Exploring the causal association of rheumatoid arthritis with atrial fibrillation: a Mendelian randomization study.
Atrial fibrillation (AF)
Genome-wide association study (GWAS)
Hereditary susceptibility
Mendelian randomization (MR)
Rheumatoid arthritis (RA)
Journal
Clinical rheumatology
ISSN: 1434-9949
Titre abrégé: Clin Rheumatol
Pays: Germany
ID NLM: 8211469
Informations de publication
Date de publication:
06 Nov 2023
06 Nov 2023
Historique:
received:
14
06
2023
accepted:
24
10
2023
revised:
23
10
2023
medline:
6
11
2023
pubmed:
6
11
2023
entrez:
6
11
2023
Statut:
aheadofprint
Résumé
It has been proved that rheumatoid arthritis (RA) patients have high incidence of atrial fibrillation (AF). Nevertheless, whether they have causal relevance is uncertain. This study aimed to explore and verify the authenticity of causal relationship between RA and AF using Mendelian randomization (MR). The genome-wide association study (GWAS) summary data from Biobank Japan Project (BBJ) (RA, 4199 cases and 208,254 controls) were regarded as exposure data and the GWAS data from European Bio-informatics Institute database (EBI) (AF, 15,979 cases and 102,776 controls) as outcome data. The causal effect was appraised by the inverse variance weighted (IVW) method, MR-Egger regression, and weighted median estimator. MR-robust adjusted profile score (MR-RAPS) method was delivered to examine the robustness of causal relationship and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) method to control horizontal (directional) pleiotropy. The results indicated that RA increased the risk of AF (IVW, the odds ratio (OR) = 1.060; 95% confidence interval (CI), 1.028 to 1.092; p = 1.411 × 10 There is a causal association between RA and AF. RA patients are genetically more vulnerable to AF. This study may contribute to further exploring early clinical prevention and fundamental mechanism of AF in patients with RA. Key Points • We provided some genetic evidence for the causal link between rheumatoid arthritis (RA) and atrial fibrillation (AF) with multiple Mendelian randomization (MR) methods. • RA patients were genetically more vulnerable to AF. • This study partly shed light on latent fundamental mechanisms underlying RA-induced AF and inspired future studies on RA-AF relationship.
Sections du résumé
BACKGROUND
BACKGROUND
It has been proved that rheumatoid arthritis (RA) patients have high incidence of atrial fibrillation (AF). Nevertheless, whether they have causal relevance is uncertain. This study aimed to explore and verify the authenticity of causal relationship between RA and AF using Mendelian randomization (MR).
METHODS
METHODS
The genome-wide association study (GWAS) summary data from Biobank Japan Project (BBJ) (RA, 4199 cases and 208,254 controls) were regarded as exposure data and the GWAS data from European Bio-informatics Institute database (EBI) (AF, 15,979 cases and 102,776 controls) as outcome data. The causal effect was appraised by the inverse variance weighted (IVW) method, MR-Egger regression, and weighted median estimator. MR-robust adjusted profile score (MR-RAPS) method was delivered to examine the robustness of causal relationship and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) method to control horizontal (directional) pleiotropy.
RESULTS
RESULTS
The results indicated that RA increased the risk of AF (IVW, the odds ratio (OR) = 1.060; 95% confidence interval (CI), 1.028 to 1.092; p = 1.411 × 10
CONCLUSION
CONCLUSIONS
There is a causal association between RA and AF. RA patients are genetically more vulnerable to AF. This study may contribute to further exploring early clinical prevention and fundamental mechanism of AF in patients with RA. Key Points • We provided some genetic evidence for the causal link between rheumatoid arthritis (RA) and atrial fibrillation (AF) with multiple Mendelian randomization (MR) methods. • RA patients were genetically more vulnerable to AF. • This study partly shed light on latent fundamental mechanisms underlying RA-induced AF and inspired future studies on RA-AF relationship.
Identifiants
pubmed: 37930596
doi: 10.1007/s10067-023-06804-4
pii: 10.1007/s10067-023-06804-4
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : The Medical Health Science and Technology Project of Zhejiang Provincial Health Commission
ID : Grant No. 2021KY1072
Informations de copyright
© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).
