Causal relationship between female reproductive behavior and rheumatoid arthritis: a Mendelian randomization study_Chinese Journal of Evidence-Based Medicine

Authors：

LIU Chenxi ¹ , WANG Yabei ¹ ,  WANG Yue ²

1. The First Clinical School of Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China;
2. Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, P. R. China;

Corresponding author：

WANG Yue, Email: wangyue@njucm.edu.cn

Keywords：

Mendelian randomization; Reproductive behavior; Rheumatoid arthritis; Causal inference

DOI：

10.7507/1672-2531.202312120

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To investigate the potential causal relationship between four types of reproductive behaviors and rheumatoid arthritis (RA), with the goal of establishing a theoretical foundation for clinical prevention and treatment strategies. Methods Pooled gene-wide association study (GWAS) data were obtained from large publicly searchable databases. Four characteristics like menarche, menopause, the age of first pregnancy and the age of last pregnancy, which related to reproductive behavior were selected as the exposure factors and RA as the outcome factors. Single nucleotide polymorphisms (SNPs), which were strongly correlated with the phenotype of the exposure factors, were screened as the instrumental variables, and two-sample Mendelian randomization analyses were used to assess the potential causal relationship between the exposure and the disease. Results ① The Mendelian randomization analysis utilizing the inverse variance weighted method on two distinct samples revealed a significant negative correlation between the age of first pregnancy and last pregnancy with the risk of RA (OR=0.91, 95%CI 0.85 to 0.98, P=0.011; OR=0.54, 95%CI 0.31 to 0.93, P=0.026). Conversely, no causal relationship was observed between menarche and menopause with RA. Sensitivity analysis confirmed the robustness of the causal relationship, while MR Egger intercept analysis did not identify any potential horizontal pleiotropy (P_{age of first gestation -RA}=0.169, P_{age of last gestation -RA}=0.283). ② Reverse Mendelian randomization analysis revealed a significant positive causal association between RA and the age of first pregnancy, while no causal relationship was observed with the age of last pregnancy (OR=1.07, 95%CI 1.02 to 1.11, P=0.001). ③ Multivariate Mendelian randomization analysis demonstrated that both the age of first pregnancy and last pregnancy in women were inversely associated with the risk of RA (OR=0.88, 95%CI 0.80 to 0.97, P=0.010; OR=0.68, 95%CI 0.48 to 0.97, P=0.033). ④ There existed a negative correlation between the age of pregnancy in women and the risk of developing RA, suggesting a potential protective effect. Conclusion Pregnancy age may have a negative causal relationship with the risk of RA, while menarche and menopause have no causal relationship with RA.

Citation： LIU Chenxi, WANG Yabei, WANG Yue. Causal relationship between female reproductive behavior and rheumatoid arthritis: a Mendelian randomization study. Chinese Journal of Evidence-Based Medicine, 2024, 24(10): 1149-1155. doi: 10.7507/1672-2531.202312120 Copy

