Causal Relationships between Circulating Immune Cell Traits and the Risk of Rheumatoid Arthritis and Osteoarthritis: A Bidirectional Two-Sample Mendelian Randomization Study
-
Dujuan Mao
,
Shan Li
,
Xiufang Li
,
Lijuan You
,
Jiaqi Yu
,
Yaohua Wu
,
Quanshui Hao
,
Heng Du
Abstract
Background: Rheumatoid arthritis (RA) and osteoarthritis (OA) are prevalent chronic joint disorders with immunological pathogenesis. However, the causal relationships between circulating immune cells and them remain largely unknown. Therefore, we conducted a bidirectional two-sample Mendelian randomization (MR) study to determine their causal relationship.
Methods: Genome-wide association study summary statistics were extracted from publicly available databases regarding immune cell phenotypes, RA, and OA. MR analysis was conducted using five MR methods, with inverse-variance-weighted (IVW) as the primary analysis method. False discovery rate correction (FDR) was used to reduce the likelihood of type 1 errors. We also conducted MR-Egger intercept tests to evaluate horizontal pleiotropy.
Results: After FDR adjustment of the P values for the IVW method, the CD27 expression on memory B cells was negatively related to the risk of RA (P < 0.001), and the human leukocyte antigen (HLA)--DR expression on CD14+ monocytes was negatively related to the risk of OA (P < 0.001). We also found that RA was negatively associated with the expression of HLA-DR on myeloid dendritic cells (P < 0.001), but significant horizontal pleiotropy was observed.
Conclusion: Our study demonstrates a causal relationship between specific immune cell traits and RA as well as OA, providing further insight into the role of immune cells in the pathogenesis of these disorders.
1. Collaborators GBDRA (2023). Global, regional, and national burden of rheumatoid arthritis, 1990-2020, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021. Lancet Rheumatol, 5(10):e594-e610.
2. Collaborators GBDO (2023). Global, regional, and national burden of osteoarthritis, 1990-2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Rheumatol, 5(9):e508-e522.
3. Smolen JS, Aletaha D, McInnes IB (2016). Rheumatoid arthritis. Lancet, 388(10055):2023-2038.
4. Glyn-Jones S, Palmer AJ, Agricola R, et al (2015). Osteoarthritis. Lancet, 386(9991):376-387.
5. Guan SY, Zheng JX, Sam NB, et al (2023). Global burden and risk factors of musculoskeletal disorders among adolescents and young adults in 204 countries and territories, 1990-2019. Autoimmun Rev, 22(8):103361.
6. Burmester GR, Pope JE (2017). Novel treatment strategies in rheumatoid arthritis. Lancet, 389(10086):2338-2348.
7. Conaghan PG, Cook AD, Hamilton JA, et al (2019). Therapeutic options for targeting inflammatory osteoarthritis pain. Nat Rev Rheumatol, 15(6):355-363.
8. Gao Y, Zhang Y, Liu X (2024). Rheumatoid arthritis: pathogenesis and therapeutic advances. MedComm (2020), 5(3):e509.
9. Stefik D, Vranic V, Ivkovic N, et al (2021). An insight into osteoarthritis susceptibility: Integration of immunological and genetic background. Bosn J Basic Med Sci, 21(2):155-162.
10. Firestein GS, McInnes IB (2017). Immunopathogenesis of Rheumatoid Arthritis. Immunity, 46(2):183-196.
11. Robinson WH, Lepus CM, Wang Q, et al (2016). Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol, 12(10):580-592.
12. Smolen JS, Landewe R, Bijlsma J, et al (2017). EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis, 76(6):960-977.
13. Davies NM, Holmes MV, Davey Smith G (2018). Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ, 362:k601.
14. Lawlor DA, Harbord RM, Sterne JA, et al (2008). Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med, 27(8):1133-1163.
15. Davey Smith G, Hemani G (2014). Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet, 23(R1):R89-98.
16. Ho J, Mak CCH, Sharma V, et al (2022). Mendelian Randomization Studies of Lifestyle-Related Risk Factors for Osteoarthritis: A PRISMA Review and Meta-Analysis. Int J Mol Sci, 23(19): 11906.
17. Hong H, Chen L, Zhong Y, et al (2023). Associations of Homocysteine, Folate, and Vitamin B12 with Osteoarthritis: A Mendelian Randomization Study. Nutrients, 15(7):1636.
18. Gu Y, Jin Q, Hu J, et al (2023). Causality of genetically determined metabolites and metabolic pathways on osteoarthritis: a two-sample mendelian randomization study. J Transl Med, 21(1):357.