Références
Klareskog L, Catrina AI, Paget S (2009) Rheumatoid arthritis. Lancet 373:659–672. https://doi.org/10.1016/S0140-6736(09)60008-8
doi: 10.1016/S0140-6736(09)60008-8
pubmed: 19157532
England BR, Thiele GM, Anderson DR, Mikuls TR (2018) Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications. BMJ 361:k1036. https://doi.org/10.1136/bmj.k1036
doi: 10.1136/bmj.k1036
pubmed: 29685876
pmcid: 6889899
Sodergren A, Stegmayr B, Lundberg V, Ohman ML, Wallberg-Jonsson S (2007) Increased incidence of and impaired prognosis after acute myocardial infarction among patients with seropositive rheumatoid arthritis. Ann Rheum Dis 66:263–266. https://doi.org/10.1136/ard.2006.052456
doi: 10.1136/ard.2006.052456
pubmed: 16854951
Meune C, Touze E, Trinquart L, Allanore Y (2010) High risk of clinical cardiovascular events in rheumatoid arthritis: levels of associations of myocardial infarction and stroke through a systematic review and meta-analysis. Arch Cardiovasc Dis 103:253–261. https://doi.org/10.1016/j.acvd.2010.03.007
doi: 10.1016/j.acvd.2010.03.007
pubmed: 20656636
Jang SY, Kang KW, Jo M, Park M (2021) Risk of new-onset acute coronary syndrome and atrial fibrillation in patients with rheumatoid arthritis compared with a risk-set and propensity score-matched cohort - a nationwide cohort study. Circ J 85:194–200. https://doi.org/10.1253/circj.CJ-20-0825
doi: 10.1253/circj.CJ-20-0825
pubmed: 33328426
Lazzerini PE, Capecchi PL, Laghi-Pasini F (2017) Systemic inflammation and arrhythmic risk: lessons from rheumatoid arthritis. Eur Heart J 38:1717–1727. https://doi.org/10.1093/eurheartj/ehw208
doi: 10.1093/eurheartj/ehw208
pubmed: 27252448
Joseph PG, Healey JS, Raina P et al (2021) Global variations in the prevalence, treatment, and impact of atrial fibrillation in a multi-national cohort of 153 152 middle-aged individuals. Cardiovasc Res 117:1523–1531. https://doi.org/10.1093/cvr/cvaa241
doi: 10.1093/cvr/cvaa241
pubmed: 32777820
Du X, Guo L, Xia S, Du J, Anderson C, Arima H, Huffman M, Yuan Y, Zheng Y, Wu S, Guang X, Zhou X, Lin H, Cheng X, Dong J, Ma C (2021) Atrial fibrillation prevalence, awareness and management in a nationwide survey of adults in China. Heart 107:535–541. https://doi.org/10.1136/heartjnl-2020-317915
doi: 10.1136/heartjnl-2020-317915
pubmed: 33509976
Hindricks G, Potpara T, Dagres N et al (2021) Corrigendum to: 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 42:4194. https://doi.org/10.1093/eurheartj/ehab648
doi: 10.1093/eurheartj/ehab648
pubmed: 34520521
Bacani AK, Crowson CS, Roger VL, Gabriel SE, Matteson EL (2015) Increased incidence of atrial fibrillation in patients with rheumatoid arthritis. Biomed Res Int 2015:809514. https://doi.org/10.1155/2015/809514
doi: 10.1155/2015/809514
pubmed: 25815336
pmcid: 4359868
Kim SC, Liu J, Solomon DH (2014) The risk of atrial fibrillation in patients with rheumatoid arthritis. Ann Rheum Dis 73:1091–1095. https://doi.org/10.1136/annrheumdis-2013-203343
doi: 10.1136/annrheumdis-2013-203343
pubmed: 23606703
Lindhardsen J, Ahlehoff O, Gislason GH, Madsen OR, Olesen JB, Svendsen JH, Torp-Pedersen C, Hansen PR (2012) Risk of atrial fibrillation and stroke in rheumatoid arthritis: Danish nationwide cohort study. BMJ 344:e1257. https://doi.org/10.1136/bmj.e1257
doi: 10.1136/bmj.e1257
pubmed: 22403267
pmcid: 3297675
Ungprasert P, Srivali N, Kittanamongkolchai W (2017) Risk of incident atrial fibrillation in patients with rheumatoid arthritis: a systematic review and meta-analysis. Int J Rheum Dis 20:434–441. https://doi.org/10.1111/1756-185X.12820