1.	van der Woude D, van der Helm-van Mil AHM. Update on the epidemiology, risk factors, and disease outcomes of rheumatoid arthritis. Best Pract Res Clin Rheumatol, 2018, 32(2): 174-187.
2.	吴惠一, 袁琴, 张洋, 等. 1990−2019年我国肌肉骨骼疾病负担分析. 中华疾病控制杂志, 2023, 27(6): 655-661.
3.	Straub RH. The complex role of estrogens in inflammation. Endocr Rev, 2007, 28(5): 521-574.
4.	Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ, 2021, 375: n2233.
5.	Sekula P, Del Greco M F, Pattaro C, et al. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol, 2016, 27(11): 3253-3265.
6.	Mukamal KJ, Stampfer MJ, Rimm EB. Genetic instrumental variable analysis: time to call mendelian randomization what it is. The example of alcohol and cardiovascular disease. Eur J Epidemiol, 2020, 35(2): 93-97.
7.	Chang L, Zhou G, Xia J. mGWAS-explorer 2. 0: causal analysis and interpretation of metabolite-phenotype associations. Metabolites, 2023, 13(7): 826.
8.	Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ, 2018, 362: k601.
9.	Day FR, Thompson DJ, Helgason H, et al. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat Genet, 2017, 49(6): 834-841.
10.	Day FR, Ruth KS, Thompson DJ, et al. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nat Genet, 2015, 47(11): 1294-1303.
11.	Mills MC, Tropf FC, Brazel DM, et al. Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour. Nat Hum Behav, 2021, 5(12): 1717-1730.
12.	Sudlow C, Gallacher J, Allen N, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med, 2015, 12(3): e1001779.
13.	Kurki MI, Karjalainen J, Palta P, et al. FinnGen: unique genetic insights from combining isolated population and national health register data. MedRxiv, 2022: 2022.03. 03.22271360.
14.	Liu M, Jiang Y, Wedow R, et al. Association studies of up to 1. 2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat Genet, 2019, 51(2): 237-244.
15.	Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
16.	Burgess S, Davey SG, Davies NM, et al. Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res, 2023, 4: 186.
17.	Burgess S, Bowden J, Fall T, et al. Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology, 2017, 28(1): 30-42.
18.	Burgess S, Zuber V, Gkatzionis A, et al. Modal-based estimation via heterogeneity-penalized weighting: model averaging for consistent and efficient estimation in Mendelian randomization when a plurality of candidate instruments are valid. Int J Epidemiol, 2018, 47(4): 1242-1254.
19.	Sanderson E, Spiller W, Bowden J. Testing and correcting for weak and pleiotropic instruments in two-sample multivariable Mendelian randomization. Stat Med, 2021, 40(25): 5434-5452.
20.	Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
21.	Greco M FD, Minelli C, Sheehan NA, et al. Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat Med, 2015, 34(21): 2926-2940.
22.	Corbin LJ, Richmond RC, Wade KH, et al. BMI as a modifiable risk factor for type 2 diabetes: refining and understanding causal estimates using Mendelian randomization. Diabetes, 2016, 65(10): 3002-3007.
23.	Hernández AM, Liang MH, Willett WC, et al. Reproductive factors, smoking, and the risk for rheumatoid arthritis. Epidemiology, 1990, 1(4): 285-291.
24.	Humphreys JH, Verstappen SM, Hyrich KL, et al. The incidence of rheumatoid arthritis in the UK: comparisons using the 2010 ACR/EULAR classification criteria and the 1987 ACR classification criteria. Results from the Norfolk arthritis register. Ann Rheum Dis, 2013, 72(8): 1315-1320.
25.	Alpízar-Rodríguez D, Pluchino N, Canny G, et al. The role of female hormonal factors in the development of rheumatoid arthritis. Rheumatology (Oxford), 2017, 56(8): 1254-1263.
26.	Malutan AM, Dan M, Nicolae C, et al. Proinflammatory and anti-inflammatory cytokine changes related to menopause. Prz Menopauzalny, 2014, 13(3): 162-168.
27.	Alpizar-Rodriguez D, Mueller RB, Möller B, et al. Female hormonal factors and the development of anti-citrullinated protein antibodies in women at risk of rheumatoid arthritis. Rheumatology (Oxford), 2017, 56(9): 1579-1585.
28.	Neugarten BL, Kraines RJ. "Menopausal symptoms" in women of various ages. Psychosom Med, 1965, 27: 266-273.
29.	McKay LI, Cidlowski JA. Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr Rev, 1999, 20(4): 435-459.
30.	Cutolo M, Villaggio B, Seriolo B, et al. Synovial fluid estrogens in rheumatoid arthritis. Autoimmun Rev, 2004, 3(3): 193-198.
31.	Kobak S, Bes C. An autumn tale: geriatric rheumatoid arthritis. Ther Adv Musculoskelet Dis, 2018, 10(1): 3-11.
32.	Kuiper S, van Gestel AM, Swinkels HL, et al. Influence of sex, age, and menopausal state on the course of early rheumatoid arthritis. J Rheuma, 2001, 28(8): 1809-1816.
33.	Pawłowska J, Smoleńska Z, Daca A, et al. Older age of rheumatoid arthritis onset is associated with higher activation status of peripheral blood CD4(+) T cells and disease activity. Clin Exp Immunol, 2011, 163(2): 157-164.
34.	Camacho EM, Verstappen SM, Chipping J, et al. Learned helplessness predicts functional disability, pain and fatigue in patients with recent-onset inflammatory polyarthritis. Rheumatology (Oxford), 2013, 52(7): 1233-1238.
35.	Hench PS. The ameliorating effect of pregnancy on chronic atrophic (infectious rheumatoid) arthritis, fibrositis, and intermittent hydrarthrosis. Mayo Clin Proc, 1938, 13(7): 1-12.
36.	Ostensen M, Husby G. A prospective clinical study of the effect of pregnancy on rheumatoid arthritis and ankylosing spondylitis. Arthritis Rheum, 1983, 26(9): 1155-1159.
37.	Neely NT, Persellin RH. Activity of rheumatoid arthritis during pregnancy. Texas medicine, 1977, 73(8): 59-63.
38.	Ostensen M, Aune B, Husby G. Effect of pregnancy and hormonal changes on the activity of rheumatoid arthritis. Scand J Rheumatol, 1983, 12(2): 69-72.
39.	Zbinden A, van den Brandt S, Østensen M, et al. Risk for adverse pregnancy outcome in axial spondyloarthritis and rheumatoid arthritis: disease activity matters. Rheumatology (Oxford), 2018, 57(7): 1235-1242.
40.	Förger F, Bandoli G, Luo Y, et al. No association of discontinuing tumor necrosis factor inhibitors before gestational week twenty in well-controlled rheumatoid arthritis and juvenile idiopathic arthritis with a disease worsening in late pregnancy. Arthritis Rheumatol, 2019, 71(6): 901-907.
41.	de Man YA, Dolhain RJ, van de Geijn FE, et al. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum, 2008, 59(9): 1241-1248.
42.	Barrett JH, Brennan P, Fiddler M, et al. Does rheumatoid arthritis remit during pregnancy and relapse postpartum. Results from a nationwide study in the United Kingdom performed prospectively from late pregnancy. Arthritis Rheum, 1999, 42(6): 1219-1227.
43.	Birney E. Mendelian randomization. Cold Spring Harb Perspect Med, 2022, 12(4): a041302.
44.	Weith M, Beyer A. The next step in Mendelian randomization. Elife, 2023, 12: e86416.

