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Causal relationship between genetically predicted white blood cell count and systemic lupus erythematosus: A Mendelian randomization study.

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Title: Causal relationship between genetically predicted white blood cell count and systemic lupus erythematosus: A Mendelian randomization study.
Authors: Wang XF; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China., Zhang L; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China., Yao QY; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China., Liu J; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China., Dang ZX; School of Cyberspace Security, Xi'an University of Posts and Telecommunications, Xi'an, Shaanxi, China., Zhu YH; Institute of Endemic Diseases, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
Source: Medicine [Medicine (Baltimore)] 2026 Sep 25; Vol. 105 (39), pp. e50878.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 2985248R Publication Model: Print Cited Medium: Internet ISSN: 1536-5964 (Electronic) Linking ISSN: 00257974 NLM ISO Abbreviation: Medicine (Baltimore) Subsets: MEDLINE
Imprint Name(s): Original Publication: Hagerstown, Md : Lippincott Williams & Wilkins
MeSH Terms: Lupus Erythematosus, Systemic*/genetics , Lupus Erythematosus, Systemic*/blood , Mendelian Randomization Analysis*, Humans ; Leukocyte Count ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease
Abstract: Observational studies have suggested an association between white blood cell (WBC) count and systemic lupus erythematosus (SLE). However, the causal relationship remains uncertain because of potential confounding factors. This Mendelian randomization (MR) study aimed to investigate the causal effect of WBC count on SLE risk by using genetic instruments. Genetically predicted higher WBC counts were associated with a reduced risk of SLE (inverse-variance weighted [IVW]: odds ratio = 0.384, 95% confidence interval = 0.160-0.920, P = .031; weighted median: odds ratio = 0.326, 95% confidence interval = 0.124-0.859, P = .023). MR-Egger regression revealed no evidence of horizontal pleiotropy (intercept, P = .705), and MR polygenic residual sum and outlier (MR-PRESSO) detected 4 outliers. After outlier removal, heterogeneity decreased, and the IVW and weighted median estimates remained significant (beta = -0.96, P = .03; beta = -1.12, P = .023, respectively). We conducted a 2-sample MR analysis using summary statistics from genome-wide association studies (GWAS) of European ancestry: WBC count (GWAS ID: ieu-b-30, N = 563,946) and SLE (GWAS ID: ieu-a-815, 14,267 cases, and 43,047 controls). Sixty-five independent single-nucleotide polymorphisms (P < 5 × 10-8, clumped at r2 < 0.001) were selected as instrumental variables, with a mean F statistic of 28.6, indicating strong instrument strength. Analyses were performed using R statistical software (R Foundation for Statistical Computing) with the TwoSampleMR and MR-PRESSO packages. The primary analytical methods included IVW, weighted median, and MR-Egger regression. Sensitivity analyses included Cochran Q test for heterogeneity, MR-PRESSO outlier correction, and leave-one-out validation to ensure robustness. This MR analysis supports an independent causal protective effect of genetically predicted higher WBC counts on SLE risk. These findings should not be extrapolated as evidence for therapeutic leukocyte elevation, nor do they alter the clinical management of leukopenia observed in active SLE or during immunosuppressive therapy. The genetic signal likely reflects broader immune homeostatic regulation rather than lineage-specific effects, the mechanistic basis of which warrants dedicated functional investigation.
(Copyright © 2026 the Author(s). Published by Wolters Kluwer Health, LLC.)
Competing Interests: The authors have no conflicts of interest to declare.
