Smoking, use of smokeless tobacco, HLA genotypes and incidence of latent autoimmune diabetes in adults

Jessica Edstorp; Yuxia Wei; Emma Ahlqvist; Lars Alfredsson; Valdemar Grill; Leif Groop; Bahareh Rasouli; Elin P. Sørgjerd; Per M. Thorsby; Tiinamaija Tuomi; Bjørn O. Åsvold; Sofia Carlsson

doi:10.1007/s00125-022-05763-w

Smoking, use of smokeless tobacco, HLA genotypes and incidence of latent autoimmune diabetes in adults

Jessica Edstorp, Yuxia Wei, Emma Ahlqvist, Lars Alfredsson, Valdemar Grill, Leif Groop, Bahareh Rasouli, Elin P. Sørgjerd, Per M. Thorsby, Tiinamaija Tuomi, Bjørn O. Åsvold, Sofia Carlsson

Research output: Contribution to journal › Article › peer-review

Abstract

Aims/hypotheses: Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. Methods: Analyses were based on Swedish case–control data (collected 2010–2019) with incident cases of LADA (n=593) and type 2 diabetes (n=2038), and 3036 controls, and Norwegian prospective data (collected 1984–2019) with incident cases of LADA (n=245) and type 2 diabetes (n=3726) during 1,696,503 person-years of follow-up. Pooled RRs with 95% CIs were estimated for smoking, and ORs for snus use (case–control data only). The interaction was assessed by attributable proportion (AP) due to interaction. A two-sample Mendelian randomisation (MR) study on smoking and LADA/type 2 diabetes was conducted based on summary statistics from genome-wide association studies. Results: Smoking (RR_pooled 1.30 [95% CI 1.06, 1.59] for current vs never) and snus use (OR 1.97 [95% CI 1.20, 3.24] for ≥15 box-years vs never use) were associated with an increased risk of LADA. Corresponding estimates for type 2 diabetes were 1.38 (95% CI 1.28, 1.49) and 1.92 (95% CI 1.27, 2.90), respectively. There was interaction between smoking and HLA high-risk genotypes (AP 0.27 [95% CI 0.01, 0.53]) in relation to LADA. The positive association between smoking and LADA/type 2 diabetes was confirmed by the MR study. Conclusions/interpretation: Our findings suggest that tobacco use increases the risk of LADA and that smoking acts synergistically with genetic susceptibility in the promotion of LADA. Data availability: Analysis codes are shared through GitHub (https://github.com/jeseds/Smoking-use-of-smokeless-tobacco-HLA-genotypes-and-incidence-of-LADA). Graphical abstract: [Figure not available: see fulltext.]

Original language	English
Pages (from-to)	70-81
Journal	Diabetologia
Volume	66
DOIs	https://doi.org/10.1007/s00125-022-05763-w
Publication status	Published - 2023 Jan

Bibliographical note

Funding Information:
Open access funding provided by Karolinska Institute. The ESTRID study was funded by grants from the Swedish Research Council (2018-03035), Research Council for Health, Working Life and Welfare (FORTE, 2018-00337), the Novo Nordisk Foundation (NNF19OC0057274) and the Swedish Diabetes Foundation. The post-doctoral fellowship to BR, supported by Novo Nordisk Foundation, has grant no. NNF17OC0027580. YW received a scholarship from the China Scholarship Council (student no. 202006010041). EIRA was funded by the Swedish Research Council, the Swedish Research Council for Health, Working Life and Welfare, the Swedish Rheumatic Foundation, the AFA Insurance Company and Stockholm County Council. ANDIS was financially supported by the Swedish Research Council and the European Research Council Advanced Researcher grant (GA 269045) awarded to LG.