1. van der Woude D, van der Helm-van Mil AHM. Update on the epidemiology, risk factors, and disease outcomes of rheumatoid arthritis. Best Pract Res Clin Rheumatol, 2018, 32(2): 174-187.
2. 吴惠一, 袁琴, 张洋, 等. 1990−2019年我国肌肉骨骼疾病负担分析. 中华疾病控制杂志, 2023, 27(6): 655-661.
3. Straub RH. The complex role of estrogens in inflammation. Endocr Rev, 2007, 28(5): 521-574.
4. Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ, 2021, 375: n2233.
5. Sekula P, Del Greco M F, Pattaro C, et al. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol, 2016, 27(11): 3253-3265.
6. Mukamal KJ, Stampfer MJ, Rimm EB. Genetic instrumental variable analysis: time to call mendelian randomization what it is. The example of alcohol and cardiovascular disease. Eur J Epidemiol, 2020, 35(2): 93-97.
7. Chang L, Zhou G, Xia J. mGWAS-explorer 2. 0: causal analysis and interpretation of metabolite-phenotype associations. Metabolites, 2023, 13(7): 826.
8. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ, 2018, 362: k601.
9. Day FR, Thompson DJ, Helgason H, et al. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat Genet, 2017, 49(6): 834-841.
10. Day FR, Ruth KS, Thompson DJ, et al. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nat Genet, 2015, 47(11): 1294-1303.
11. Mills MC, Tropf FC, Brazel DM, et al. Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour. Nat Hum Behav, 2021, 5(12): 1717-1730.
12. Sudlow C, Gallacher J, Allen N, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med, 2015, 12(3): e1001779.
13. Kurki MI, Karjalainen J, Palta P, et al. FinnGen: unique genetic insights from combining isolated population and national health register data. MedRxiv, 2022: 2022.03. 03.22271360.
14. Liu M, Jiang Y, Wedow R, et al. Association studies of up to 1. 2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat Genet, 2019, 51(2): 237-244.
15. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
16. Burgess S, Davey SG, Davies NM, et al. Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res, 2023, 4: 186.
17. Burgess S, Bowden J, Fall T, et al. Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology, 2017, 28(1): 30-42.
18. Burgess S, Zuber V, Gkatzionis A, et al. Modal-based estimation via heterogeneity-penalized weighting: model averaging for consistent and efficient estimation in Mendelian randomization when a plurality of candidate instruments are valid. Int J Epidemiol, 2018, 47(4): 1242-1254.
19. Sanderson E, Spiller W, Bowden J. Testing and correcting for weak and pleiotropic instruments in two-sample multivariable Mendelian randomization. Stat Med, 2021, 40(25): 5434-5452.
20. Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
21. Greco M FD, Minelli C, Sheehan NA, et al. Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat Med, 2015, 34(21): 2926-2940.
22. Corbin LJ, Richmond RC, Wade KH, et al. BMI as a modifiable risk factor for type 2 diabetes: refining and understanding causal estimates using Mendelian randomization. Diabetes, 2016, 65(10): 3002-3007.
23. Hernández AM, Liang MH, Willett WC, et al. Reproductive factors, smoking, and the risk for rheumatoid arthritis. Epidemiology, 1990, 1(4): 285-291.
24. Humphreys JH, Verstappen SM, Hyrich KL, et al. The incidence of rheumatoid arthritis in the UK: comparisons using the 2010 ACR/EULAR classification criteria and the 1987 ACR classification criteria. Results from the Norfolk arthritis register. Ann Rheum Dis, 2013, 72(8): 1315-1320.