References: PLoS One. 2016 Feb 18;11(2):e0148963. (PMID: 26891449)
Ann Rheum Dis. 2023 Mar;82(3):351-356. (PMID: 36241363)
Biochem Biophys Rep. 2025 Mar 24;42:101977. (PMID: 40212811)
Iran J Immunol. 2007 Jun;4(2):110-5. (PMID: 17652851)
Front Biosci (Landmark Ed). 2023 Dec 28;28(12):358. (PMID: 38179775)
Rheumatol Ther. 2021 Sep;8(3):1177-1188. (PMID: 34151412)
Cell. 2020 Sep 3;182(5):1198-1213.e14. (PMID: 32888493)
Autoimmun Rev. 2013 May;12(7):784-91. (PMID: 23462431)
Q J Med. 1991 Jul;80(291):605-12. (PMID: 1946940)
Arthritis Res Ther. 2004;6(4):178-80. (PMID: 15225363)
Nat Rev Rheumatol. 2010 Dec;6(12):683-92. (PMID: 21060334)
J Clin Cell Immunol. 2013 Apr;4:. (PMID: 24244889)
Clin Exp Rheumatol. 2025 Jul;43(7):1259-1276. (PMID: 40242921)
Clin Immunol. 2017 Dec;185:59-73. (PMID: 27519955)
Rheumatology (Oxford). 2006 Aug;45(8):994-8. (PMID: 16484291)
Arthritis Rheum. 2011 Jan;63(1):212-8. (PMID: 20954190)
Nat Commun. 2023 Feb 16;14(1):872. (PMID: 36797275)
Semin Immunol. 2016 Apr;28(2):159-73. (PMID: 27036091)
Arthritis Rheumatol. 2023 Apr;75(4):574-585. (PMID: 36245280)
J Immunol. 2010 Mar 15;184(6):3284-97. (PMID: 20164424)
J Immunol. 2011 Jul 1;187(1):538-52. (PMID: 21613614)
Lupus Sci Med. 2020 May;7(1):. (PMID: 32444416)
Nat Rev Rheumatol. 2016 Oct;12(10):605-20. (PMID: 27558659)
J Immunol. 2002 Aug 15;169(4):2148-55. (PMID: 12165544)
Biochem Pharmacol. 2011 Nov 15;82(10):1391-402. (PMID: 21723852)
Acta Haematol. 2021;144(4):403-412. (PMID: 33221805)
Front Immunol. 2012 Dec 14;3:380. (PMID: 23248629)
J Rheumatol. 2023 Mar;50(3):459-460. (PMID: 36243416)
Hum Mol Genet. 2014 Sep 15;23(R1):R89-98. (PMID: 25064373)
Arthritis Rheum. 1970 Nov-Dec;13(6):802-11. (PMID: 5495391)
Rheumatology (Oxford). 2021 Nov 3;60(11):5185-5193. (PMID: 33693676)
Sci Rep. 2023 Nov 26;13(1):20768. (PMID: 38008752)
Nat Rev Rheumatol. 2011 Sep 27;7(12):691-9. (PMID: 21947176)
Semin Arthritis Rheum. 2015 Oct;45(2):190-4. (PMID: 26170228)
Grant Information: 81441016 he National Natural Science Foundation of China; 2020SF-262 Key R&D Plan in Shaanxi Province of China; 2019SF-200 Key R&D Plan in Shaanxi Province of China
Contributed Indexing: Keywords: GWAS; Mendelian randomization; R software; causal inference; systemic lupus erythematosus; white blood cell count
Entry Date(s): Date Created: 20260926 Date Completed: 20260926 Latest Revision: 20260930
Update Code: 20260930
PubMed Central ID: PMC13619244
DOI: 10.1097/MD.0000000000050878
PMID: 42798072
Database: MEDLINE
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  Data: Causal relationship between genetically predicted white blood cell count and systemic lupus erythematosus: A Mendelian randomization study.
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  Data: &lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Wang+XF%22&quot;&gt;Wang XF&lt;/searchLink&gt;; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi&#39;an Jiaotong University Health Science Center, Xi&#39;an, Shaanxi, China.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Zhang+L%22&quot;&gt;Zhang L&lt;/searchLink&gt;; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi&#39;an Jiaotong University Health Science Center, Xi&#39;an, Shaanxi, China.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Yao+QY%22&quot;&gt;Yao QY&lt;/searchLink&gt;; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi&#39;an Jiaotong University Health Science Center, Xi&#39;an, Shaanxi, China.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Liu+J%22&quot;&gt;Liu J&lt;/searchLink&gt;; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi&#39;an Jiaotong University Health Science Center, Xi&#39;an, Shaanxi, China.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Dang+ZX%22&quot;&gt;Dang ZX&lt;/searchLink&gt;; School of Cyberspace Security, Xi&#39;an University of Posts and Telecommunications, Xi&#39;an, Shaanxi, China.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Zhu+YH%22&quot;&gt;Zhu YH&lt;/searchLink&gt;; Institute of Endemic Diseases, School of Public Health, Xi&#39;an Jiaotong University Health Science Center, Xi&#39;an, Shaanxi, China.