Funding Information:
We thank the participants in ESTRID, ANDIS and HUNT, as well as administrative personnel, nurses and research team members from all the studies. Preliminary results from this work have been presented as abstracts at the virtual SSSD meeting 2021, the virtual 55th EDEG Annual Meeting 2021, and the virtual 57th EASD Annual Meeting 2021. HUNT is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology NTNU), Trøndelag County Council, Central Norway Regional Health Authority and the Norwegian Institute of Public Health. SC declares shareholding in Swedish Match AB to a value of 5000 euro. These were received as a gift at birth and were originally shares in Volvo Cars Corporation. Through investments and spin offs made by Volvo Cars, part of the shares was transferred into shares in Swedish Match by Volvo in 1996. SC has had no active management of these shares. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution to the data collection was made by SC, BR and JE (ESTRID), LG, EA and TT (ANDIS), LA (EIRA), and EPS, VG, PMT and BOÅ (HUNT). YW was responsible for performing the MR analysis. SC was responsible for conceptualising the research objectives, designed the study and thoroughly revised the manuscript. All authors contributed to the interpretation of the results and critically revised and approved the final version of the manuscript. JE developed the objectives of the study and was responsible for drafting of the manuscript, analysing the observational data and for the integrity of the work as a whole.

Publisher Copyright:
© 2022, The Author(s).

Subject classification (UKÄ)

Endocrinology and Diabetes

Free keywords

Gene–environment interaction
LADA
Latent autoimmune diabetes in adults
Mendelian randomisation analysis
Smoking
Tobacco use
ANDIS
diabetes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s00125-022-05763-wLicence: CC BY

Cite this

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title = "Smoking, use of smokeless tobacco, HLA genotypes and incidence of latent autoimmune diabetes in adults",

abstract = "Aims/hypotheses: Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. Methods: Analyses were based on Swedish case–control data (collected 2010–2019) with incident cases of LADA (n=593) and type 2 diabetes (n=2038), and 3036 controls, and Norwegian prospective data (collected 1984–2019) with incident cases of LADA (n=245) and type 2 diabetes (n=3726) during 1,696,503 person-years of follow-up. Pooled RRs with 95% CIs were estimated for smoking, and ORs for snus use (case–control data only). The interaction was assessed by attributable proportion (AP) due to interaction. A two-sample Mendelian randomisation (MR) study on smoking and LADA/type 2 diabetes was conducted based on summary statistics from genome-wide association studies. Results: Smoking (RRpooled 1.30 [95% CI 1.06, 1.59] for current vs never) and snus use (OR 1.97 [95% CI 1.20, 3.24] for ≥15 box-years vs never use) were associated with an increased risk of LADA. Corresponding estimates for type 2 diabetes were 1.38 (95% CI 1.28, 1.49) and 1.92 (95% CI 1.27, 2.90), respectively. There was interaction between smoking and HLA high-risk genotypes (AP 0.27 [95% CI 0.01, 0.53]) in relation to LADA. The positive association between smoking and LADA/type 2 diabetes was confirmed by the MR study. Conclusions/interpretation: Our findings suggest that tobacco use increases the risk of LADA and that smoking acts synergistically with genetic susceptibility in the promotion of LADA. Data availability: Analysis codes are shared through GitHub (https://github.com/jeseds/Smoking-use-of-smokeless-tobacco-HLA-genotypes-and-incidence-of-LADA). Graphical abstract: [Figure not available: see fulltext.]",

keywords = "Gene–environment interaction, LADA, Latent autoimmune diabetes in adults, Mendelian randomisation analysis, Smoking, Tobacco use, ANDIS, diabetes",

author = "Jessica Edstorp and Yuxia Wei and Emma Ahlqvist and Lars Alfredsson and Valdemar Grill and Leif Groop and Bahareh Rasouli and S{\o}rgjerd, {Elin P.} and Thorsby, {Per M.} and Tiinamaija Tuomi and {\AA}svold, {Bj{\o}rn O.} and Sofia Carlsson",