doi: 10.1111/1756-185X.12820
pubmed: 26692475
Tan JS, Liu NN, Guo TT, Hu S, Hua L (2021) Genetic predisposition to COVID-19 may increase the risk of hypertension disorders in pregnancy: a two-sample Mendelian randomization study. Pregnancy Hypertens 26:17–23. https://doi.org/10.1016/j.preghy.2021.08.112
doi: 10.1016/j.preghy.2021.08.112
pubmed: 34428710
Lawlor DA (2016) Commentary: two-sample Mendelian randomization: opportunities and challenges. Int J Epidemiol 45:908–915. https://doi.org/10.1093/ije/dyw127
doi: 10.1093/ije/dyw127
pubmed: 27427429
pmcid: 5005949
Richmond RC, Hemani G, Tilling K, Davey Smith G, Relton CL (2016) Challenges and novel approaches for investigating molecular mediation. Hum Mol Genet 25:R149–R156. https://doi.org/10.1093/hmg/ddw197
doi: 10.1093/hmg/ddw197
pubmed: 27439390
pmcid: 5036871
Christophersen IE, Rienstra M, Roselli C et al (2017) Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. Nat Genet 49:946–952. https://doi.org/10.1038/ng.3843
doi: 10.1038/ng.3843
pubmed: 28416818
pmcid: 5585859
Kamat MA, Blackshaw JA, Young R, Surendran P, Burgess S, Danesh J, Butterworth AS, Staley JR (2019) PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics 35:4851–4853. https://doi.org/10.1093/bioinformatics/btz469
doi: 10.1093/bioinformatics/btz469
pubmed: 31233103
pmcid: 6853652
Ma M, Zhi H, Yang S, Yu EY, Wang L (2022) Body mass index and the risk of atrial fibrillation: a Mendelian randomization study. Nutrients 14. https://doi.org/10.3390/nu14091878
Pierce BL, Burgess S (2013) Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am J Epidemiol 178:1177–1184. https://doi.org/10.1093/aje/kwt084
doi: 10.1093/aje/kwt084
pubmed: 23863760
pmcid: 3783091
Au Yeung SL, Luo S, Schooling CM (2018) The impact of glycated hemoglobin (HbA(1c)) on cardiovascular disease risk: a Mendelian randomization study using UK Biobank. Diabetes Care 41:1991–1997. https://doi.org/10.2337/dc18-0289
doi: 10.2337/dc18-0289
pubmed: 29950300
Hemani G, Tilling K, Davey Smith G (2017) Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet 13:e1007081. https://doi.org/10.1371/journal.pgen.1007081
doi: 10.1371/journal.pgen.1007081
pubmed: 29149188
pmcid: 5711033
Burgess S, Davey Smith G, Davies NM et al (2023) Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res 4:186. https://doi.org/10.12688/wellcomeopenres.15555.3
doi: 10.12688/wellcomeopenres.15555.3
pubmed: 32760811
pmcid: 7384151
Smith GD, Ebrahim S (2003) 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 32:1–22. https://doi.org/10.1093/ije/dyg070
doi: 10.1093/ije/dyg070
pubmed: 12689998
Burgess S, Thompson SG (2017) Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol 32:377–389. https://doi.org/10.1007/s10654-017-0255-x
doi: 10.1007/s10654-017-0255-x
pubmed: 28527048
pmcid: 5506233
Spiller W, Davies NM, Palmer TM (2019) Software application profile: mrrobust—a tool for performing two-sample summary Mendelian randomization analyses. Int J Epidemiol 48:684–690. https://doi.org/10.1093/ije/dyy195
doi: 10.1093/ije/dyy195
Tan JS, Liu NN, Guo TT, Hu S, Hua L (2021) Genetically predicted obesity and risk of deep vein thrombosis. Thromb Res 207:16–24. https://doi.org/10.1016/j.thromres.2021.08.026
doi: 10.1016/j.thromres.2021.08.026
pubmed: 34507265
Burgess S, Davey Smith G, Davies NM, Dudbridge F, Gill D, Glymour MM, Hartwig FP, Holmes MV, Minelli C, Relton CL, Theodoratou E (2019) Guidelines for performing Mendelian randomization investigations. Wellcome Open Res 4:186. https://doi.org/10.12688/wellcomeopenres.15555.2