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  Data: &lt;searchLink fieldCode=&quot;MM&quot; term=&quot;%22Lupus+Erythematosus%2C+Systemic%22&quot;&gt;Lupus Erythematosus, Systemic*&lt;/searchLink&gt;/&lt;searchLink fieldCode=&quot;MM&quot; term=&quot;%22Lupus+Erythematosus%2C+Systemic+genetics%22&quot;&gt;genetics&lt;/searchLink&gt; &lt;br /&gt;&lt;searchLink fieldCode=&quot;MM&quot; term=&quot;%22Lupus+Erythematosus%2C+Systemic%22&quot;&gt;Lupus Erythematosus, Systemic*&lt;/searchLink&gt;/&lt;searchLink fieldCode=&quot;MM&quot; term=&quot;%22Lupus+Erythematosus%2C+Systemic+blood%22&quot;&gt;blood&lt;/searchLink&gt; &lt;br /&gt;&lt;searchLink fieldCode=&quot;MM&quot; term=&quot;%22Mendelian+Randomization+Analysis%22&quot;&gt;Mendelian Randomization Analysis*&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;MH&quot; term=&quot;%22Humans%22&quot;&gt;Humans&lt;/searchLink&gt; ; &lt;searchLink fieldCode=&quot;MH&quot; term=&quot;%22Leukocyte+Count%22&quot;&gt;Leukocyte Count&lt;/searchLink&gt; ; &lt;searchLink fieldCode=&quot;MH&quot; term=&quot;%22Genome-Wide+Association+Study%22&quot;&gt;Genome-Wide Association Study&lt;/searchLink&gt; ; &lt;searchLink fieldCode=&quot;MH&quot; term=&quot;%22Polymorphism%2C+Single+Nucleotide%22&quot;&gt;Polymorphism, Single Nucleotide&lt;/searchLink&gt; ; &lt;searchLink fieldCode=&quot;MH&quot; term=&quot;%22Genetic+Predisposition+to+Disease%22&quot;&gt;Genetic Predisposition to Disease&lt;/searchLink&gt;
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  Data: Observational studies have suggested an association between white blood cell (WBC) count and systemic lupus erythematosus (SLE). However, the causal relationship remains uncertain because of potential confounding factors. This Mendelian randomization (MR) study aimed to investigate the causal effect of WBC count on SLE risk by using genetic instruments. Genetically predicted higher WBC counts were associated with a reduced risk of SLE (inverse-variance weighted [IVW]: odds ratio = 0.384, 95% confidence interval = 0.160-0.920, P = .031; weighted median: odds ratio = 0.326, 95% confidence interval = 0.124-0.859, P = .023). MR-Egger regression revealed no evidence of horizontal pleiotropy (intercept, P = .705), and MR polygenic residual sum and outlier (MR-PRESSO) detected 4 outliers. After outlier removal, heterogeneity decreased, and the IVW and weighted median estimates remained significant (beta = -0.96, P = .03; beta = -1.12, P = .023, respectively). We conducted a 2-sample MR analysis using summary statistics from genome-wide association studies (GWAS) of European ancestry: WBC count (GWAS ID: ieu-b-30, N = 563,946) and SLE (GWAS ID: ieu-a-815, 14,267 cases, and 43,047 controls). Sixty-five independent single-nucleotide polymorphisms (P &amp;lt; 5 &#215; 10-8, clumped at r2 &amp;lt; 0.001) were selected as instrumental variables, with a mean F statistic of 28.6, indicating strong instrument strength. Analyses were performed using R statistical software (R Foundation for Statistical Computing) with the TwoSampleMR and MR-PRESSO packages. The primary analytical methods included IVW, weighted median, and MR-Egger regression. Sensitivity analyses included Cochran Q test for heterogeneity, MR-PRESSO outlier correction, and leave-one-out validation to ensure robustness. This MR analysis supports an independent causal protective effect of genetically predicted higher WBC counts on SLE risk. These findings should not be extrapolated as evidence for therapeutic leukocyte elevation, nor do they alter the clinical management of leukopenia observed in active SLE or during immunosuppressive therapy. The genetic signal likely reflects broader immune homeostatic regulation rather than lineage-specific effects, the mechanistic basis of which warrants dedicated functional investigation.&lt;br /&gt; (Copyright &#169; 2026 the Author(s). Published by Wolters Kluwer Health, LLC.)
