Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Nutrition and Health (including climate and ecological aspects)

Causal analysis of serum polyunsaturated fatty acids with juvenile idiopathic arthritis and ocular comorbidity


Background & objective

To investigate the causal effects of plasma Polyunsaturated fatty acids (PUFAs) on the risk of juvenile idiopathic arthritis (JIA) and ocular comorbidity through Mendelian randomization (MR) analysis.


Genetic variants (formerly single nucleotide polymorphisms, SNPs) that are strongly associated with PUFAs levels (P < 5×10−8) were selected as instrumental variables. Summary-level MR was performed with outcome estimates for JIA (n = 31,142) and JIA associated iridocyclitis (n = 94,197). The inverse variance-weighted (IVW) method was employed as the main approach to combine the estimation for each SNP. Two set of models with summary statistics were conducted and multiple sensitivity analyses were applied for testing of pleiotropic bias.


In model 1, genetically predicted n-6 PUFAs linoleic acid (LA) and arachidonic acid (AA) were associated with lower and higher risk of JIA associated iridocyclitis using IVW (ORLA = 0.940, 95% CI: 0.895–0.988, P = 0.015; ORAA = 1.053, 95% CI: 1.007–1.101, P = 0.024). No such association was observed between each plasma PUFAs and JIA susceptibility (P > 0.05). In further MR analysis, results from model 2 also showed a consistent trend. Besides, multiple sensitivity analyses revealed that there was no obvious evidence for unknown pleiotropy (P > 0.05).


Our MR study provides genetic evidence on the possible causality that plasma LA level might protect against JIA associated iridocyclitis, whereas AA was responsible for opposite effect.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Principles of Mendelian randomization (MR) and the assumptions required to obtain an unbiased causal effect estimate.
Fig. 2: Summary MR estimates of association between plasma n-6 PUFAs and JIA associated iridocyclitis.

Data availability

The data and material that support the findings of this study are available from public datasets in NHGRIEBI GWAS Catalog and MRC IEU Open GWAS Project.


  1. Manners PJ, Bower C. Worldwide prevalence of juvenile arthritis why does it vary so much? J Rheumatol. 2002;29:1520–30. e-pub ahead of print 2002/07/26

    PubMed  Google Scholar 

  2. Tugal-Tutkun I, Quartier P, Bodaghi B. Disease of the year: juvenile idiopathic arthritis-associated uveitis-classification and diagnostic approach. Ocul Immunol Inflamm. 2014;22:56–63. e-pub ahead of print 2014/01/15

    Article  PubMed  Google Scholar 

  3. Tugal-Tutkun I, Havrlikova K, Power WJ, Foster CS. Changing patterns in uveitis of childhood. Ophthalmology. 1996;103:375–83. e-pub ahead of print 1996/03/01

    CAS  Article  PubMed  Google Scholar 

  4. Al-Mayouf SM, Al Mutairi M, Bouayed K, Habjoka S, Hadef D, Lotfy HM, et al. Epidemiology and demographics of juvenile idiopathic arthritis in Africa and Middle East. Pediatr Rheumatol Online J. 2021;19:166 e-pub ahead of print 2021/12/04

    Article  PubMed  PubMed Central  Google Scholar 

  5. Finch SL, Rosenberg AM, Vatanparast H. Vitamin D and juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2018;16:34 e-pub ahead of print 2018/05/18

    Article  PubMed  PubMed Central  Google Scholar 

  6. Majumder S, Aggarwal A. Juvenile idiopathic arthritis and the gut microbiome: Where are we now. Best Pr Res Clin Rheumatol. 2019;33:101496 e-pub ahead of print 2020/03/17

    Article  Google Scholar 

  7. Gorska A, Urban M, Pietrewicz E, Gorski S. Composition of linoleic and arachidonic acids in phosphatidylcholine of erythrocytes membrane and IL-6 and TNF-alpha in serum and C-reactive protein concentration in children with juvenile idiopathic arthritis. Pol Merkur Lekarski. 2006;21:551–3. e-pub ahead of print 2007/04/05

    CAS  PubMed  Google Scholar 

  8. Gorczyca D, Postepski J, Czajkowska A, Pasciak M, Prescha A, Olesinska E, et al. The profile of polyunsaturated fatty acids in juvenile idiopathic arthritis and association with disease activity. Clin Rheumatol. 2017;36:1269–79. e-pub ahead of print 2017/03/02

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kremer JM, Lawrence DA, Jubiz W, DiGiacomo R, Rynes R, Bartholomew LE, et al. Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Clin immunologic Eff Arthritis Rheum. 1990;33:810–20. e-pub ahead of print 1990/06/01

    CAS  Article  Google Scholar 

  10. Miles EA, Calder PC. Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis. Br J Nutr. 2012;107(Suppl 2):S171–184. e-pub ahead of print 2012/05/25

