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Body mass index and type 2 diabetes liability in osteomyelitis and cellulitis: A cross-biobank Mendelian randomization study.

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Τίτλος: Body mass index and type 2 diabetes liability in osteomyelitis and cellulitis: A cross-biobank Mendelian randomization study.
Συγγραφείς: Liu F; Department of Orthopedic Trauma, Longgang Central Hospital of Shenzhen, Shenzhen, Guangdong, China., Luo K; The Affiliated Qingyuan People's Hospital of Guangzhou Medical University (Qingyuan People's Hospital), Qingyuan, Guangdong, China., Liu H; Department of Orthopedic Trauma, Longgang Central Hospital of Shenzhen, Shenzhen, Guangdong, China.
Πηγή: Medicine [Medicine (Baltimore)] 2026 Oct 02; Vol. 105 (40), pp. e50945.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: 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
Ιατρικοί όροι (MeSH): Diabetes Mellitus, Type 2*/genetics , Diabetes Mellitus, Type 2*/complications , Diabetes Mellitus, Type 2*/epidemiology , Osteomyelitis*/genetics , Osteomyelitis*/epidemiology , Cellulitis*/genetics , Cellulitis*/epidemiology , Body Mass Index*, Obesity/genetics ; Humans ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; Biological Specimen Banks ; Female ; Male
Περίληψη: Previous Mendelian randomization (MR) studies have linked obesity and type 2 diabetes (T2D) liability to osteomyelitis and skin or soft-tissue infection, but the reproducibility of these associations across independent outcome biobanks remains uncertain. We conducted cross-biobank univariable MR and multivariable MR analyses using European-ancestry genome-wide association study summary statistics. FinnGen Release 13 osteomyelitis (2519 cases and 471,012 controls) was designated as the primary clinical outcome, whereas cellulitis (10,223 cases and 468,418 controls) served as a comparative infection outcome; UK Biobank (UKB)-derived outcomes were used for replication. Exposure instruments containing UKB participants were restricted to FinnGen analyses, while separate non-UKB instruments were used for replication and cross-biobank pooling. Inverse-variance weighting was the primary estimator, with instrument-strength, pleiotropy, directionality, influential-variant, and multivariable conditional-strength analyses used to assess robustness. In FinnGen, each 1-standard-deviation increase in genetically predicted body mass index (BMI) on the source-GWAS standardized scale was associated with osteomyelitis (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.33-1.93) and cellulitis (OR 1.50, 95% CI 1.37-1.63), while T2D liability was associated with osteomyelitis (OR 1.41, 95% CI 1.24-1.61). Using non-UKB instruments, BMI-osteomyelitis estimates were directionally consistent across FinnGen and UKB (pooled OR 1.38, 95% CI 1.13-1.67; I2 = 0%), whereas BMI-cellulitis was positive in both biobanks despite heterogeneity in magnitude (I2 = 78.1%). T2D liability was associated with osteomyelitis in FinnGen but was not supported in UKB univariable MR, with substantial cross-biobank heterogeneity (I2 = 84.8%); the corresponding UKB multivariable MR estimate was nominal. In multivariable analyses, BMI-cellulitis remained supported across datasets, whereas BMI-osteomyelitis estimates attenuated after adjustment for T2D liability. BMI-cellulitis showed the greatest reproducibility. For osteomyelitis, BMI showed a reproducible total association but weaker evidence after adjustment for T2D liability, whereas T2D liability was consistently associated with osteomyelitis in FinnGen but was not robustly replicated in UKB. These findings emphasize the importance of external replication and evidence grading when interpreting metabolic-infection MR associations.
(Copyright © 2026 the Author(s). Published by Wolters Kluwer Health, LLC.)
Competing Interests: The authors have no funding and conflicts of interest to declare.
References: Genet Epidemiol. 2016 May;40(4):304-14. (PMID: 27061298)
BMJ. 2018 Jul 12;362:k601. (PMID: 30002074)
Nat Genet. 2012 Sep;44(9):981-90. (PMID: 22885922)
Hum Mol Genet. 2018 Oct 15;27(20):3641-3649. (PMID: 30124842)
Int J Epidemiol. 2017 Dec 1;46(6):1985-1998. (PMID: 29040600)
Int J Epidemiol. 2019 Jun 1;48(3):713-727. (PMID: 30535378)
Infect Dis Clin North Am. 2017 Jun;31(2):325-338. (PMID: 28483044)
Nat Genet. 2018 Apr;50(4):559-571. (PMID: 29632382)
Medicine (Baltimore). 2024 May 17;103(20):e38214. (PMID: 38758842)
Curr Diabetes Rev. 2020;16(5):442-449. (PMID: 31657690)
Nature. 2015 Feb 12;518(7538):197-206. (PMID: 25673413)
Proc Nutr Soc. 2012 May;71(2):298-306. (PMID: 22414338)
Front Endocrinol (Lausanne). 2022 Dec 07;13:996863. (PMID: 36568121)
Genet Epidemiol. 2013 Nov;37(7):658-65. (PMID: 24114802)
Control Clin Trials. 1986 Sep;7(3):177-88. (PMID: 3802833)
JAMA. 2021 Oct 26;326(16):1614-1621. (PMID: 34698778)
Int J Epidemiol. 2013 Oct;42(5):1497-501. (PMID: 24159078)
Am J Epidemiol. 2015 Feb 15;181(4):251-60. (PMID: 25632051)
JMIR Dermatol. 2024 Aug 20;7:e54302. (PMID: 39163102)
Int J Epidemiol. 2015 Apr;44(2):512-25. (PMID: 26050253)
Nat Genet. 2018 May;50(5):693-698. (PMID: 29686387)
Medicine (Baltimore). 2024 Sep 27;103(39):e39833. (PMID: 39331936)
Nature. 2023 Jan;613(7944):508-518. (PMID: 36653562)
Stat Med. 2021 Nov 10;40(25):5434-5452. (PMID: 34338327)
Nucleic Acids Res. 2019 Jan 8;47(D1):D1005-D1012. (PMID: 30445434)
Medicine (Baltimore). 2025 Mar 07;104(10):e41688. (PMID: 40068038)
PLoS Genet. 2017 Nov 17;13(11):e1007081. (PMID: 29149188)
Contributed Indexing: Keywords: Mendelian randomization; body mass index; cellulitis; genome-wide association study; osteomyelitis; type 2 diabetes
Entry Date(s): Date Created: 20261002 Date Completed: 20261002 Latest Revision: 20261005
Update Code: 20261005
PubMed Central ID: PMC13632998
DOI: 10.1097/MD.0000000000050945
PMID: 42826290
Βάση Δεδομένων: MEDLINE
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  Data: Body mass index and type 2 diabetes liability in osteomyelitis and cellulitis: A cross-biobank Mendelian randomization study.
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  Data: <searchLink fieldCode="AU" term="%22Liu+F%22">Liu F</searchLink>; Department of Orthopedic Trauma, Longgang Central Hospital of Shenzhen, Shenzhen, Guangdong, China.<br /><searchLink fieldCode="AU" term="%22Luo+K%22">Luo K</searchLink>; The Affiliated Qingyuan People's Hospital of Guangzhou Medical University (Qingyuan People's Hospital), Qingyuan, Guangdong, China.<br /><searchLink fieldCode="AU" term="%22Liu+H%22">Liu H</searchLink>; Department of Orthopedic Trauma, Longgang Central Hospital of Shenzhen, Shenzhen, Guangdong, China.
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  Data: <searchLink fieldCode="MM" term="%22Diabetes+Mellitus%2C+Type+2%22">Diabetes Mellitus, Type 2*</searchLink>/<searchLink fieldCode="MM" term="%22Diabetes+Mellitus%2C+Type+2+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Diabetes+Mellitus%2C+Type+2%22">Diabetes Mellitus, Type 2*</searchLink>/<searchLink fieldCode="MM" term="%22Diabetes+Mellitus%2C+Type+2+complications%22">complications</searchLink> <br /><searchLink fieldCode="MM" term="%22Diabetes+Mellitus%2C+Type+2%22">Diabetes Mellitus, Type 2*</searchLink>/<searchLink fieldCode="MM" term="%22Diabetes+Mellitus%2C+Type+2+epidemiology%22">epidemiology</searchLink> <br /><searchLink fieldCode="MM" term="%22Osteomyelitis%22">Osteomyelitis*</searchLink>/<searchLink fieldCode="MM" term="%22Osteomyelitis+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Osteomyelitis%22">Osteomyelitis*</searchLink>/<searchLink fieldCode="MM" term="%22Osteomyelitis+epidemiology%22">epidemiology</searchLink> <br /><searchLink fieldCode="MM" term="%22Cellulitis%22">Cellulitis*</searchLink>/<searchLink