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: The authors have no conflicts of interest to declare.
– Name: Ref
  Label: References
  Group: RefInfo
  Data: PLoS One. 2016 Feb 18;11(2):e0148963. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2226891449%22&quot;&gt;26891449)&lt;/searchLink&gt;&lt;br /&gt;Ann Rheum Dis. 2023 Mar;82(3):351-356. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2236241363%22&quot;&gt;36241363)&lt;/searchLink&gt;&lt;br /&gt;Biochem Biophys Rep. 2025 Mar 24;42:101977. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2240212811%22&quot;&gt;40212811)&lt;/searchLink&gt;&lt;br /&gt;Iran J Immunol. 2007 Jun;4(2):110-5. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2217652851%22&quot;&gt;17652851)&lt;/searchLink&gt;&lt;br /&gt;Front Biosci (Landmark Ed). 2023 Dec 28;28(12):358. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2238179775%22&quot;&gt;38179775)&lt;/searchLink&gt;&lt;br /&gt;Rheumatol Ther. 2021 Sep;8(3):1177-1188. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2234151412%22&quot;&gt;34151412)&lt;/searchLink&gt;&lt;br /&gt;Cell. 2020 Sep 3;182(5):1198-1213.e14. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2232888493%22&quot;&gt;32888493)&lt;/searchLink&gt;&lt;br /&gt;Autoimmun Rev. 2013 May;12(7):784-91. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2223462431%22&quot;&gt;23462431)&lt;/searchLink&gt;&lt;br /&gt;Q J Med. 1991 Jul;80(291):605-12. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%221946940%22&quot;&gt;1946940)&lt;/searchLink&gt;&lt;br /&gt;Arthritis Res Ther. 2004;6(4):178-80. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2215225363%22&quot;&gt;15225363)&lt;/searchLink&gt;&lt;br /&gt;Nat Rev Rheumatol. 2010 Dec;6(12):683-92. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2221060334%22&quot;&gt;21060334)&lt;/searchLink&gt;&lt;br /&gt;J Clin Cell Immunol. 2013 Apr;4:. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2224244889%22&quot;&gt;24244889)&lt;/searchLink&gt;&lt;br /&gt;Clin Exp Rheumatol. 2025 Jul;43(7):1259-1276. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2240242921%22&quot;&gt;40242921)&lt;/searchLink&gt;&lt;br /&gt;Clin Immunol. 2017 Dec;185:59-73. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2227519955%22&quot;&gt;27519955)&lt;/searchLink&gt;&lt;br /&gt;Rheumatology (Oxford). 2006 Aug;45(8):994-8. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2216484291%22&quot;&gt;16484291)&lt;/searchLink&gt;&lt;br /&gt;Arthritis Rheum. 2011 Jan;63(1):212-8. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2220954190%22&quot;&gt;20954190)&lt;/searchLink&gt;&lt;br /&gt;Nat Commun. 2023 Feb 16;14(1):872. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2236797275%22&quot;&gt;36797275)&lt;/searchLink&gt;&lt;br /&gt;Semin Immunol. 2016 Apr;28(2):159-73. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2227036091%22&quot;&gt;27036091)&lt;/searchLink&gt;&lt;br /&gt;Arthritis Rheumatol. 2023 Apr;75(4):574-585. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2236245280%22&quot;&gt;36245280)&lt;/searchLink&gt;&lt;br /&gt;J Immunol. 2010 Mar 15;184(6):3284-97. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2220164424%22&quot;&gt;20164424)&lt;/searchLink&gt;&lt;br /&gt;J Immunol. 2011 Jul 1;187(1):538-52. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2221613614%22&quot;&gt;21613614)&lt;/searchLink&gt;&lt;br /&gt;Lupus Sci Med. 2020 May;7(1):. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2232444416%22&quot;&gt;32444416)&lt;/searchLink&gt;&lt;br /&gt;Nat Rev Rheumatol. 2016 Oct;12(10):605-20. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2227558659%22&quot;&gt;27558659)&lt;/searchLink&gt;&lt;br /&gt;J Immunol. 2002 Aug 15;169(4):2148-55. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2212165544%22&quot;&gt;12165544)&lt;/searchLink&gt;&lt;br /&gt;Biochem Pharmacol. 2011 Nov 15;82(10):1391-402. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2221723852%22&quot;&gt;21723852)&lt;/searchLink&gt;&lt;br /&gt;Acta Haematol. 2021;144(4):403-412. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2233221805%22&quot;&gt;33221805)&lt;/searchLink&gt;&lt;br /&gt;Front Immunol. 2012 Dec 14;3:380. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2223248629%22&quot;&gt;23248629)&lt;/searchLink&gt;&lt;br /&gt;J Rheumatol. 2023 Mar;50(3):459-460. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2236243416%22&quot;&gt;36243416)&lt;/searchLink&gt;&lt;br /&gt;Hum Mol Genet. 2014 Sep 15;23(R1):R89-98. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2225064373%22&quot;&gt;25064373)&lt;/searchLink&gt;&lt;br /&gt;Arthritis Rheum. 1970 Nov-Dec;13(6):802-11. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%225495391%22&quot;&gt;5495391)&lt;/searchLink&gt;&lt;br /&gt;Rheumatology (Oxford). 2021 Nov 3;60(11):5185-5193. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2233693676%22&quot;&gt;33693676)&lt;/searchLink&gt;&lt;br /&gt;Sci Rep. 2023 Nov 26;13(1):20768. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2238008752%22&quot;&gt;38008752)&lt;/searchLink&gt;&lt;br /&gt;Nat Rev Rheumatol. 2011 Sep 27;7(12):691-9. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2221947176%22&quot;&gt;21947176)&lt;/searchLink&gt;&lt;br /&gt;Semin Arthritis Rheum. 2015 Oct;45(2):190-4. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2226170228%22&quot;&gt;26170228)&lt;/searchLink&gt;
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  Data: 81441016 he National Natural Science Foundation of China; 2020SF-262 Key R&amp;D Plan in Shaanxi Province of China; 2019SF-200 Key R&amp;D Plan in Shaanxi Province of China
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  Data: &lt;i&gt;Keywords: &lt;/i&gt;GWAS; Mendelian randomization; R software; causal inference; systemic lupus erythematosus; white blood cell count
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      – SubjectFull: Humans
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      – SubjectFull: Leukocyte Count
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      – SubjectFull: Genome-Wide Association Study
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      – SubjectFull: Lupus Erythematosus, Systemic blood
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      – SubjectFull: Mendelian Randomization Analysis
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      – TitleFull: Causal relationship between genetically predicted white blood cell count and systemic lupus erythematosus: A Mendelian randomization study.
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      – PersonEntity:
          Name:
            NameFull: Wang XF
      – PersonEntity:
          Name:
            NameFull: Zhang L
      – PersonEntity:
          Name:
            NameFull: Yao QY
      – PersonEntity:
          Name:
            NameFull: Liu J
      – PersonEntity:
          Name:
            NameFull: Dang ZX
      – PersonEntity:
          Name:
            NameFull: Zhu YH
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 25
              M: 09
              Text: 2026 Sep 25
              Type: published
              Y: 2026
          Identifiers:
            – Type: issn-electronic
              Value: 1536-5964
          Numbering:
            – Type: volume
              Value: 105
            – Type: issue
              Value: 39
          Titles:
            – TitleFull: Medicine
              Type: main
ResultId 1