note = "Funding Information: Open access funding provided by Karolinska Institute. The ESTRID study was funded by grants from the Swedish Research Council (2018-03035), Research Council for Health, Working Life and Welfare (FORTE, 2018-00337), the Novo Nordisk Foundation (NNF19OC0057274) and the Swedish Diabetes Foundation. The post-doctoral fellowship to BR, supported by Novo Nordisk Foundation, has grant no. NNF17OC0027580. YW received a scholarship from the China Scholarship Council (student no. 202006010041). EIRA was funded by the Swedish Research Council, the Swedish Research Council for Health, Working Life and Welfare, the Swedish Rheumatic Foundation, the AFA Insurance Company and Stockholm County Council. ANDIS was financially supported by the Swedish Research Council and the European Research Council Advanced Researcher grant (GA 269045) awarded to LG. Funding Information: We thank the participants in ESTRID, ANDIS and HUNT, as well as administrative personnel, nurses and research team members from all the studies. Preliminary results from this work have been presented as abstracts at the virtual SSSD meeting 2021, the virtual 55th EDEG Annual Meeting 2021, and the virtual 57th EASD Annual Meeting 2021. HUNT is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology NTNU), Tr{\o}ndelag County Council, Central Norway Regional Health Authority and the Norwegian Institute of Public Health. SC declares shareholding in Swedish Match AB to a value of 5000 euro. These were received as a gift at birth and were originally shares in Volvo Cars Corporation. Through investments and spin offs made by Volvo Cars, part of the shares was transferred into shares in Swedish Match by Volvo in 1996. SC has had no active management of these shares. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution to the data collection was made by SC, BR and JE (ESTRID), LG, EA and TT (ANDIS), LA (EIRA), and EPS, VG, PMT and BO{\AA} (HUNT). YW was responsible for performing the MR analysis. SC was responsible for conceptualising the research objectives, designed the study and thoroughly revised the manuscript. All authors contributed to the interpretation of the results and critically revised and approved the final version of the manuscript. JE developed the objectives of the study and was responsible for drafting of the manuscript, analysing the observational data and for the integrity of the work as a whole. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2023",

month = jan,

doi = "10.1007/s00125-022-05763-w",

language = "English",

volume = "66",

pages = "70--81",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer",

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TY - JOUR

T1 - Smoking, use of smokeless tobacco, HLA genotypes and incidence of latent autoimmune diabetes in adults

AU - Edstorp, Jessica

AU - Wei, Yuxia

AU - Ahlqvist, Emma

AU - Alfredsson, Lars

AU - Grill, Valdemar

AU - Groop, Leif

AU - Rasouli, Bahareh

AU - Sørgjerd, Elin P.

AU - Thorsby, Per M.

AU - Tuomi, Tiinamaija

AU - Åsvold, Bjørn O.

AU - Carlsson, Sofia

N1 - Funding Information: Open access funding provided by Karolinska Institute. The ESTRID study was funded by grants from the Swedish Research Council (2018-03035), Research Council for Health, Working Life and Welfare (FORTE, 2018-00337), the Novo Nordisk Foundation (NNF19OC0057274) and the Swedish Diabetes Foundation. The post-doctoral fellowship to BR, supported by Novo Nordisk Foundation, has grant no. NNF17OC0027580. YW received a scholarship from the China Scholarship Council (student no. 202006010041). EIRA was funded by the Swedish Research Council, the Swedish Research Council for Health, Working Life and Welfare, the Swedish Rheumatic Foundation, the AFA Insurance Company and Stockholm County Council. ANDIS was financially supported by the Swedish Research Council and the European Research Council Advanced Researcher grant (GA 269045) awarded to LG. Funding Information: We thank the participants in ESTRID, ANDIS and HUNT, as well as administrative personnel, nurses and research team members from all the studies. Preliminary results from this work have been presented as abstracts at the virtual SSSD meeting 2021, the virtual 55th EDEG Annual Meeting 2021, and the virtual 57th EASD Annual Meeting 2021. HUNT is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology NTNU), Trøndelag County Council, Central Norway Regional Health Authority and the Norwegian Institute of Public Health. SC declares shareholding in Swedish Match AB to a value of 5000 euro. These were received as a gift at birth and were originally shares in Volvo Cars Corporation. Through investments and spin offs made by Volvo Cars, part of the shares was transferred into shares in Swedish Match by Volvo in 1996. SC has had no active management of these shares. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution to the data collection was made by SC, BR and JE (ESTRID), LG, EA and TT (ANDIS), LA (EIRA), and EPS, VG, PMT and BOÅ (HUNT). YW was responsible for performing the MR analysis. SC was responsible for conceptualising the research objectives, designed the study and thoroughly revised the manuscript. All authors contributed to the interpretation of the results and critically revised and approved the final version of the manuscript. JE developed the objectives of the study and was responsible for drafting of the manuscript, analysing the observational data and for the integrity of the work as a whole. Publisher Copyright: © 2022, The Author(s).