25. Alpízar-Rodríguez D, Pluchino N, Canny G, et al. The role of female hormonal factors in the development of rheumatoid arthritis. Rheumatology (Oxford), 2017, 56(8): 1254-1263.
26. Malutan AM, Dan M, Nicolae C, et al. Proinflammatory and anti-inflammatory cytokine changes related to menopause. Prz Menopauzalny, 2014, 13(3): 162-168.
27. Alpizar-Rodriguez D, Mueller RB, Möller B, et al. Female hormonal factors and the development of anti-citrullinated protein antibodies in women at risk of rheumatoid arthritis. Rheumatology (Oxford), 2017, 56(9): 1579-1585.
28. Neugarten BL, Kraines RJ. "Menopausal symptoms" in women of various ages. Psychosom Med, 1965, 27: 266-273.
29. McKay LI, Cidlowski JA. Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr Rev, 1999, 20(4): 435-459.
30. Cutolo M, Villaggio B, Seriolo B, et al. Synovial fluid estrogens in rheumatoid arthritis. Autoimmun Rev, 2004, 3(3): 193-198.
31. Kobak S, Bes C. An autumn tale: geriatric rheumatoid arthritis. Ther Adv Musculoskelet Dis, 2018, 10(1): 3-11.
32. Kuiper S, van Gestel AM, Swinkels HL, et al. Influence of sex, age, and menopausal state on the course of early rheumatoid arthritis. J Rheuma, 2001, 28(8): 1809-1816.
33. Pawłowska J, Smoleńska Z, Daca A, et al. Older age of rheumatoid arthritis onset is associated with higher activation status of peripheral blood CD4(+) T cells and disease activity. Clin Exp Immunol, 2011, 163(2): 157-164.
34. Camacho EM, Verstappen SM, Chipping J, et al. Learned helplessness predicts functional disability, pain and fatigue in patients with recent-onset inflammatory polyarthritis. Rheumatology (Oxford), 2013, 52(7): 1233-1238.
35. Hench PS. The ameliorating effect of pregnancy on chronic atrophic (infectious rheumatoid) arthritis, fibrositis, and intermittent hydrarthrosis. Mayo Clin Proc, 1938, 13(7): 1-12.
36. Ostensen M, Husby G. A prospective clinical study of the effect of pregnancy on rheumatoid arthritis and ankylosing spondylitis. Arthritis Rheum, 1983, 26(9): 1155-1159.
37. Neely NT, Persellin RH. Activity of rheumatoid arthritis during pregnancy. Texas medicine, 1977, 73(8): 59-63.
38. Ostensen M, Aune B, Husby G. Effect of pregnancy and hormonal changes on the activity of rheumatoid arthritis. Scand J Rheumatol, 1983, 12(2): 69-72.
39. Zbinden A, van den Brandt S, Østensen M, et al. Risk for adverse pregnancy outcome in axial spondyloarthritis and rheumatoid arthritis: disease activity matters. Rheumatology (Oxford), 2018, 57(7): 1235-1242.
40. Förger F, Bandoli G, Luo Y, et al. No association of discontinuing tumor necrosis factor inhibitors before gestational week twenty in well-controlled rheumatoid arthritis and juvenile idiopathic arthritis with a disease worsening in late pregnancy. Arthritis Rheumatol, 2019, 71(6): 901-907.
41. de Man YA, Dolhain RJ, van de Geijn FE, et al. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum, 2008, 59(9): 1241-1248.
42. Barrett JH, Brennan P, Fiddler M, et al. Does rheumatoid arthritis remit during pregnancy and relapse postpartum. Results from a nationwide study in the United Kingdom performed prospectively from late pregnancy. Arthritis Rheum, 1999, 42(6): 1219-1227.
43. Birney E. Mendelian randomization. Cold Spring Harb Perspect Med, 2022, 12(4): a041302.
44. Weith M, Beyer A. The next step in Mendelian randomization. Elife, 2023, 12: e86416.

Chinese Journal of Evidence-Based Medicine

Causal relationship between female reproductive behavior and rheumatoid arthritis: a Mendelian randomization study

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