19. Zhang J, Fang XY, Leng R, et al (2023). Metabolic Signature of Healthy Lifestyle and Risk of Rheumatoid Arthritis: Observational and Mendelian Randomization Study. Am J Clin Nutr, 118(1):183-193.
20. Yuan S, Li X, Lin A, et al (2022). Interleukins and rheumatoid arthritis: bi-directional Mendelian randomization investigation. Semin Arthritis Rheum, 53:151958.
21. Sanderson E, Glymour MM, Holmes MV, et al (2022). Mendelian randomization. Nat Rev Methods Primers, 2:6.
22. Lu Y, Ma L (2023). Investigation of the causal relationship between breast cancer and autoimmune diseases: A bidirectional mendelian randomization study. Medicine (Baltimore), 102(34):e34612.
23. Wu J, Fan Q, He Q, et al (2023). Potential drug targets for myocardial infarction identified through Mendelian randomization analysis and Genetic colocalization. Medicine (Baltimore), 102(49):e36284.
24. Orru V, Steri M, Sidore C, et al (2020). Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat Genet, 52(10):1036-1045.
25. Sidore C, Busonero F, Maschio A, et al (2015). Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers. Nat Genet, 47(11):1272-1281.
26. Ha E, Bae SC, Kim K (2021). Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci. Ann Rheum Dis, 80(5):558-565.
27. Tachmazidou I, Hatzikotoulas K, Southam L, et al (2019). Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet, 51(2):230-236.
28. Wang C, Zhu D, Zhang D, et al (2023). Causal role of immune cells in schizophrenia: Mendelian randomization (MR) study. BMC Psychiatry, 23(1):590.
29. Gu J, Yan GM, Kong XL, et al (2023). Assessing the causal relationship between immune traits and systemic lupus erythematosus by bi-directional Mendelian randomization analysis. Mol Genet Genomics, 298(6):1493-1503.
30. Genomes Project C, Auton A, Brooks LD, et al (2015). A global reference for human genetic variation. Nature, 526(7571):68-74.
31. Tan Z, Zhu S, Liu C, et al (2023). Causal Link between Inflammatory Bowel Disease and Fistula: Evidence from Mendelian Randomization Study. J Clin Med, 12(7): 2482.
32. Kamat MA, Blackshaw JA, Young R, et al (2019). PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics, 35(22):4851-4853.
33. Meng Y, Tan Z, Liu C, et al (2023). Association between Inflammatory Bowel Disease and Iridocyclitis: A Mendelian Randomization Study. J Clin Med, 12(4): 1282.
34. Burgess S, Small DS, Thompson SG (2017). A review of instrumental variable estimators for Mendelian randomization. Stat Methods Med Res, 26(5):2333-2355.
35. Burgess S, Thompson SG (2017). Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 32(5):377-389.
36. Hu F, Zhang W, Shi L, et al (2018). Impaired CD27(+)IgD(+) B Cells With Altered Gene Signature in Rheumatoid Arthritis. Front Immunol, 9:626.
37. Gazeau P, Alegria GC, Devauchelle-Pensec V, et al (2017). Memory B Cells and Response to Abatacept in Rheumatoid Arthritis. Clin Rev Allergy Immunol, 53(2):166-176.
38. Rao DA, Gurish MF, Marshall JL, et al (2017). Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature, 542(7639):110-114.
39. Yu MB, Langridge WHR (2017). The function of myeloid dendritic cells in rheumatoid arthritis. Rheumatol Int, 37(7):1043-1051.
40. Suwa Y, Nagafuchi Y, Yamada S, et al (2023). The role of dendritic cells and their immunometabolism in rheumatoid arthritis. Front Immunol, 14:1161148.
41. Moret FM, Hack CE, van der Wurff-Jacobs KM, et al (2013). Intra-articular CD1c-expressing myeloid dendritic cells from rheumatoid arthritis patients express a unique set of T cell-attracting chemokines and spontaneously induce Th1, Th17 and Th2 cell activity. Arthritis Res Ther, 15(5):R155.
42. Jongbloed SL, Lebre MC, Fraser AR, et al (2006). Enumeration and phenotypical analysis of distinct dendritic cell subsets in psoriatic arthritis and rheumatoid arthritis. Arthritis Res Ther, 8(1):R15.
43. Kondo N, Kuroda T, Kobayashi D (2021). Cytokine Networks in the Pathogenesis of Rheumatoid Arthritis. Int J Mol Sci, 22(20):10922.