    CAS  Article  PubMed  Google Scholar 

  11. de Pablo P, Romaguera D, Fisk HL, Calder PC, Quirke AM, Cartwright AJ, et al. High erythrocyte levels of the n-6 polyunsaturated fatty acid linoleic acid are associated with lower risk of subsequent rheumatoid arthritis in a southern European nested case-control study. Ann Rheum Dis. 2018;77:981–7. e-pub ahead of print 2018/02/14

    CAS  Article  PubMed  Google Scholar 

  12. Park Y, Lee A, Shim SC, Lee JH, Choe JY, Ahn H, et al. Effect of n-3 polyunsaturated fatty acid supplementation in patients with rheumatoid arthritis: a 16-week randomized, double-blind, placebo-controlled, parallel-design multicenter study in Korea. J Nutr Biochem. 2013;24:1367–72. e-pub ahead of print 2013/01/22

    CAS  Article  PubMed  Google Scholar 

  13. Bosdriesz JR, Stel VS, van Diepen M, Meuleman Y, Dekker FW, Zoccali C, et al. Evidence-based medicine-When observational studies are better than randomized controlled trials. Nephrol (Carlton). 2020;25:737–43. e-pub ahead of print 2020/06/17

    Article  Google Scholar 

  14. Smith GD, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32:1–22. e-pub ahead of print 2003/04/12

    Article  PubMed  Google Scholar 

  15. Burgess S, Scott RA, Timpson NJ, Davey Smith G, Thompson SG, Consortium E-I. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol. 2015;30:543–52. e-pub ahead of print 2015/03/17

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lopez-Isac E, Smith SL, Marion MC, Wood A, Sudman M, Yarwood A et al. Combined genetic analysis of juvenile idiopathic arthritis clinical subtypes identifies novel risk loci, target genes and key regulatory mechanisms. Ann Rheum Dis 2020. e-pub ahead of print 2020/10/28;

  17. Lemaitre RN, Tanaka T, Tang W, Manichaikul A, Foy M, Kabagambe EK, et al. Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium. PLoS Genet. 2011;7:e1002193 e-pub ahead of print 2011/08/11

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Guan W, Steffen BT, Lemaitre RN, Wu JHY, Tanaka T, Manichaikul A, et al. Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium. Circ Cardiovasc Genet. 2014;7:321–31. e-pub ahead of print 2014/05/16

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Tomata Y, Larsson SC, Hagg S. Polyunsaturated fatty acids and risk of Alzheimer’s disease: a Mendelian randomization study. Eur J Nutr. 2020;59:1763–6. e-pub ahead of print 2019/11/05

    CAS  Article  PubMed  Google Scholar 

  20. Wang K, Zhong Y, Yang F, Hu C, Liu X, Zhu Y, et al. Causal effects of N-6 polyunsaturated fatty acids on age-related macular degeneration: a mendelian randomization study. J Clin Endocrinol Metab. 2021;106:e3565–e3572. e-pub ahead of print 2021/05/14

    Article  PubMed  Google Scholar 

  21. Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50:693–8. e-pub ahead of print 2018/04/25

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37:658–65. e-pub ahead of print 2013/10/12

    Article  PubMed  PubMed Central  Google Scholar 

  23. Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32:377–89. e-pub ahead of print 2017/05/21

    Article  PubMed  PubMed Central  Google Scholar 

  24. Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40:304–14. e-pub ahead of print 2016/04/12

    Article  PubMed  PubMed Central  Google Scholar 

  25. May-Wilson S, Sud A, Law PJ, Palin K, Tuupanen S, Gylfe A, et al. Pro-inflammatory fatty acid profile and colorectal cancer risk: A Mendelian randomisation analysis. Eur J Cancer. 2017;84:228–38. e-pub ahead of print 2017/08/23

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Illig T, Gieger C, Zhai G, Romisch-Margl W, Wang-Sattler R, Prehn C, et al. A genome-wide perspective of genetic variation in human metabolism. Nat Genet. 2010;42:137–41. e-pub ahead of print 2009/12/29

    CAS  Article  PubMed  Google Scholar 

  27. Hoglund J, Rafati N, Rask-Andersen M, Enroth S, Karlsson T, Ek WE, et al. Improved power and precision with whole genome sequencing data in genome-wide association studies of inflammatory biomarkers. Sci Rep. 2019;9:16844 e-pub ahead of print 2019/11/16

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Gheita T, Kamel S, Helmy N, El-Laithy N, Monir A. Omega-3 fatty acids in juvenile idiopathic arthritis: effect on cytokines (IL-1 and TNF-alpha), disease activity and response criteria. Clin Rheumatol. 2012;31:363–6. e-pub ahead of print 2011/09/17

    Article  PubMed  Google Scholar 

  29. Huang X, Ye Z, Cao Q, Su G, Wang Q, Deng J, et al. Gut Microbiota Composition and Fecal Metabolic Phenotype in Patients With Acute Anterior Uveitis. Invest Ophthalmol Vis Sci. 2018;59:1523–31. e-pub ahead of print 2018/04/07

    CAS  Article  PubMed  Google Scholar 

  30. Uchi SH, Yanai R, Kobayashi M, Hatano M, Kobayashi Y, Yamashiro C, et al. Dendritic cells mediate the anti-inflammatory action of omega-3 long-chain polyunsaturated fatty acids in experimental autoimmune uveitis. PLoS One. 2019;14:e0219405 e-pub ahead of print 2019/07/25

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Shoda H, Yanai R, Yoshimura T, Nagai T, Kimura K, Sobrin L, et al. Dietary omega-3 fatty acids suppress experimental autoimmune uveitis in association with inhibition of Th1 and Th17 cell function. PLoS One. 2015;10:e0138241 e-pub ahead of print 2015/09/24

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Chu X, Jaeger M, Beumer J, Bakker OB, Aguirre-Gamboa R, Oosting M, et al. Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease. Genome Biol. 2021;22:198 e-pub ahead of print 2021/07/08

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Porcu E, Gilardi F, Darrous L, Yengo L, Bararpour N, Gasser M, et al. Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes. Sci Rep. 2021;11:6197 e-pub ahead of print 2021/03/20

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601 e-pub ahead of print 2018/07/14

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zhao JV, Schooling CM. Role of linoleic acid in autoimmune disorders: a Mendelian randomisation study. Ann Rheum Dis. 2019;78:711–3. e-pub ahead of print 2018/11/10

    CAS  Article  PubMed  Google Scholar 

  36. Park S, Lee S, Kim Y, Lee Y, Kang M, Kim K et al. Causal Effects of Serum Levels of n-3 or n-6 Polyunsaturated Fatty Acids on Coronary Artery Disease: Mendelian Randomization Study. Nutrients; 13. e-pub ahead of print 2021/05/01; 2021

  37. Zhao JV, Schooling CM. Effect of linoleic acid on ischemic heart disease and its risk factors: a Mendelian randomization study. BMC Med. 2019;17:61 e-pub ahead of print 2019/03/15

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zhao JV, Schooling CM. The role of linoleic acid in asthma and inflammatory markers: a Mendelian randomization study. Am J Clin Nutr. 2019;110:685–90. e-pub ahead of print 2019/07/10

    Article  PubMed  Google Scholar 

  39. Zaripova LN, Midgley A, Christmas SE, Beresford MW, Baildam EM, Oldershaw RA. Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches. Pediatr Rheumatol Online J. 2021;19:135 e-pub ahead of print 2021/08/25

    Article  PubMed  PubMed Central  Google Scholar 

  40. Barut K, Adrovic A, Sahin S, Kasapcopur O. Juvenile Idiopathic Arthritis. Balk Med J. 2017;34:90–101. e-pub ahead of print 2017/04/19

    Article  Google Scholar 

  41. Huang X, Yi S, Hu J, Du Z, Wang Q, Ye Z, et al. Linoleic acid inhibits in vitro function of human and murine dendritic cells, CD4(+)T cells and retinal pigment epithelial cells. Graefes Arch Clin Exp Ophthalmol. 2021;259:987–98. e-pub ahead of print 2020/10/21

    CAS  Article  PubMed  Google Scholar 

  42. Elison JR, Weinstein JE, Sheets KG, Regan CE Jr, Lentz JJ, Reinoso M, et al. Platelet-activating factor (PAF) receptor antagonism modulates inflammatory signaling in experimental uveitis. Curr Eye Res. 2018;43:821–7. e-pub ahead of print 2018/04/12

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Liao T, Ke Y, Shao WH, Haribabu B, Kaplan HJ, Sun D, et al. Blockade of the interaction of leukotriene b4 with its receptor prevents development of autoimmune uveitis. Invest Ophthalmol Vis Sci. 2006;47:1543–9. e-pub ahead of print 2006/03/28

    Article  PubMed  Google Scholar 

  44. Eskandarpour M, Nunn MA, Weston-Davies W, Calder VL. Immune-Mediated Retinal Vasculitis in Posterior Uveitis and Experimental Models: The Leukotriene (LT)B4-VEGF Axis. Cells; 10. e-pub ahead of print 2021/03/07; 2021

  45. Adam O, Beringer C, Kless T, Lemmen C, Adam A, Wiseman M, et al. Anti-inflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis. Rheumatol Int. 2003;23:27–36. e-pub ahead of print 2003/01/28

    CAS  Article  PubMed  Google Scholar 

Download references


We thank all the investigators of the NHGRIEBI GWAS Catalog and the MRC IEU Open GWAS Project for providing the data publicly.

Author information

Authors and Affiliations



QS, CZ, and JY were involved in the conceptualization, the design of the study and drafted the manuscript; QS and CZ acquired and analyzed the data; YL, SH and JM helped to design the research; JZ revise the manuscript, supervise the study and perform data interpretation.

Corresponding author

Correspondence to Jun Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

All analyses were based on previous published studies; thus, no ethical approval and patient consent are required.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shu, Q., Zhao, C., Yu, J. et al. Causal analysis of serum polyunsaturated fatty acids with juvenile idiopathic arthritis and ocular comorbidity. Eur J Clin Nutr (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI:


Quick links