doi: 10.12688/wellcomeopenres.15555.2
pubmed: 32760811
Kaltoft M, Langsted A, Nordestgaard BG (2020) Obesity as a causal risk factor for aortic valve stenosis. J Am Coll Cardiol 75:163–176. https://doi.org/10.1016/j.jacc.2019.10.050
doi: 10.1016/j.jacc.2019.10.050
pubmed: 31948645
Broadbent JR, Foley CN, Grant AJ, Mason AM, Staley JR, Burgess S (2020) MendelianRandomization v0.5.0: updates to an R package for performing Mendelian randomization analyses using summarized data. Wellcome Open Res 5:252. https://doi.org/10.12688/wellcomeopenres.16374.2
doi: 10.12688/wellcomeopenres.16374.2
pubmed: 33381656
pmcid: 7745186
Verbanck M, Chen CY, Neale B, Do R (2018) Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet 50:693–698. https://doi.org/10.1038/s41588-018-0099-7
doi: 10.1038/s41588-018-0099-7
pubmed: 29686387
pmcid: 6083837
Wang M, Chao C, Mei K, Di D, Qian Y, Wang B, Zhang X (2023) Relationship between rheumatoid arthritis and cardiovascular comorbidity, causation or co-occurrence: a Mendelian randomization study. Front Cardiovasc Med 10:1099861. https://doi.org/10.3389/fcvm.2023.1099861
doi: 10.3389/fcvm.2023.1099861
pubmed: 37008317
pmcid: 10063906
Cupido AJ, Asselbergs FW, Natarajan P, Group CIW, Ridker PM, Hovingh GK, Schmidt AF (2022) Dissecting the IL-6 pathway in cardiometabolic disease: a Mendelian randomization study on both IL6 and IL6R. Br J Clin Pharmacol 88:2875–2884. https://doi.org/10.1111/bcp.15191
doi: 10.1111/bcp.15191
pubmed: 34931349
Rosa M, Chignon A, Li Z, Boulanger MC, Arsenault BJ, Bosse Y, Theriault S, Mathieu P (2019) A Mendelian randomization study of IL6 signaling in cardiovascular diseases, immune-related disorders and longevity. NPJ Genom Med 4:23. https://doi.org/10.1038/s41525-019-0097-4
doi: 10.1038/s41525-019-0097-4
pubmed: 31552141
pmcid: 6754413
Dai H, Wang X, Yin S, Zhang Y, Han Y, Yang N, Xu J, Sun L, Yuan Y, Sheng L, Gong Y, Li Y (2017) Atrial fibrillation promotion in a rat model of rheumatoid arthritis. J Am Heart Assoc 6. https://doi.org/10.1161/JAHA.117.007320
Wang X, Fan H, Wang Y, Yin X, Liu G, Gao C, Li X, Liang B (2021) Elevated peripheral T helper cells are associated with atrial fibrillation in patients with rheumatoid arthritis. Front Immunol 12:744254. https://doi.org/10.3389/fimmu.2021.744254
doi: 10.3389/fimmu.2021.744254
pubmed: 34721413
pmcid: 8554094
Wang Q, Shi Q, Lu J, Wang Z, Hou J (2022) Causal relationships between inflammatory factors and multiple myeloma: a bidirectional Mendelian randomization study. Int J Cancer 151:1750–1759. https://doi.org/10.1002/ijc.34214
doi: 10.1002/ijc.34214
pubmed: 35841389
Yang C, Pring M, Wear MA, Huang M, Cooper JA, Svitkina TM, Zigmond SH (2005) Mammalian CARMIL inhibits actin filament capping by capping protein. Dev Cell 9:209–221. https://doi.org/10.1016/j.devcel.2005.06.008
doi: 10.1016/j.devcel.2005.06.008
pubmed: 16054028
pmcid: 2628720
Liang Y, Niederstrasser H, Edwards M, Jackson CE, Cooper JA (2009) Distinct roles for CARMIL isoforms in cell migration. Mol Biol Cell 20:5290–5305. https://doi.org/10.1091/mbc.e08-10-1071
doi: 10.1091/mbc.e08-10-1071
pubmed: 19846667
pmcid: 2793302
Takahashi N, Coluccio A, Thorball CW, Planet E, Shi H, Offner S, Turelli P, Imbeault M, Ferguson-Smith AC, Trono D (2019) ZNF445 is a primary regulator of genomic imprinting. Genes Dev 33:49–54. https://doi.org/10.1101/gad.320069.118
doi: 10.1101/gad.320069.118
pubmed: 30602440
pmcid: 6317318
Mackay DJ, Callaway JL, Marks SM, White HE, Acerini CL, Boonen SE, Dayanikli P, Firth HV, Goodship JA, Haemers AP, Hahnemann JM, Kordonouri O, Masoud AF, Oestergaard E, Storr J, Ellard S, Hattersley AT, Robinson DO, Temple IK (2008) Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet 40:949–951. https://doi.org/10.1038/ng.187
doi: 10.1038/ng.187
pubmed: 18622393
Shi H, Li S, Geng Y, Fan H, Zhang R, Zhang Y, Pan J, Song G, Ge L, Xie T, Wang L (2022) Euphorbia factor L3 ameliorates rheumatoid arthritis by suppressing the inflammatory response by targeting Rac family small GTPase 1. Bioengineered 13:10984–10997. https://doi.org/10.1080/21655979.2022.2066761
doi: 10.1080/21655979.2022.2066761
pubmed: 35475473
Berntsson J, Smith JG, Johnson LSB, Soderholm M, Borne Y, Melander O, Orho-Melander M, Nilsson J, Engstrom G (2019) Increased vascular endothelial growth factor D is associated with atrial fibrillation and ischaemic stroke. Heart 105:553–558. https://doi.org/10.1136/heartjnl-2018-313684
doi: 10.1136/heartjnl-2018-313684
pubmed: 30327392
Chang JH, Cheng CC, Lu YY, Chung CC, Yeh YH, Chen YC, Higa S, Chen SA, Chen YJ (2021) Vascular endothelial growth factor modulates pulmonary vein arrhythmogenesis via vascular endothelial growth factor receptor 1/NOS pathway. Eur J Pharmacol 911:174547. https://doi.org/10.1016/j.ejphar.2021.174547
doi: 10.1016/j.ejphar.2021.174547
pubmed: 34624234
Mezache L, Struckman HL, Greer-Short A, Baine S, Gyorke S, Radwanski PB, Hund TJ, Veeraraghavan R (2020) Vascular endothelial growth factor promotes atrial arrhythmias by inducing acute intercalated disk remodeling. Sci Rep 10:20463. https://doi.org/10.1038/s41598-020-77562-5
doi: 10.1038/s41598-020-77562-5
pubmed: 33235263
pmcid: 7687901
Igarashi Y, Nochioka K, Sakata Y, Tamai T, Ohkouchi S, Irokawa T, Ogawa H, Hayashi H, Fujihashi T, Yamanaka S, Shiroto T, Miyata S, Hata J, Yamada S, Ninomiya T, Yasuda S, Kurosawa H, Shimokawa H (2021) Risk prediction for new-onset atrial fibrillation using the Minnesota code electrocardiography classification system. Int J Cardiol Heart Vasc 34:100762. https://doi.org/10.1016/j.ijcha.2021.100762
doi: 10.1016/j.ijcha.2021.100762
pubmed: 33889712
pmcid: 8050367
Murakami T, Takahata Y, Hata K, Ebina K, Hirose K, Ruengsinpinya L, Nakaminami Y, Etani Y, Kobayashi S, Maruyama T, Nakano H, Kaneko T, Toyosawa S, Asahara H, Nishimura R (2022) Semaphorin 4D induces articular cartilage destruction and inflammation in joints by transcriptionally reprogramming chondrocytes. Sci Signal 15:eabl5304. https://doi.org/10.1126/scisignal.abl5304
doi: 10.1126/scisignal.abl5304
pubmed: 36318619
Qian K, Zheng XX, Wang C, Huang WG, Liu XB, Xu SD, Liu DK, Liu MY, Lin CS (2021) beta-sitosterol inhibits rheumatoid synovial angiogenesis through suppressing VEGF signaling pathway. Front Pharmacol 12:816477. https://doi.org/10.3389/fphar.2021.816477
doi: 10.3389/fphar.2021.816477
pubmed: 35295740
Alipour P, Senkevich K, Ross JP, Spiegelman D, Manousaki D, Dion PA, Rouleau GA (2022) Investigation of the causal relationship between ALS and autoimmune disorders: a Mendelian randomization study. BMC Med 20:382. https://doi.org/10.1186/s12916-022-02578-9
doi: 10.1186/s12916-022-02578-9
pubmed: 36320012
pmcid: 9628014
Ishigaki K, Sakaue S, Terao C et al (2022) Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis. Nat Genet 54:1640–1651. https://doi.org/10.1038/s41588-022-01213-w
doi: 10.1038/s41588-022-01213-w
pubmed: 36333501
pmcid: 10165422