44. Stern LJ, Calvo-Calle JM (2009). HLA-DR: molecular insights and vaccine design. Curr Pharm Des, 15(28):3249-3261.
45. Gomez-Aristizabal A, Gandhi R, Mahomed NN, et al (2019). Synovial fluid monocyte/macrophage subsets and their correlation to patient-reported outcomes in osteoarthritic patients: a cohort study. Arthritis Res Ther, 21(1):26.
46. Luster AD, Alon R, von Andrian UH (2005). Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol, 6(12):1182-1190.
47. Nefla M, Holzinger D, Berenbaum F, et al (2016). The danger from within: alarmins in arthritis. Nat Rev Rheumatol, 12(11):669-683.
2. Collaborators GBDO (2023). Global, regional, and national burden of osteoarthritis, 1990-2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Rheumatol, 5(9):e508-e522.
3. Smolen JS, Aletaha D, McInnes IB (2016). Rheumatoid arthritis. Lancet, 388(10055):2023-2038.
4. Glyn-Jones S, Palmer AJ, Agricola R, et al (2015). Osteoarthritis. Lancet, 386(9991):376-387.
5. Guan SY, Zheng JX, Sam NB, et al (2023). Global burden and risk factors of musculoskeletal disorders among adolescents and young adults in 204 countries and territories, 1990-2019. Autoimmun Rev, 22(8):103361.
6. Burmester GR, Pope JE (2017). Novel treatment strategies in rheumatoid arthritis. Lancet, 389(10086):2338-2348.
7. Conaghan PG, Cook AD, Hamilton JA, et al (2019). Therapeutic options for targeting inflammatory osteoarthritis pain. Nat Rev Rheumatol, 15(6):355-363.
8. Gao Y, Zhang Y, Liu X (2024). Rheumatoid arthritis: pathogenesis and therapeutic advances. MedComm (2020), 5(3):e509.
9. Stefik D, Vranic V, Ivkovic N, et al (2021). An insight into osteoarthritis susceptibility: Integration of immunological and genetic background. Bosn J Basic Med Sci, 21(2):155-162.
10. Firestein GS, McInnes IB (2017). Immunopathogenesis of Rheumatoid Arthritis. Immunity, 46(2):183-196.
11. Robinson WH, Lepus CM, Wang Q, et al (2016). Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol, 12(10):580-592.
12. Smolen JS, Landewe R, Bijlsma J, et al (2017). EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis, 76(6):960-977.
13. Davies NM, Holmes MV, Davey Smith G (2018). Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ, 362:k601.
14. Lawlor DA, Harbord RM, Sterne JA, et al (2008). Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med, 27(8):1133-1163.
15. Davey Smith G, Hemani G (2014). Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet, 23(R1):R89-98.
16. Ho J, Mak CCH, Sharma V, et al (2022). Mendelian Randomization Studies of Lifestyle-Related Risk Factors for Osteoarthritis: A PRISMA Review and Meta-Analysis. Int J Mol Sci, 23(19): 11906.
17. Hong H, Chen L, Zhong Y, et al (2023). Associations of Homocysteine, Folate, and Vitamin B12 with Osteoarthritis: A Mendelian Randomization Study. Nutrients, 15(7):1636.
18. Gu Y, Jin Q, Hu J, et al (2023). Causality of genetically determined metabolites and metabolic pathways on osteoarthritis: a two-sample mendelian randomization study. J Transl Med, 21(1):357.
19. Zhang J, Fang XY, Leng R, et al (2023). Metabolic Signature of Healthy Lifestyle and Risk of Rheumatoid Arthritis: Observational and Mendelian Randomization Study. Am J Clin Nutr, 118(1):183-193.
20. Yuan S, Li X, Lin A, et al (2022). Interleukins and rheumatoid arthritis: bi-directional Mendelian randomization investigation. Semin Arthritis Rheum, 53:151958.
21. Sanderson E, Glymour MM, Holmes MV, et al (2022). Mendelian randomization. Nat Rev Methods Primers, 2:6.
22. Lu Y, Ma L (2023). Investigation of the causal relationship between breast cancer and autoimmune diseases: A bidirectional mendelian randomization study. Medicine (Baltimore), 102(34):e34612.
23. Wu J, Fan Q, He Q, et al (2023). Potential drug targets for myocardial infarction identified through Mendelian randomization analysis and Genetic colocalization. Medicine (Baltimore), 102(49):e36284.
24. Orru V, Steri M, Sidore C, et al (2020). Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat Genet, 52(10):1036-1045.
25. Sidore C, Busonero F, Maschio A, et al (2015). Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers. Nat Genet, 47(11):1272-1281.
