2019;48:619-29.	Sox-9, EZH2
Luo et al.¹⁶16 Luo Z, Ma Y, Di T, Ma B, Li H, An J, Wang Y, Zhang H. DNMT3B decreases extracellular matrix degradation and alleviates intervertebral disc degeneration through TRPA1 methylation to inhibit the COX2/YAP axis. Aging. 2021;;13(16):20258-76.	DNMT3B, TRPA1,COX2,YAP
Adhikari et al.²⁰20 Adhikari B, Starkweather A, Xu W, Acabchuk Rl, Ramesh D, Eze B, Yang Y, Yang Gs, Walker J, Laubenbacher R, Park CL. A feasibility study on yoga’s mechanism of action for chronic low back pain: psychological and neurophysiological changes, including global gene expression and DNA methylation, following a yoga intervention for chronic low back pain. Pilot Feasibility Stud. 2022;8(1):142.	PSMD1, PSMD12, PSMA3, PSMB6, PSMB10, KLRK1, KPNB1, LAPTM5, ICAM-3 e RPL23A
Li et al.²³23 Li G, Luo R, Zhang W, He S, Wang B, Liang H, Song Y, Ke W, Shi Y, Feng X, Zhao K, Wu X, Zhang Y, Wang K, Yang C. M6A hypomethylation of DNMT3B regulated by ALKBH5 promotes intervertebral disc degeneration via E4F1 deficiency. Clin Transl Med. 2022;12(3):e765.	ALKBH5, DNMT3B
Sukenaga et al.¹⁹19 Sukenaga N, Ikeda-Miyagawa Y, Tanada D, Tunetoh T, Nakano S, Inui T, Satoh K, Okutani H, Noguchi K, Hirose M. Correlation between DNA methylation of TRPA1 and chronic pain states in human whole blood cells. Pain Med. 2016;17(10):1906-10.	TRPA1

Authors	Aroke et al.¹⁵15 Aroke EN, Overstreet DS, Penn TM, Crossman DK, Jackson P, Tollefsbol TO, Quinn TL, Yi N, Goodin BR. Identification of DNA methylation associated enrichment pathways in adults with non-specific chronic low back pain. Mol Pain. 2020;16:1744806920972889.	Cao et al.²¹21 Cao Y, Zhan Y, Qiu S, Chen Z, Gong K, Ni S, Duan Y. Integrative analysis of genome-wide DNA methylation and single-nucleotide polymorphism identified ACSM5 as a suppressor of lumbar ligamentum flavum hypertrophy. Arthritis Res Ther. 2021;23(1):251.	Grégoire et al.¹⁰10 Grégoire S, Cheishvili D, Salmon-Divon M, Dymov S, Topham L, Calderon V, Shir Y, Szyf M, Stone LS. Epigenetic signature of chronic low back pain in human T cells. Pain Rep. 2021;3;6(4):e960.	Jiang et al.¹⁴14 Jiang C, Guo Q, Jin Y, Xu JJ, Sun ZM, Zhu DC, Lin JH, Tian NF, Sun LJ, Zhang XL, Wu YS. Inhibition of EZH2 ameliorates cartilage endplate degeneration and attenuates the progression of intervertebral disc degeneration via demethylation of Sox-9. EBioMedicine. 2019;48:619-29.	Luo et al.²⁵	Adhikari et al.²⁰¹	Li et al.²⁷	Sukenaga et al.¹⁹19 Sukenaga N, Ikeda-Miyagawa Y, Tanada D, Tunetoh T, Nakano S, Inui T, Satoh K, Okutani H, Noguchi K, Hirose M. Correlation between DNA methylation of TRPA1 and chronic pain states in human whole blood cells. Pain Med. 2016;17(10):1906-10.
Was the study’s target population a close representation of the national population in relation to relevant variables?	No	No	No	No	No	No	No	No
Was the sampling frame a true or close representation of the target population?	Yes	Yes	Yes	No	No	Yes	Yes	Yes
Was some form of random selection used to select the sample, OR was a census undertaken?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Was the likelihood of nonresponse bias minimal?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Were data collected directly from the subjects (as opposed to a proxy)?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Was an acceptable case definition used in the study?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Was the study instrument that measured the parameter of interest shown to have validity and reliability?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Was the same mode of data collection used for all subjects?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Was the length of the shortest prevalence period for the parameter of interest appropriate?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes

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[1] Conflict of interests: none

LILACS, Scielo, BVS Regional Portal	Low back pain AND DNA methylation; low back pain AND epigenetic; low back pain AND DNA methylation AND epigenetic - research also carried out in the Portuguese language
Pubmed	Low back pain AND DNA methylation; low back pain AND epigenetic; low back pain AND DNA methylation AND epigenetic

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Analysis of low back pain through the methylation process in specific genes. Systematic review

HIGHLIGHTS

ABSTRACT

BACKGROUND AND OBJECTIVES:

CONTENTS:

CONCLUSION: