Causal relationship between dietary habits and systemic lupus erythematosus: a Mendelian randomization analysis_Chinese Journal of Evidence-Based Medicine

Authors：

YUAN Hongxiu ^1,2 , ZENG Hong ³ , TANG Fajuan ^1,2 ,  LI Xihong ^1,2

1. Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, P. R. China;
2. Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, P. R. China;
3. Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

LI Xihong, Email: hilixihong@163.com

Keywords：

Dietary habits; Systemic lupus erythematosus; Mendelian randomization analysis; Genome-wide association study; Causal inference

DOI：

10.7507/1672-2531.202404027

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective This study employs Mendelian randomization analysis to explore the causal relationship between dietary habits and systemic lupus erythematosus (SLE). Methods We obtained data from the MRC-IEU database on five dietary habits as instrumental variables for exposure “never eating dairy products” “never eating eggs or foods containing eggs” “never eating sugar or foods/drinks containing sugar” “never eating wheat products” and “I eat all of the above”. Summary data related to SLE were retrieved from the MRC-IEU database for the discovery cohort (designated as MSLE) and from a Finnish database for the validation cohort (recorded as FSLE). Two-sample Mendelian randomization analyses were conducted using inverse variance weighting (IVW), MR-Egger, weighted median, Simple Mode, and Weighted Mode methods to investigate the causal relationship between dietary habits and SLE. The MR-Egger intercept test was performed to assess the presence of horizontal pleiotropy, while the leave-one-out method was employed to verify the stability of the results, with Cochran’s Q test and funnel plots used to evaluate heterogeneity. Results Mendelian randomization analysis indicated that never eating wheat products increases the risk of developing SLE (IVW P<0.05). In contrast, there was no significant causal relationship between the consumption of dairy products, eggs or foods containing eggs, or the consumption of all of the above with SLE (IVW P>0.05). Additionally, there was no significant causal relationship between never sugar or foods/drinks containing sugar and MSLE (IVW P=0.877), although a potential causal association with FSLE was suggested (IVW P=0.016). The MR-Egger intercept test indicated no evidence of horizontal pleiotropy (P>0.05). Conclusion Never eating wheat products may be an independent risk factor for SLE. However, the causal relationship between never sugar or foods/drinks containing sugar and SLE remains indeterminate.

1.	Durcan L, O'Dwyer T, Petri M. Management strategies and future directions for systemic lupus erythematosus in adults. Lancet, 2019, 393(10188): 2332-2343.
2.	Tektonidou MG, Lewandowski LB, Hu J, et al. Survival in adults and children with systemic lupus erythematosus: a systematic review and Bayesian meta-analysis of studies from 1950 to 2016. Ann Rheum Dis, 2017, 76(12): 2009-2016.
3.	Kuo CF, Grainge MJ, Valdes AM, et al. Familial aggregation of systemic lupus erythematosus and coaggregation of autoimmune diseases in affected families. JAMA Intern Med, 2015, 175(9): 1518-1526.
4.	Armstrong DL, Zidovetzki R, Alarcón-Riquelme ME, et al. GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region. Genes Immun, 2014, 15(6): 347-354.
5.	Islam MA, Khandker SS, Kotyla PJ, et al. Immunomodulatory effects of diet and nutrients in systemic lupus erythematosus (SLE): a systematic review. Front Immunol, 2020, 11: 1477.
6.	Jiao H, Acar G, Robinson GA, et al. Diet and systemic lupus erythematosus (SLE): from supplementation to intervention. Int J Environ Res Public Health, 2022, 19(19): 11895.
7.	Wang H, Li XB, Huang RG, et al. Essential trace element status in systemic lupus erythematosus: a meta-analysis based on case-control studies. Biol Trace Elem Res, 2023, 201(5): 2170-2182.
8.	Touil H, Mounts K, De Jager PL. Differential impact of environmental factors on systemic and localized autoimmunity. Front Immunol, 2023, 14: 1147447.
9.	Gwinnutt JM, Wieczorek M, Rodríguez-Carrio J, et al. Effects of diet on the outcomes of rheumatic and musculoskeletal diseases (RMDs): systematic review and meta-analyses informing the 2021 EULAR recommendations for lifestyle improvements in people with RMDs. RMD Open, 2022, 8(2): e002167.
10.	Guagnano MT, D'Angelo C, Caniglia D, et al. Improvement of inflammation and pain after three months' exclusion diet in rheumatoid arthritis patients. Nutrients, 2021, 13(10): 3535.
11.	Du Z, Guo S, Sun Y, et al. Causal relationships between dietary habits and five major mental disorders: a two-sample Mendelian randomization study. J Affect Disord, 2023, 340: 607-615.
12.	Meza-Meza MR, Vizmanos-Lamotte B, Muñoz-Valle JF, et al. Relationship of excess weight with clinical activity and dietary intake deficiencies in systemic lupus erythematosus patients. Nutrients, 2019, 11(11): 2683.
13.	Comstock GW, Burke AE, Hoffman SC, et al. Serum concentrations of alpha tocopherol, beta carotene, and retinol preceding the diagnosis of rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis, 1997, 56(5): 323-325.
14.	Vučković F, Krištić J, Gudelj I, et al. Association of systemic lupus erythematosus with decreased immunosuppressive potential of the IgG glycome. Arthritis Rheumatol, 2015, 67(11): 2978-2989.
15.	Matei L, Matei I. Lectin-binding profile of serum IgA in women suffering from systemic autoimmune rheumatic disorders. Rom J Intern Med, 2000, -2001,38-39: 73-82.
16.	Castro-Webb N, Cozier YC, Barbhaiya M, et al. Association of macronutrients and dietary patterns with risk of systemic lupus erythematosus in the black women's health study. Am J Clin Nutr, 2021, 114(4): 1486-1494.
17.	于天琦, 徐文涛, 苏雅娜, 等. 孟德尔随机化研究基本原理、方法和局限性. 中国循证医学杂志, 2021, 21(10): 1227-1234.
18.	Bentham J, Morris DL, Graham DSC, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet, 2015, 47(12): 1457-1464.
19.	Fadista J, Manning AK, Florez JC, et al. The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants. Eur J Hum Genet, 2016, 24(8): 1202-1205.
20.	Li H, Pan X, Zhang S, et al. Association of autoimmune diseases with the occurrence and 28-day mortality of sepsis: an observational and Mendelian randomization study. Crit Care, 2023, 27(1): 476.
21.	尚文茹, 柯立鑫, 王子怡, 等. 牛奶、咖啡摄入与非酒精性脂肪性肝病的因果关联: 两样本孟德尔随机化研究. 中国循证医学杂志, 2023, 23(12): 1373-1377.
22.	Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol, 2011, 40(3): 755-764.
23.	Levin MG, Judy R, Gill D, et al. Genetics of height and risk of atrial fibrillation: a Mendelian randomization study. PLoS Med, 2020, 17(10): e1003288.
24.	Burgess S, Scott RA, Timpson NJ, et al. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol, 2015, 30(7): 543-552.
25.	Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
26.	Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol, 2017, 46(6): 1985-1998.
27.	Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
28.	Maeshima E, Liang XM, Goda M, et al. The efficacy of vitamin E against oxidative damage and autoantibody production in systemic lupus erythematosus: a preliminary study. Clin Rheumatol, 2007, 26(3): 401-404.
29.	Hsieh CC, Lin BF. The effects of vitamin E supplementation on autoimmune-prone New Zealand black x New Zealand white F1 mice fed an oxidised oil diet. Br J Nutr, 2005, 93(5): 655-662.
30.	Hsieh CC, Lin BF. Opposite effects of low and high dose supplementation of vitamin E on survival of MRL/lpr mice. Nutrition, 2005, 21(9): 940-948.
31.	Ray D, Strickland FM, Richardson BC. Oxidative stress and dietary micronutrient deficiencies contribute to overexpression of epigenetically regulated genes by lupus T cells. Clin Immunol, 2018, 196: 97-102.
32.	Fasano S, Milone A, Nicoletti GF, et al. Precision medicine in systemic lupus erythematosus. Nat Rev Rheumatol, 2023, 19(6): 331-342.
33.	Coit P, Ortiz-Fernandez L, Lewis EE, et al. A longitudinal and transancestral analysis of DNA methylation patterns and disease activity in lupus patients. JCI Insight, 2020, 5(22): e143654.
34.	Sun L, Zeng K, Wang Q. Study of riboflavin nutritional status in patients with systemic lupus erythematosus. Mod Prev Med, 2007, 1: 53-55.
35.	Minami Y, Hirabayashi Y, Nagata C, et al. Intakes of vitamin B6 and dietary fiber and clinical course of systemic lupus erythematosus: a prospective study of Japanese female patients. J Epidemiol, 2011, 21(4): 246-254.
36.	Borges MC, dos Santos Fde M, Telles RW, et al. Nutritional status and food intake in patients with systemic lupus erythematosus. Nutrition, 2012, 28(11-12): 1098-1103.
37.	Du X, Zhao D, Wang Y, et al. Low serum calcium concentration in patients with systemic lupus erythematosus accompanied by the enhanced peripheral cellular immunity. Front Immunol, 2022, 13: 901854.
38.	Mathieu C, Van Etten E, Gysemans C, et al. In vitro and in vivo analysis of the immune system of vitamin D receptor knockout mice. J Bone Miner Res, 2001, 16(11): 2057-2065.
39.	Athanassiou L, Kostoglou-Athanassiou I, Koutsilieris M, et al. Vitamin D and autoimmune rheumatic diseases. Biomolecules, 2023, 13(4): 709.
40.	Sassi F, Tamone C, D'Amelio P. Vitamin D: nutrient, hormone, and immunomodulator. Nutrients, 2018, 10(11): 1656.
41.	González S, Gutie Rrez-Díaz I, Lo Pez P, et al. Microbiota and oxidant-antioxidant balance in systemic lupus erythematosus. Nutr Hosp, 2017, 34(4): 934-941.
42.	Pedro EM, da Rosa Franchi Santos LF, Scavuzzi BM, et al. Trace elements associated with systemic lupus erythematosus and insulin resistance. Biol Trace Elem Res, 2019, 191(1): 34-44.
43.	Tóth CN, Baranyai E, Csípő I, et al. Elemental analysis of whole and protein separated blood serum of patients with systemic lupus erythematosus and sjögren's syndrome. Biol Trace Elem Res, 2017, 179(1): 14-22.
44.	Jahan I, Das DC, Hussain MS, et al. Alterations of serum trace elements and other biochemical parameters are correlated with the pathogenesis of systemic lupus erythematosus: a preliminary study on Bangladeshi population. J Trace Elem Med Biol, 2021, 68: 126861.
45.	Sahebari M, Abrishami-Moghaddam M, Moezzi A, et al. Association between serum trace element concentrations and the disease activity of systemic lupus erythematosus. Lupus, 2014, 23(8): 793-801.
46.	Yilmaz A, Sari RA, Gundogdu M, et al. Trace elements and some extracellular antioxidant proteins levels in serum of patients with systemic lupus erythematosus. Clin Rheumatol, 2005, 24(4): 331-335.
47.	He A, Wang W, Prakash NT, et al. Integrating genome-wide association study summaries and element-gene interaction datasets identified multiple associations between elements and complex diseases. Genet Epidemiol, 2018, 42(2): 168-173.
48.	Koca SS, Isik A, Ustundag B, et al. Serum pro-hepcidin levels in rheumatoid arthritis and systemic lupus erythematosus. Inflammation, 2008, 31(3): 146-153.
49.	Gamal NM, Khedr TM, Ismail NM, et al. Is it useful to measure serum ferritin level in systemic lupus erythematosus patients. Egypt Rheumatol, 2020, 42(1): 17-21.
50.	Lozovoy MA, Simão AN, Oliveira SR, et al. Relationship between iron metabolism, oxidative stress, and insulin resistance in patients with systemic lupus erythematosus. Scand J Rheumatol, 2013, 42(4): 303-310.
51.	Leiter LM, Reuhl KR, Racis SP, et al. Iron status alters murine systemic lupus erythematosus. J Nutr, 1995, 125(3): 474-484.
52.	Knippenberg A, Robinson GA, Wincup C, et al. Plant-based dietary changes may improve symptoms in patients with systemic lupus erythematosus. Lupus, 2022, 31(1): 65-76.

1. Durcan L, O'Dwyer T, Petri M. Management strategies and future directions for systemic lupus erythematosus in adults. Lancet, 2019, 393(10188): 2332-2343.
2. Tektonidou MG, Lewandowski LB, Hu J, et al. Survival in adults and children with systemic lupus erythematosus: a systematic review and Bayesian meta-analysis of studies from 1950 to 2016. Ann Rheum Dis, 2017, 76(12): 2009-2016.
3. Kuo CF, Grainge MJ, Valdes AM, et al. Familial aggregation of systemic lupus erythematosus and coaggregation of autoimmune diseases in affected families. JAMA Intern Med, 2015, 175(9): 1518-1526.
4. Armstrong DL, Zidovetzki R, Alarcón-Riquelme ME, et al. GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region. Genes Immun, 2014, 15(6): 347-354.
5. Islam MA, Khandker SS, Kotyla PJ, et al. Immunomodulatory effects of diet and nutrients in systemic lupus erythematosus (SLE): a systematic review. Front Immunol, 2020, 11: 1477.
6. Jiao H, Acar G, Robinson GA, et al. Diet and systemic lupus erythematosus (SLE): from supplementation to intervention. Int J Environ Res Public Health, 2022, 19(19): 11895.
7. Wang H, Li XB, Huang RG, et al. Essential trace element status in systemic lupus erythematosus: a meta-analysis based on case-control studies. Biol Trace Elem Res, 2023, 201(5): 2170-2182.
8. Touil H, Mounts K, De Jager PL. Differential impact of environmental factors on systemic and localized autoimmunity. Front Immunol, 2023, 14: 1147447.
9. Gwinnutt JM, Wieczorek M, Rodríguez-Carrio J, et al. Effects of diet on the outcomes of rheumatic and musculoskeletal diseases (RMDs): systematic review and meta-analyses informing the 2021 EULAR recommendations for lifestyle improvements in people with RMDs. RMD Open, 2022, 8(2): e002167.
10. Guagnano MT, D'Angelo C, Caniglia D, et al. Improvement of inflammation and pain after three months' exclusion diet in rheumatoid arthritis patients. Nutrients, 2021, 13(10): 3535.
11. Du Z, Guo S, Sun Y, et al. Causal relationships between dietary habits and five major mental disorders: a two-sample Mendelian randomization study. J Affect Disord, 2023, 340: 607-615.
12. Meza-Meza MR, Vizmanos-Lamotte B, Muñoz-Valle JF, et al. Relationship of excess weight with clinical activity and dietary intake deficiencies in systemic lupus erythematosus patients. Nutrients, 2019, 11(11): 2683.
13. Comstock GW, Burke AE, Hoffman SC, et al. Serum concentrations of alpha tocopherol, beta carotene, and retinol preceding the diagnosis of rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis, 1997, 56(5): 323-325.
14. Vučković F, Krištić J, Gudelj I, et al. Association of systemic lupus erythematosus with decreased immunosuppressive potential of the IgG glycome. Arthritis Rheumatol, 2015, 67(11): 2978-2989.
15. Matei L, Matei I. Lectin-binding profile of serum IgA in women suffering from systemic autoimmune rheumatic disorders. Rom J Intern Med, 2000, -2001,38-39: 73-82.
16. Castro-Webb N, Cozier YC, Barbhaiya M, et al. Association of macronutrients and dietary patterns with risk of systemic lupus erythematosus in the black women's health study. Am J Clin Nutr, 2021, 114(4): 1486-1494.
17. 于天琦, 徐文涛, 苏雅娜, 等. 孟德尔随机化研究基本原理、方法和局限性. 中国循证医学杂志, 2021, 21(10): 1227-1234.
18. Bentham J, Morris DL, Graham DSC, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet, 2015, 47(12): 1457-1464.
19. Fadista J, Manning AK, Florez JC, et al. The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants. Eur J Hum Genet, 2016, 24(8): 1202-1205.
20. Li H, Pan X, Zhang S, et al. Association of autoimmune diseases with the occurrence and 28-day mortality of sepsis: an observational and Mendelian randomization study. Crit Care, 2023, 27(1): 476.
21. 尚文茹, 柯立鑫, 王子怡, 等. 牛奶、咖啡摄入与非酒精性脂肪性肝病的因果关联: 两样本孟德尔随机化研究. 中国循证医学杂志, 2023, 23(12): 1373-1377.
22. Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol, 2011, 40(3): 755-764.
23. Levin MG, Judy R, Gill D, et al. Genetics of height and risk of atrial fibrillation: a Mendelian randomization study. PLoS Med, 2020, 17(10): e1003288.
24. Burgess S, Scott RA, Timpson NJ, et al. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol, 2015, 30(7): 543-552.
25. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
26. Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol, 2017, 46(6): 1985-1998.
27. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
28. Maeshima E, Liang XM, Goda M, et al. The efficacy of vitamin E against oxidative damage and autoantibody production in systemic lupus erythematosus: a preliminary study. Clin Rheumatol, 2007, 26(3): 401-404.
29. Hsieh CC, Lin BF. The effects of vitamin E supplementation on autoimmune-prone New Zealand black x New Zealand white F1 mice fed an oxidised oil diet. Br J Nutr, 2005, 93(5): 655-662.
30. Hsieh CC, Lin BF. Opposite effects of low and high dose supplementation of vitamin E on survival of MRL/lpr mice. Nutrition, 2005, 21(9): 940-948.
31. Ray D, Strickland FM, Richardson BC. Oxidative stress and dietary micronutrient deficiencies contribute to overexpression of epigenetically regulated genes by lupus T cells. Clin Immunol, 2018, 196: 97-102.
32. Fasano S, Milone A, Nicoletti GF, et al. Precision medicine in systemic lupus erythematosus. Nat Rev Rheumatol, 2023, 19(6): 331-342.
33. Coit P, Ortiz-Fernandez L, Lewis EE, et al. A longitudinal and transancestral analysis of DNA methylation patterns and disease activity in lupus patients. JCI Insight, 2020, 5(22): e143654.
34. Sun L, Zeng K, Wang Q. Study of riboflavin nutritional status in patients with systemic lupus erythematosus. Mod Prev Med, 2007, 1: 53-55.
35. Minami Y, Hirabayashi Y, Nagata C, et al. Intakes of vitamin B6 and dietary fiber and clinical course of systemic lupus erythematosus: a prospective study of Japanese female patients. J Epidemiol, 2011, 21(4): 246-254.
36. Borges MC, dos Santos Fde M, Telles RW, et al. Nutritional status and food intake in patients with systemic lupus erythematosus. Nutrition, 2012, 28(11-12): 1098-1103.
37. Du X, Zhao D, Wang Y, et al. Low serum calcium concentration in patients with systemic lupus erythematosus accompanied by the enhanced peripheral cellular immunity. Front Immunol, 2022, 13: 901854.
38. Mathieu C, Van Etten E, Gysemans C, et al. In vitro and in vivo analysis of the immune system of vitamin D receptor knockout mice. J Bone Miner Res, 2001, 16(11): 2057-2065.
39. Athanassiou L, Kostoglou-Athanassiou I, Koutsilieris M, et al. Vitamin D and autoimmune rheumatic diseases. Biomolecules, 2023, 13(4): 709.
40. Sassi F, Tamone C, D'Amelio P. Vitamin D: nutrient, hormone, and immunomodulator. Nutrients, 2018, 10(11): 1656.
41. González S, Gutie Rrez-Díaz I, Lo Pez P, et al. Microbiota and oxidant-antioxidant balance in systemic lupus erythematosus. Nutr Hosp, 2017, 34(4): 934-941.
42. Pedro EM, da Rosa Franchi Santos LF, Scavuzzi BM, et al. Trace elements associated with systemic lupus erythematosus and insulin resistance. Biol Trace Elem Res, 2019, 191(1): 34-44.
43. Tóth CN, Baranyai E, Csípő I, et al. Elemental analysis of whole and protein separated blood serum of patients with systemic lupus erythematosus and sjögren's syndrome. Biol Trace Elem Res, 2017, 179(1): 14-22.
44. Jahan I, Das DC, Hussain MS, et al. Alterations of serum trace elements and other biochemical parameters are correlated with the pathogenesis of systemic lupus erythematosus: a preliminary study on Bangladeshi population. J Trace Elem Med Biol, 2021, 68: 126861.
45. Sahebari M, Abrishami-Moghaddam M, Moezzi A, et al. Association between serum trace element concentrations and the disease activity of systemic lupus erythematosus. Lupus, 2014, 23(8): 793-801.
46. Yilmaz A, Sari RA, Gundogdu M, et al. Trace elements and some extracellular antioxidant proteins levels in serum of patients with systemic lupus erythematosus. Clin Rheumatol, 2005, 24(4): 331-335.
47. He A, Wang W, Prakash NT, et al. Integrating genome-wide association study summaries and element-gene interaction datasets identified multiple associations between elements and complex diseases. Genet Epidemiol, 2018, 42(2): 168-173.
48. Koca SS, Isik A, Ustundag B, et al. Serum pro-hepcidin levels in rheumatoid arthritis and systemic lupus erythematosus. Inflammation, 2008, 31(3): 146-153.
49. Gamal NM, Khedr TM, Ismail NM, et al. Is it useful to measure serum ferritin level in systemic lupus erythematosus patients. Egypt Rheumatol, 2020, 42(1): 17-21.
50. Lozovoy MA, Simão AN, Oliveira SR, et al. Relationship between iron metabolism, oxidative stress, and insulin resistance in patients with systemic lupus erythematosus. Scand J Rheumatol, 2013, 42(4): 303-310.
51. Leiter LM, Reuhl KR, Racis SP, et al. Iron status alters murine systemic lupus erythematosus. J Nutr, 1995, 125(3): 474-484.
52. Knippenberg A, Robinson GA, Wincup C, et al. Plant-based dietary changes may improve symptoms in patients with systemic lupus erythematosus. Lupus, 2022, 31(1): 65-76.

Chinese Journal of Evidence-Based Medicine

Latest ArticlesCausal relationship between dietary habits and systemic lupus erythematosus: a Mendelian randomization analysis

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