PY - 2023/1

Y1 - 2023/1

N2 - Aims/hypotheses: Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. Methods: Analyses were based on Swedish case–control data (collected 2010–2019) with incident cases of LADA (n=593) and type 2 diabetes (n=2038), and 3036 controls, and Norwegian prospective data (collected 1984–2019) with incident cases of LADA (n=245) and type 2 diabetes (n=3726) during 1,696,503 person-years of follow-up. Pooled RRs with 95% CIs were estimated for smoking, and ORs for snus use (case–control data only). The interaction was assessed by attributable proportion (AP) due to interaction. A two-sample Mendelian randomisation (MR) study on smoking and LADA/type 2 diabetes was conducted based on summary statistics from genome-wide association studies. Results: Smoking (RRpooled 1.30 [95% CI 1.06, 1.59] for current vs never) and snus use (OR 1.97 [95% CI 1.20, 3.24] for ≥15 box-years vs never use) were associated with an increased risk of LADA. Corresponding estimates for type 2 diabetes were 1.38 (95% CI 1.28, 1.49) and 1.92 (95% CI 1.27, 2.90), respectively. There was interaction between smoking and HLA high-risk genotypes (AP 0.27 [95% CI 0.01, 0.53]) in relation to LADA. The positive association between smoking and LADA/type 2 diabetes was confirmed by the MR study. Conclusions/interpretation: Our findings suggest that tobacco use increases the risk of LADA and that smoking acts synergistically with genetic susceptibility in the promotion of LADA. Data availability: Analysis codes are shared through GitHub (https://github.com/jeseds/Smoking-use-of-smokeless-tobacco-HLA-genotypes-and-incidence-of-LADA). Graphical abstract: [Figure not available: see fulltext.]

AB - Aims/hypotheses: Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. Methods: Analyses were based on Swedish case–control data (collected 2010–2019) with incident cases of LADA (n=593) and type 2 diabetes (n=2038), and 3036 controls, and Norwegian prospective data (collected 1984–2019) with incident cases of LADA (n=245) and type 2 diabetes (n=3726) during 1,696,503 person-years of follow-up. Pooled RRs with 95% CIs were estimated for smoking, and ORs for snus use (case–control data only). The interaction was assessed by attributable proportion (AP) due to interaction. A two-sample Mendelian randomisation (MR) study on smoking and LADA/type 2 diabetes was conducted based on summary statistics from genome-wide association studies. Results: Smoking (RRpooled 1.30 [95% CI 1.06, 1.59] for current vs never) and snus use (OR 1.97 [95% CI 1.20, 3.24] for ≥15 box-years vs never use) were associated with an increased risk of LADA. Corresponding estimates for type 2 diabetes were 1.38 (95% CI 1.28, 1.49) and 1.92 (95% CI 1.27, 2.90), respectively. There was interaction between smoking and HLA high-risk genotypes (AP 0.27 [95% CI 0.01, 0.53]) in relation to LADA. The positive association between smoking and LADA/type 2 diabetes was confirmed by the MR study. Conclusions/interpretation: Our findings suggest that tobacco use increases the risk of LADA and that smoking acts synergistically with genetic susceptibility in the promotion of LADA. Data availability: Analysis codes are shared through GitHub (https://github.com/jeseds/Smoking-use-of-smokeless-tobacco-HLA-genotypes-and-incidence-of-LADA). Graphical abstract: [Figure not available: see fulltext.]

KW - Gene–environment interaction

KW - LADA

KW - Latent autoimmune diabetes in adults

KW - Mendelian randomisation analysis

KW - Smoking

KW - Tobacco use

KW - ANDIS

KW - diabetes

U2 - 10.1007/s00125-022-05763-w

DO - 10.1007/s00125-022-05763-w

M3 - Article

C2 - 35900371

AN - SCOPUS:85143505472

SN - 0012-186X

VL - 66

SP - 70

EP - 81

JO - Diabetologia

JF - Diabetologia

ER -

Smoking, use of smokeless tobacco, HLA genotypes and incidence of latent autoimmune diabetes in adults

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

UN SDGs

Access to Document

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