26. Ha E, Bae SC, Kim K (2021). Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci. Ann Rheum Dis, 80(5):558-565.
27. Tachmazidou I, Hatzikotoulas K, Southam L, et al (2019). Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet, 51(2):230-236.
28. Wang C, Zhu D, Zhang D, et al (2023). Causal role of immune cells in schizophrenia: Mendelian randomization (MR) study. BMC Psychiatry, 23(1):590.
29. Gu J, Yan GM, Kong XL, et al (2023). Assessing the causal relationship between immune traits and systemic lupus erythematosus by bi-directional Mendelian randomization analysis. Mol Genet Genomics, 298(6):1493-1503.
30. Genomes Project C, Auton A, Brooks LD, et al (2015). A global reference for human genetic variation. Nature, 526(7571):68-74.
31. Tan Z, Zhu S, Liu C, et al (2023). Causal Link between Inflammatory Bowel Disease and Fistula: Evidence from Mendelian Randomization Study. J Clin Med, 12(7): 2482.
32. Kamat MA, Blackshaw JA, Young R, et al (2019). PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics, 35(22):4851-4853.
33. Meng Y, Tan Z, Liu C, et al (2023). Association between Inflammatory Bowel Disease and Iridocyclitis: A Mendelian Randomization Study. J Clin Med, 12(4): 1282.
34. Burgess S, Small DS, Thompson SG (2017). A review of instrumental variable estimators for Mendelian randomization. Stat Methods Med Res, 26(5):2333-2355.
35. Burgess S, Thompson SG (2017). Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 32(5):377-389.
36. Hu F, Zhang W, Shi L, et al (2018). Impaired CD27(+)IgD(+) B Cells With Altered Gene Signature in Rheumatoid Arthritis. Front Immunol, 9:626.
37. Gazeau P, Alegria GC, Devauchelle-Pensec V, et al (2017). Memory B Cells and Response to Abatacept in Rheumatoid Arthritis. Clin Rev Allergy Immunol, 53(2):166-176.
38. Rao DA, Gurish MF, Marshall JL, et al (2017). Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature, 542(7639):110-114.
39. Yu MB, Langridge WHR (2017). The function of myeloid dendritic cells in rheumatoid arthritis. Rheumatol Int, 37(7):1043-1051.
40. Suwa Y, Nagafuchi Y, Yamada S, et al (2023). The role of dendritic cells and their immunometabolism in rheumatoid arthritis. Front Immunol, 14:1161148.
41. Moret FM, Hack CE, van der Wurff-Jacobs KM, et al (2013). Intra-articular CD1c-expressing myeloid dendritic cells from rheumatoid arthritis patients express a unique set of T cell-attracting chemokines and spontaneously induce Th1, Th17 and Th2 cell activity. Arthritis Res Ther, 15(5):R155.
42. Jongbloed SL, Lebre MC, Fraser AR, et al (2006). Enumeration and phenotypical analysis of distinct dendritic cell subsets in psoriatic arthritis and rheumatoid arthritis. Arthritis Res Ther, 8(1):R15.
43. Kondo N, Kuroda T, Kobayashi D (2021). Cytokine Networks in the Pathogenesis of Rheumatoid Arthritis. Int J Mol Sci, 22(20):10922.
44. Stern LJ, Calvo-Calle JM (2009). HLA-DR: molecular insights and vaccine design. Curr Pharm Des, 15(28):3249-3261.
45. Gomez-Aristizabal A, Gandhi R, Mahomed NN, et al (2019). Synovial fluid monocyte/macrophage subsets and their correlation to patient-reported outcomes in osteoarthritic patients: a cohort study. Arthritis Res Ther, 21(1):26.
46. Luster AD, Alon R, von Andrian UH (2005). Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol, 6(12):1182-1190.
47. Nefla M, Holzinger D, Berenbaum F, et al (2016). The danger from within: alarmins in arthritis. Nat Rev Rheumatol, 12(11):669-683.
| Files | ||
| Issue | Vol 53 No 10 (2024) | |
| Section | Original Article(s) | |
| Keywords | ||
| Immune cells Rheumatoid arthritis Osteoarthritis Mendelian randomization Causal association | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Mao D, Li S, Li X, You L, Yu J, Wu Y, Hao Q, Du H. Causal Relationships between Circulating Immune Cell Traits and the Risk of Rheumatoid Arthritis and Osteoarthritis: A Bidirectional Two-Sample Mendelian Randomization Study. Iran J Public Health. 2024;53(10):2307-2317.