fieldCode="MM" term="%22Cellulitis+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Cellulitis%22">Cellulitis*</searchLink>/<searchLink fieldCode="MM" term="%22Cellulitis+epidemiology%22">epidemiology</searchLink> <br /><searchLink fieldCode="MM" term="%22Body+Mass+Index%22">Body Mass Index*</searchLink><br /><searchLink fieldCode="MH" term="%22Obesity%22">Obesity</searchLink>/<searchLink fieldCode="MH" term="%22Obesity+genetics%22">genetics</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Mendelian+Randomization+Analysis%22">Mendelian Randomization Analysis</searchLink> ; <searchLink fieldCode="MH" term="%22Genome-Wide+Association+Study%22">Genome-Wide Association Study</searchLink> ; <searchLink fieldCode="MH" term="%22Biological+Specimen+Banks%22">Biological Specimen Banks</searchLink> ; <searchLink fieldCode="MH" term="%22Female%22">Female</searchLink> ; <searchLink fieldCode="MH" term="%22Male%22">Male</searchLink>
– Name: Abstract
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  Data: Previous Mendelian randomization (MR) studies have linked obesity and type 2 diabetes (T2D) liability to osteomyelitis and skin or soft-tissue infection, but the reproducibility of these associations across independent outcome biobanks remains uncertain. We conducted cross-biobank univariable MR and multivariable MR analyses using European-ancestry genome-wide association study summary statistics. FinnGen Release 13 osteomyelitis (2519 cases and 471,012 controls) was designated as the primary clinical outcome, whereas cellulitis (10,223 cases and 468,418 controls) served as a comparative infection outcome; UK Biobank (UKB)-derived outcomes were used for replication. Exposure instruments containing UKB participants were restricted to FinnGen analyses, while separate non-UKB instruments were used for replication and cross-biobank pooling. Inverse-variance weighting was the primary estimator, with instrument-strength, pleiotropy, directionality, influential-variant, and multivariable conditional-strength analyses used to assess robustness. In FinnGen, each 1-standard-deviation increase in genetically predicted body mass index (BMI) on the source-GWAS standardized scale was associated with osteomyelitis (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.33-1.93) and cellulitis (OR 1.50, 95% CI 1.37-1.63), while T2D liability was associated with osteomyelitis (OR 1.41, 95% CI 1.24-1.61). Using non-UKB instruments, BMI-osteomyelitis estimates were directionally consistent across FinnGen and UKB (pooled OR 1.38, 95% CI 1.13-1.67; I2 = 0%), whereas BMI-cellulitis was positive in both biobanks despite heterogeneity in magnitude (I2 = 78.1%). T2D liability was associated with osteomyelitis in FinnGen but was not supported in UKB univariable MR, with substantial cross-biobank heterogeneity (I2 = 84.8%); the corresponding UKB multivariable MR estimate was nominal. In multivariable analyses, BMI-cellulitis remained supported across datasets, whereas BMI-osteomyelitis estimates attenuated after adjustment for T2D liability. BMI-cellulitis showed the greatest reproducibility. For osteomyelitis, BMI showed a reproducible total association but weaker evidence after adjustment for T2D liability, whereas T2D liability was consistently associated with osteomyelitis in FinnGen but was not robustly replicated in UKB. These findings emphasize the importance of external replication and evidence grading when interpreting metabolic-infection MR associations.<br /> (Copyright © 2026 the Author(s). Published by Wolters Kluwer Health, LLC.)
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  Label: Competing Interests
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  Data: The authors have no funding and conflicts of interest to declare.
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  Label: References
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  Data: Genet Epidemiol. 2016 May;40(4):304-14. (PMID: <searchLink fieldCode="PM" term="%2227061298%22">27061298)</searchLink><br />BMJ. 2018 Jul 12;362:k601. (PMID: <searchLink fieldCode="PM" term="%2230002074%22">30002074)</searchLink><br />Nat Genet. 2012 Sep;44(9):981-90. (PMID: <searchLink fieldCode="PM" term="%2222885922%22">22885922)</searchLink><br />Hum Mol Genet. 2018 Oct 15;27(20):3641-3649. (PMID: <searchLink fieldCode="PM" term="%2230124842%22">30124842)</searchLink><br />Int J Epidemiol. 2017 Dec 1;46(6):1985-1998. (PMID: <searchLink fieldCode="PM" term="%2229040600%22">29040600)</searchLink><br />Int J Epidemiol. 2019 Jun 1;48(3):713-727. (PMID: <searchLink fieldCode="PM" term="%2230535378%22">30535378)</searchLink><br />Infect Dis Clin North Am. 2017 Jun;31(2):325-338. (PMID: <searchLink fieldCode="PM" term="%2228483044%22">28483044)</searchLink><br />Nat Genet. 2018 Apr;50(4):559-571. (PMID: <searchLink fieldCode="PM" term="%2229632382%22">29632382)</searchLink><br />Medicine (Baltimore). 2024 May 17;103(20):e38214. (PMID: <searchLink fieldCode="PM" term="%2238758842%22">38758842)</searchLink><br />Curr Diabetes Rev. 2020;16(5):442-449. (PMID: <searchLink fieldCode="PM" term="%2231657690%22">31657690)</searchLink><br />Nature. 2015 Feb 12;518(7538):197-206. (PMID: <searchLink fieldCode="PM" term="%2225673413%22">25673413)</searchLink><br />Proc Nutr Soc. 2012 May;71(2):298-306. (PMID: <searchLink fieldCode="PM" term="%2222414338%22">22414338)</searchLink><br />Front Endocrinol (Lausanne). 2022 Dec 07;13:996863. (PMID: <searchLink fieldCode="PM" term="%2236568121%22">36568121)</searchLink><br />Genet Epidemiol. 2013 Nov;37(7):658-65. (PMID: <searchLink fieldCode="PM" term="%2224114802%22">24114802)</searchLink><br />Control Clin Trials. 1986 Sep;7(3):177-88. (PMID: <searchLink fieldCode="PM" term="%223802833%22">3802833)</searchLink><br />JAMA. 2021 Oct 26;326(16):1614-1621. (PMID: <searchLink fieldCode="PM" term="%2234698778%22">34698778)</searchLink><br />Int J Epidemiol. 2013 Oct;42(5):1497-501. (PMID: <searchLink fieldCode="PM" term="%2224159078%22">24159078)</searchLink><br />Am J Epidemiol. 2015 Feb 15;181(4):251-60. (PMID: <searchLink fieldCode="PM" term="%2225632051%22">25632051)</searchLink><br />JMIR Dermatol. 2024 Aug 20;7:e54302. (PMID: <searchLink fieldCode="PM" term="%2239163102%22">39163102)</searchLink><br />Int J Epidemiol. 2015 Apr;44(2):512-25. (PMID: <searchLink fieldCode="PM" term="%2226050253%22">26050253)</searchLink><br />Nat Genet. 2018 May;50(5):693-698. (PMID: <searchLink fieldCode="PM" term="%2229686387%22">29686387)</searchLink><br />Medicine (Baltimore). 2024 Sep 27;103(39):e39833. (PMID: <searchLink fieldCode="PM" term="%2239331936%22">39331936)</searchLink><br />Nature. 2023 Jan;613(7944):508-518. (PMID: <searchLink fieldCode="PM" term="%2236653562%22">36653562)</searchLink><br />Stat Med. 2021 Nov 10;40(25):5434-5452. (PMID: <searchLink fieldCode="PM" term="%2234338327%22">34338327)</searchLink><br />Nucleic Acids Res. 2019 Jan 8;47(D1):D1005-D1012. (PMID: <searchLink fieldCode="PM" term="%2230445434%22">30445434)</searchLink><br />Medicine (Baltimore). 2025 Mar 07;104(10):e41688. (PMID: <searchLink fieldCode="PM" term="%2240068038%22">40068038)</searchLink><br />PLoS Genet. 2017 Nov 17;13(11):e1007081. (PMID: <searchLink fieldCode="PM" term="%2229149188%22">29149188)</searchLink>
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  Data: <i>Keywords: </i>Mendelian randomization; body mass index; cellulitis; genome-wide association study; osteomyelitis; type 2 diabetes
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        Text: English
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        StartPage: e50945
    Subjects:
      – SubjectFull: Obesity genetics
        Type: general
      – SubjectFull: Humans
        Type: general
      – SubjectFull: Mendelian Randomization Analysis
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      – SubjectFull: Diabetes Mellitus, Type 2 genetics
        Type: general
      – SubjectFull: Diabetes Mellitus, Type 2 complications
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      – SubjectFull: Diabetes Mellitus, Type 2 epidemiology
        Type: general
      – SubjectFull: Osteomyelitis genetics
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      – SubjectFull: Osteomyelitis epidemiology
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      – SubjectFull: Cellulitis genetics
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      – SubjectFull: Body Mass Index
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      – TitleFull: Body mass index and type 2 diabetes liability in osteomyelitis and cellulitis: A cross-biobank Mendelian randomization study.
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              Text: 2026 Oct 02
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